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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Evidence of Gene–Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors</title><author><name sortKey="Nickels, Stefan" sort="Nickels, Stefan" uniqKey="Nickels S" first="Stefan" last="Nickels">Stefan Nickels</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Truong, Therese" sort="Truong, Therese" uniqKey="Truong T" first="Thérèse" last="Truong">Thérèse Truong</name><affiliation><nlm:aff id="aff2"><addr-line>Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hein, Rebecca" sort="Hein, Rebecca" uniqKey="Hein R" first="Rebecca" last="Hein">Rebecca Hein</name><affiliation><nlm:aff id="aff3"><addr-line>PMV Research Group at the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stevens, Kristen" sort="Stevens, Kristen" uniqKey="Stevens K" first="Kristen" last="Stevens">Kristen Stevens</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Buck, Katharina" sort="Buck, Katharina" uniqKey="Buck K" first="Katharina" last="Buck">Katharina Buck</name><affiliation><nlm:aff id="aff5"><addr-line>Department of Preventive Oncology, National Center of Tumor Diseases, Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Behrens, Sabine" sort="Behrens, Sabine" uniqKey="Behrens S" first="Sabine" last="Behrens">Sabine Behrens</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Eilber, Ursula" sort="Eilber, Ursula" uniqKey="Eilber U" first="Ursula" last="Eilber">Ursula Eilber</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schmidt, Martina" sort="Schmidt, Martina" uniqKey="Schmidt M" first="Martina" last="Schmidt">Martina Schmidt</name><affiliation><nlm:aff id="aff6"><addr-line>Unit of Environmental Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="H Berle, Lothar" sort="H Berle, Lothar" uniqKey="H Berle L" first="Lothar" last="H Berle">Lothar H Berle</name><affiliation><nlm:aff id="aff7"><addr-line>Department of Gynecology and Obstetrics, University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Vrieling, Alina" sort="Vrieling, Alina" uniqKey="Vrieling A" first="Alina" last="Vrieling">Alina Vrieling</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><addr-line>Department for Health Evidence, Radboud University Medical Centre, Nijmegen, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gaudet, Mia" sort="Gaudet, Mia" uniqKey="Gaudet M" first="Mia" last="Gaudet">Mia Gaudet</name><affiliation><nlm:aff id="aff9"><addr-line>Epidemiology Research Program, Division of Cancer Epidemiology, American Cancer Society, Atlanta, Georgia, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Figueroa, Jonine" sort="Figueroa, Jonine" uniqKey="Figueroa J" first="Jonine" last="Figueroa">Jonine Figueroa</name><affiliation><nlm:aff id="aff10"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schoof, Nils" sort="Schoof, Nils" uniqKey="Schoof N" first="Nils" last="Schoof">Nils Schoof</name><affiliation><nlm:aff id="aff11"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B." last="Spurdle">Amanda B. Spurdle</name><affiliation><nlm:aff id="aff12"><addr-line>Queensland Institute of Medical Research, Herston, Queensland, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rudolph, Anja" sort="Rudolph, Anja" uniqKey="Rudolph A" first="Anja" last="Rudolph">Anja Rudolph</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fasching, Peter A" sort="Fasching, Peter A" uniqKey="Fasching P" first="Peter A." last="Fasching">Peter A. Fasching</name><affiliation><nlm:aff id="aff7"><addr-line>Department of Gynecology and Obstetrics, University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff13"><addr-line>Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L." last="Hopper">John L. Hopper</name><affiliation><nlm:aff id="aff14"><addr-line>Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Makalic, Enes" sort="Makalic, Enes" uniqKey="Makalic E" first="Enes" last="Makalic">Enes Makalic</name><affiliation><nlm:aff id="aff14"><addr-line>Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schmidt, Daniel F" sort="Schmidt, Daniel F" uniqKey="Schmidt D" first="Daniel F." last="Schmidt">Daniel F. Schmidt</name><affiliation><nlm:aff id="aff14"><addr-line>Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C." last="Southey">Melissa C. Southey</name><affiliation><nlm:aff id="aff15"><addr-line>Department of Pathology, University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Beckmann, Matthias W" sort="Beckmann, Matthias W" uniqKey="Beckmann M" first="Matthias W." last="Beckmann">Matthias W. Beckmann</name><affiliation><nlm:aff id="aff7"><addr-line>Department of Gynecology and Obstetrics, University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ekici, Arif B" sort="Ekici, Arif B" uniqKey="Ekici A" first="Arif B." last="Ekici">Arif B. Ekici</name><affiliation><nlm:aff id="aff16"><addr-line>Institute of Human Genetics, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fletcher, Olivia" sort="Fletcher, Olivia" uniqKey="Fletcher O" first="Olivia" last="Fletcher">Olivia Fletcher</name><affiliation><nlm:aff id="aff17"><addr-line>Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gibson, Lorna" sort="Gibson, Lorna" uniqKey="Gibson L" first="Lorna" last="Gibson">Lorna Gibson</name><affiliation><nlm:aff id="aff18"><addr-line>London School of Hygiene and Tropical Medicine, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dos Santos Silva, Isabel" sort="Dos Santos Silva, Isabel" uniqKey="Dos Santos Silva I" first="Isabel" last="Dos Santos Silva">Isabel Dos Santos Silva</name><affiliation><nlm:aff id="aff18"><addr-line>London School of Hygiene and Tropical Medicine, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Peto, Julian" sort="Peto, Julian" uniqKey="Peto J" first="Julian" last="Peto">Julian Peto</name><affiliation><nlm:aff id="aff18"><addr-line>London School of Hygiene and Tropical Medicine, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Humphreys, Manjeet K" sort="Humphreys, Manjeet K" uniqKey="Humphreys M" first="Manjeet K." last="Humphreys">Manjeet K. Humphreys</name><affiliation><nlm:aff id="aff19"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wang, Jean" sort="Wang, Jean" uniqKey="Wang J" first="Jean" last="Wang">Jean Wang</name><affiliation><nlm:aff id="aff19"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cordina Duverger, Emilie" sort="Cordina Duverger, Emilie" uniqKey="Cordina Duverger E" first="Emilie" last="Cordina-Duverger">Emilie Cordina-Duverger</name><affiliation><nlm:aff id="aff2"><addr-line>Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Menegaux, Florence" sort="Menegaux, Florence" uniqKey="Menegaux F" first="Florence" last="Menegaux">Florence Menegaux</name><affiliation><nlm:aff id="aff2"><addr-line>Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Nordestgaard, B Rge G" sort="Nordestgaard, B Rge G" uniqKey="Nordestgaard B" first="B Rge G." last="Nordestgaard">B Rge G. Nordestgaard</name><affiliation><nlm:aff id="aff20"><addr-line>Copenhagen General Population Study and Department of Clinical Biochemistry, Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bojesen, Stig E" sort="Bojesen, Stig E" uniqKey="Bojesen S" first="Stig E." last="Bojesen">Stig E. Bojesen</name><affiliation><nlm:aff id="aff20"><addr-line>Copenhagen General Population Study and Department of Clinical Biochemistry, Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lanng, Charlotte" sort="Lanng, Charlotte" uniqKey="Lanng C" first="Charlotte" last="Lanng">Charlotte Lanng</name><affiliation><nlm:aff id="aff21"><addr-line>Department of Breast Surgery, Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Anton Culver, Hoda" sort="Anton Culver, Hoda" uniqKey="Anton Culver H" first="Hoda" last="Anton-Culver">Hoda Anton-Culver</name><affiliation><nlm:aff id="aff22"><addr-line>Department of Epidemiology, University of California Irvine, Irvine, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ziogas, Argyrios" sort="Ziogas, Argyrios" uniqKey="Ziogas A" first="Argyrios" last="Ziogas">Argyrios Ziogas</name><affiliation><nlm:aff id="aff22"><addr-line>Department of Epidemiology, University of California Irvine, Irvine, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bernstein, Leslie" sort="Bernstein, Leslie" uniqKey="Bernstein L" first="Leslie" last="Bernstein">Leslie Bernstein</name><affiliation><nlm:aff id="aff23"><addr-line>Beckman Research Institute of the City of Hope, Duarte, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Clarke, Christina A" sort="Clarke, Christina A" uniqKey="Clarke C" first="Christina A." last="Clarke">Christina A. Clarke</name><affiliation><nlm:aff id="aff24"><addr-line>Cancer Prevention Institute of California, Fremont, California, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff25"><addr-line>Division of Epidemiology, Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brenner, Hermann" sort="Brenner, Hermann" uniqKey="Brenner H" first="Hermann" last="Brenner">Hermann Brenner</name><affiliation><nlm:aff id="aff26"><addr-line>Division of Clinical Epidemiology and Ageing Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Muller, Heiko" sort="Muller, Heiko" uniqKey="Muller H" first="Heiko" last="Müller">Heiko Müller</name><affiliation><nlm:aff id="aff26"><addr-line>Division of Clinical Epidemiology and Ageing Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Arndt, Volker" sort="Arndt, Volker" uniqKey="Arndt V" first="Volker" last="Arndt">Volker Arndt</name><affiliation><nlm:aff id="aff26"><addr-line>Division of Clinical Epidemiology and Ageing Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stegmaier, Christa" sort="Stegmaier, Christa" uniqKey="Stegmaier C" first="Christa" last="Stegmaier">Christa Stegmaier</name><affiliation><nlm:aff id="aff27"><addr-line>Saarland Cancer Registry, Saarbrücken, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brauch, Hiltrud" sort="Brauch, Hiltrud" uniqKey="Brauch H" first="Hiltrud" last="Brauch">Hiltrud Brauch</name><affiliation><nlm:aff id="aff28"><addr-line>Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff29"><addr-line>University of Tübingen, Tübingen, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bruning, Thomas" sort="Bruning, Thomas" uniqKey="Bruning T" first="Thomas" last="Brüning">Thomas Brüning</name><affiliation><nlm:aff id="aff30"><addr-line>Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-Universität Bochum (IPA), Bochum, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Harth, Volker" sort="Harth, Volker" uniqKey="Harth V" first="Volker" last="Harth">Volker Harth</name><affiliation><nlm:aff id="aff31"><addr-line>Institute and Outpatient Clinic of Occupational Medicine, Saarland University Medical Center and Saarland University Faculty of Medicine, Homburg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff32"><addr-line>Institute for Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mannermaa, Arto" sort="Mannermaa, Arto" uniqKey="Mannermaa A" first="Arto" last="Mannermaa">Arto Mannermaa</name><affiliation><nlm:aff id="aff36"><addr-line>School of Medicine, Institute of Clinical Medicine, Department of Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff37"><addr-line>Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kataja, Vesa" sort="Kataja, Vesa" uniqKey="Kataja V" first="Vesa" last="Kataja">Vesa Kataja</name><affiliation><nlm:aff id="aff37"><addr-line>Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff38"><addr-line>School of Medicine, Institute of Clinical Medicine, Department of Oncology, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kosma, Veli Matti" sort="Kosma, Veli Matti" uniqKey="Kosma V" first="Veli-Matti" last="Kosma">Veli-Matti Kosma</name><affiliation><nlm:aff id="aff36"><addr-line>School of Medicine, Institute of Clinical Medicine, Department of Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff37"><addr-line>Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hartikainen, Jaana M" sort="Hartikainen, Jaana M" uniqKey="Hartikainen J" first="Jaana M." last="Hartikainen">Jaana M. Hartikainen</name><affiliation><nlm:aff id="aff36"><addr-line>School of Medicine, Institute of Clinical Medicine, Department of Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff37"><addr-line>Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Group, Aocs Management" sort="Group, Aocs Management" uniqKey="Group A" first="Aocs Management" last="Group">Aocs Management Group</name><affiliation><nlm:aff id="aff12"><addr-line>Queensland Institute of Medical Research, Herston, Queensland, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff39"><addr-line>The Kathleen Cuningham Foundation for Resesarch into Familial Breast Cancer (kConFab), Peter MacCallum Cancer Centre, East Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lambrechts, Diether" sort="Lambrechts, Diether" uniqKey="Lambrechts D" first="Diether" last="Lambrechts">Diether Lambrechts</name><affiliation><nlm:aff id="aff40"><addr-line>Vesalius Research Center (VRC), VIB, Leuven, Belgium</addr-line></nlm:aff></affiliation></author><author><name sortKey="Smeets, Dominiek" sort="Smeets, Dominiek" uniqKey="Smeets D" first="Dominiek" last="Smeets">Dominiek Smeets</name><affiliation><nlm:aff id="aff40"><addr-line>Vesalius Research Center (VRC), VIB, Leuven, Belgium</addr-line></nlm:aff></affiliation></author><author><name sortKey="Neven, Patrick" sort="Neven, Patrick" uniqKey="Neven P" first="Patrick" last="Neven">Patrick Neven</name><affiliation><nlm:aff id="aff41"><addr-line>Multidisciplinary Breast Center, University Hospital Gasthuisberg, Leuven, Belgium</addr-line></nlm:aff></affiliation></author><author><name sortKey="Paridaens, Robert" sort="Paridaens, Robert" uniqKey="Paridaens R" first="Robert" last="Paridaens">Robert Paridaens</name><affiliation><nlm:aff id="aff41"><addr-line>Multidisciplinary Breast Center, University Hospital Gasthuisberg, Leuven, Belgium</addr-line></nlm:aff></affiliation></author><author><name sortKey="Flesch Janys, Dieter" sort="Flesch Janys, Dieter" uniqKey="Flesch Janys D" first="Dieter" last="Flesch-Janys">Dieter Flesch-Janys</name><affiliation><nlm:aff id="aff42"><addr-line>Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Obi, Nadia" sort="Obi, Nadia" uniqKey="Obi N" first="Nadia" last="Obi">Nadia Obi</name><affiliation><nlm:aff id="aff42"><addr-line>Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wang Gohrke, Shan" sort="Wang Gohrke, Shan" uniqKey="Wang Gohrke S" first="Shan" last="Wang-Gohrke">Shan Wang-Gohrke</name><affiliation><nlm:aff id="aff43"><addr-line>Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Couch, Fergus J" sort="Couch, Fergus J" uniqKey="Couch F" first="Fergus J." last="Couch">Fergus J. Couch</name><affiliation><nlm:aff id="aff44"><addr-line>Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Olson, Janet E" sort="Olson, Janet E" uniqKey="Olson J" first="Janet E." last="Olson">Janet E. Olson</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Vachon, Celine M" sort="Vachon, Celine M" uniqKey="Vachon C" first="Celine M." last="Vachon">Celine M. Vachon</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G." last="Giles">Graham G. Giles</name><affiliation><nlm:aff id="aff45"><addr-line>Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff46"><addr-line>Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, University of Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Severi, Gianluca" sort="Severi, Gianluca" uniqKey="Severi G" first="Gianluca" last="Severi">Gianluca Severi</name><affiliation><nlm:aff id="aff45"><addr-line>Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff46"><addr-line>Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, University of Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Baglietto, Laura" sort="Baglietto, Laura" uniqKey="Baglietto L" first="Laura" last="Baglietto">Laura Baglietto</name><affiliation><nlm:aff id="aff45"><addr-line>Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff46"><addr-line>Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, University of Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Offit, Kenneth" sort="Offit, Kenneth" uniqKey="Offit K" first="Kenneth" last="Offit">Kenneth Offit</name><affiliation><nlm:aff id="aff47"><addr-line>Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="John, Esther M" sort="John, Esther M" uniqKey="John E" first="Esther M." last="John">Esther M. John</name><affiliation><nlm:aff id="aff24"><addr-line>Cancer Prevention Institute of California, Fremont, California, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff25"><addr-line>Division of Epidemiology, Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Miron, Alexander" sort="Miron, Alexander" uniqKey="Miron A" first="Alexander" last="Miron">Alexander Miron</name><affiliation><nlm:aff id="aff48"><addr-line>Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Andrulis, Irene L" sort="Andrulis, Irene L" uniqKey="Andrulis I" first="Irene L." last="Andrulis">Irene L. Andrulis</name><affiliation><nlm:aff id="aff49"><addr-line>Ontario Cancer Genetics Network, Fred A. Litwin Center for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff50"><addr-line>Department of Molecular Genetics, University of Toronto, Toronto, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Knight, Julia A" sort="Knight, Julia A" uniqKey="Knight J" first="Julia A." last="Knight">Julia A. Knight</name><affiliation><nlm:aff id="aff51"><addr-line>Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff52"><addr-line>Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Glendon, Gord" sort="Glendon, Gord" uniqKey="Glendon G" first="Gord" last="Glendon">Gord Glendon</name><affiliation><nlm:aff id="aff53"><addr-line>Ontario Cancer Genetics Network, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mulligan, Anna Marie" sort="Mulligan, Anna Marie" uniqKey="Mulligan A" first="Anna Marie" last="Mulligan">Anna Marie Mulligan</name><affiliation><nlm:aff id="aff54"><addr-line>Laboratory Medicine Program, University Health Network, Toronto, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff55"><addr-line>Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chanock, Stephen J" sort="Chanock, Stephen J" uniqKey="Chanock S" first="Stephen J." last="Chanock">Stephen J. Chanock</name><affiliation><nlm:aff id="aff56"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lissowska, Jolanta" sort="Lissowska, Jolanta" uniqKey="Lissowska J" first="Jolanta" last="Lissowska">Jolanta Lissowska</name><affiliation><nlm:aff id="aff57"><addr-line>Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Liu, Jianjun" sort="Liu, Jianjun" uniqKey="Liu J" first="Jianjun" last="Liu">Jianjun Liu</name><affiliation><nlm:aff id="aff58"><addr-line>Human Genetics, Genome Institute of Singapore, Singapore, Singapore</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cox, Angela" sort="Cox, Angela" uniqKey="Cox A" first="Angela" last="Cox">Angela Cox</name><affiliation><nlm:aff id="aff59"><addr-line>Institute for Cancer Studies, Department of Oncology, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cramp, Helen" sort="Cramp, Helen" uniqKey="Cramp H" first="Helen" last="Cramp">Helen Cramp</name><affiliation><nlm:aff id="aff59"><addr-line>Institute for Cancer Studies, Department of Oncology, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Connley, Dan" sort="Connley, Dan" uniqKey="Connley D" first="Dan" last="Connley">Dan Connley</name><affiliation><nlm:aff id="aff59"><addr-line>Institute for Cancer Studies, Department of Oncology, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Balasubramanian, Sabapathy" sort="Balasubramanian, Sabapathy" uniqKey="Balasubramanian S" first="Sabapathy" last="Balasubramanian">Sabapathy Balasubramanian</name><affiliation><nlm:aff id="aff60"><addr-line>Academic Unit of Surgical Oncology, Department of Oncology, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dunning, Alison M" sort="Dunning, Alison M" uniqKey="Dunning A" first="Alison M." last="Dunning">Alison M. Dunning</name><affiliation><nlm:aff id="aff61"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Shah, Mitul" sort="Shah, Mitul" uniqKey="Shah M" first="Mitul" last="Shah">Mitul Shah</name><affiliation><nlm:aff id="aff61"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Trentham Dietz, Amy" sort="Trentham Dietz, Amy" uniqKey="Trentham Dietz A" first="Amy" last="Trentham-Dietz">Amy Trentham-Dietz</name><affiliation><nlm:aff id="aff62"><addr-line>University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Newcomb, Polly" sort="Newcomb, Polly" uniqKey="Newcomb P" first="Polly" last="Newcomb">Polly Newcomb</name><affiliation><nlm:aff id="aff62"><addr-line>University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff63"><addr-line>Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Titus, Linda" sort="Titus, Linda" uniqKey="Titus L" first="Linda" last="Titus">Linda Titus</name><affiliation><nlm:aff id="aff64"><addr-line>Department of Community and Family Medicine, Department of Pediatrics, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Egan, Kathleen" sort="Egan, Kathleen" uniqKey="Egan K" first="Kathleen" last="Egan">Kathleen Egan</name><affiliation><nlm:aff id="aff65"><addr-line>Division of Population Sciences, Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cahoon, Elizabeth K" sort="Cahoon, Elizabeth K" uniqKey="Cahoon E" first="Elizabeth K." last="Cahoon">Elizabeth K. Cahoon</name><affiliation><nlm:aff id="aff66"><addr-line>Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rajaraman, Preetha" sort="Rajaraman, Preetha" uniqKey="Rajaraman P" first="Preetha" last="Rajaraman">Preetha Rajaraman</name><affiliation><nlm:aff id="aff66"><addr-line>Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sigurdson, Alice J" sort="Sigurdson, Alice J" uniqKey="Sigurdson A" first="Alice J." last="Sigurdson">Alice J. Sigurdson</name><affiliation><nlm:aff id="aff66"><addr-line>Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Doody, Michele M" sort="Doody, Michele M" uniqKey="Doody M" first="Michele M." last="Doody">Michele M. Doody</name><affiliation><nlm:aff id="aff66"><addr-line>Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Guenel, Pascal" sort="Guenel, Pascal" uniqKey="Guenel P" first="Pascal" last="Guénel">Pascal Guénel</name><affiliation><nlm:aff id="aff2"><addr-line>Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pharoah, Paul D P" sort="Pharoah, Paul D P" uniqKey="Pharoah P" first="Paul D. P." last="Pharoah">Paul D. P. Pharoah</name><affiliation><nlm:aff id="aff67"><addr-line>Department of Oncology and Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schmidt, Marjanka K" sort="Schmidt, Marjanka K" uniqKey="Schmidt M" first="Marjanka K." last="Schmidt">Marjanka K. Schmidt</name><affiliation><nlm:aff id="aff68"><addr-line>Division of Molecular Pathology and Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hall, Per" sort="Hall, Per" uniqKey="Hall P" first="Per" last="Hall">Per Hall</name><affiliation><nlm:aff id="aff10"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Easton, Doug F" sort="Easton, Doug F" uniqKey="Easton D" first="Doug F." last="Easton">Doug F. Easton</name><affiliation><nlm:aff id="aff19"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Garcia Closas, Montserrat" sort="Garcia Closas, Montserrat" uniqKey="Garcia Closas M" first="Montserrat" last="Garcia-Closas">Montserrat Garcia-Closas</name><affiliation><nlm:aff id="aff56"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff69"><addr-line>Sections of Epidemiology and Genetics, Institute of Cancer Research and Breakthrough Breast Cancer Research Centre, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Milne, Roger L" sort="Milne, Roger L" uniqKey="Milne R" first="Roger L." last="Milne">Roger L. Milne</name><affiliation><nlm:aff id="aff70"><addr-line>Genetic and Molecular Epidemiology Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chang Claude, Jenny" sort="Chang Claude, Jenny" uniqKey="Chang Claude J" first="Jenny" last="Chang-Claude">Jenny Chang-Claude</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23544014</idno><idno type="pmc">3609648</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609648</idno><idno type="RBID">PMC:3609648</idno><idno type="doi">10.1371/journal.pgen.1003284</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">002887</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002887</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Evidence of Gene–Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors</title><author><name sortKey="Nickels, Stefan" sort="Nickels, Stefan" uniqKey="Nickels S" first="Stefan" last="Nickels">Stefan Nickels</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Truong, Therese" sort="Truong, Therese" uniqKey="Truong T" first="Thérèse" last="Truong">Thérèse Truong</name><affiliation><nlm:aff id="aff2"><addr-line>Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hein, Rebecca" sort="Hein, Rebecca" uniqKey="Hein R" first="Rebecca" last="Hein">Rebecca Hein</name><affiliation><nlm:aff id="aff3"><addr-line>PMV Research Group at the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stevens, Kristen" sort="Stevens, Kristen" uniqKey="Stevens K" first="Kristen" last="Stevens">Kristen Stevens</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Buck, Katharina" sort="Buck, Katharina" uniqKey="Buck K" first="Katharina" last="Buck">Katharina Buck</name><affiliation><nlm:aff id="aff5"><addr-line>Department of Preventive Oncology, National Center of Tumor Diseases, Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Behrens, Sabine" sort="Behrens, Sabine" uniqKey="Behrens S" first="Sabine" last="Behrens">Sabine Behrens</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Eilber, Ursula" sort="Eilber, Ursula" uniqKey="Eilber U" first="Ursula" last="Eilber">Ursula Eilber</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schmidt, Martina" sort="Schmidt, Martina" uniqKey="Schmidt M" first="Martina" last="Schmidt">Martina Schmidt</name><affiliation><nlm:aff id="aff6"><addr-line>Unit of Environmental Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="H Berle, Lothar" sort="H Berle, Lothar" uniqKey="H Berle L" first="Lothar" last="H Berle">Lothar H Berle</name><affiliation><nlm:aff id="aff7"><addr-line>Department of Gynecology and Obstetrics, University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Vrieling, Alina" sort="Vrieling, Alina" uniqKey="Vrieling A" first="Alina" last="Vrieling">Alina Vrieling</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><addr-line>Department for Health Evidence, Radboud University Medical Centre, Nijmegen, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gaudet, Mia" sort="Gaudet, Mia" uniqKey="Gaudet M" first="Mia" last="Gaudet">Mia Gaudet</name><affiliation><nlm:aff id="aff9"><addr-line>Epidemiology Research Program, Division of Cancer Epidemiology, American Cancer Society, Atlanta, Georgia, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Figueroa, Jonine" sort="Figueroa, Jonine" uniqKey="Figueroa J" first="Jonine" last="Figueroa">Jonine Figueroa</name><affiliation><nlm:aff id="aff10"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schoof, Nils" sort="Schoof, Nils" uniqKey="Schoof N" first="Nils" last="Schoof">Nils Schoof</name><affiliation><nlm:aff id="aff11"><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B." last="Spurdle">Amanda B. Spurdle</name><affiliation><nlm:aff id="aff12"><addr-line>Queensland Institute of Medical Research, Herston, Queensland, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rudolph, Anja" sort="Rudolph, Anja" uniqKey="Rudolph A" first="Anja" last="Rudolph">Anja Rudolph</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fasching, Peter A" sort="Fasching, Peter A" uniqKey="Fasching P" first="Peter A." last="Fasching">Peter A. Fasching</name><affiliation><nlm:aff id="aff7"><addr-line>Department of Gynecology and Obstetrics, University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff13"><addr-line>Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L." last="Hopper">John L. Hopper</name><affiliation><nlm:aff id="aff14"><addr-line>Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Makalic, Enes" sort="Makalic, Enes" uniqKey="Makalic E" first="Enes" last="Makalic">Enes Makalic</name><affiliation><nlm:aff id="aff14"><addr-line>Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schmidt, Daniel F" sort="Schmidt, Daniel F" uniqKey="Schmidt D" first="Daniel F." last="Schmidt">Daniel F. Schmidt</name><affiliation><nlm:aff id="aff14"><addr-line>Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C." last="Southey">Melissa C. Southey</name><affiliation><nlm:aff id="aff15"><addr-line>Department of Pathology, University of Melbourne, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Beckmann, Matthias W" sort="Beckmann, Matthias W" uniqKey="Beckmann M" first="Matthias W." last="Beckmann">Matthias W. Beckmann</name><affiliation><nlm:aff id="aff7"><addr-line>Department of Gynecology and Obstetrics, University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ekici, Arif B" sort="Ekici, Arif B" uniqKey="Ekici A" first="Arif B." last="Ekici">Arif B. Ekici</name><affiliation><nlm:aff id="aff16"><addr-line>Institute of Human Genetics, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fletcher, Olivia" sort="Fletcher, Olivia" uniqKey="Fletcher O" first="Olivia" last="Fletcher">Olivia Fletcher</name><affiliation><nlm:aff id="aff17"><addr-line>Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gibson, Lorna" sort="Gibson, Lorna" uniqKey="Gibson L" first="Lorna" last="Gibson">Lorna Gibson</name><affiliation><nlm:aff id="aff18"><addr-line>London School of Hygiene and Tropical Medicine, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dos Santos Silva, Isabel" sort="Dos Santos Silva, Isabel" uniqKey="Dos Santos Silva I" first="Isabel" last="Dos Santos Silva">Isabel Dos Santos Silva</name><affiliation><nlm:aff id="aff18"><addr-line>London School of Hygiene and Tropical Medicine, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Peto, Julian" sort="Peto, Julian" uniqKey="Peto J" first="Julian" last="Peto">Julian Peto</name><affiliation><nlm:aff id="aff18"><addr-line>London School of Hygiene and Tropical Medicine, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Humphreys, Manjeet K" sort="Humphreys, Manjeet K" uniqKey="Humphreys M" first="Manjeet K." last="Humphreys">Manjeet K. Humphreys</name><affiliation><nlm:aff id="aff19"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wang, Jean" sort="Wang, Jean" uniqKey="Wang J" first="Jean" last="Wang">Jean Wang</name><affiliation><nlm:aff id="aff19"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cordina Duverger, Emilie" sort="Cordina Duverger, Emilie" uniqKey="Cordina Duverger E" first="Emilie" last="Cordina-Duverger">Emilie Cordina-Duverger</name><affiliation><nlm:aff id="aff2"><addr-line>Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Menegaux, Florence" sort="Menegaux, Florence" uniqKey="Menegaux F" first="Florence" last="Menegaux">Florence Menegaux</name><affiliation><nlm:aff id="aff2"><addr-line>Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Nordestgaard, B Rge G" sort="Nordestgaard, B Rge G" uniqKey="Nordestgaard B" first="B Rge G." last="Nordestgaard">B Rge G. Nordestgaard</name><affiliation><nlm:aff id="aff20"><addr-line>Copenhagen General Population Study and Department of Clinical Biochemistry, Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bojesen, Stig E" sort="Bojesen, Stig E" uniqKey="Bojesen S" first="Stig E." last="Bojesen">Stig E. Bojesen</name><affiliation><nlm:aff id="aff20"><addr-line>Copenhagen General Population Study and Department of Clinical Biochemistry, Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lanng, Charlotte" sort="Lanng, Charlotte" uniqKey="Lanng C" first="Charlotte" last="Lanng">Charlotte Lanng</name><affiliation><nlm:aff id="aff21"><addr-line>Department of Breast Surgery, Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark</addr-line></nlm:aff></affiliation></author><author><name sortKey="Anton Culver, Hoda" sort="Anton Culver, Hoda" uniqKey="Anton Culver H" first="Hoda" last="Anton-Culver">Hoda Anton-Culver</name><affiliation><nlm:aff id="aff22"><addr-line>Department of Epidemiology, University of California Irvine, Irvine, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ziogas, Argyrios" sort="Ziogas, Argyrios" uniqKey="Ziogas A" first="Argyrios" last="Ziogas">Argyrios Ziogas</name><affiliation><nlm:aff id="aff22"><addr-line>Department of Epidemiology, University of California Irvine, Irvine, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bernstein, Leslie" sort="Bernstein, Leslie" uniqKey="Bernstein L" first="Leslie" last="Bernstein">Leslie Bernstein</name><affiliation><nlm:aff id="aff23"><addr-line>Beckman Research Institute of the City of Hope, Duarte, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Clarke, Christina A" sort="Clarke, Christina A" uniqKey="Clarke C" first="Christina A." last="Clarke">Christina A. Clarke</name><affiliation><nlm:aff id="aff24"><addr-line>Cancer Prevention Institute of California, Fremont, California, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff25"><addr-line>Division of Epidemiology, Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brenner, Hermann" sort="Brenner, Hermann" uniqKey="Brenner H" first="Hermann" last="Brenner">Hermann Brenner</name><affiliation><nlm:aff id="aff26"><addr-line>Division of Clinical Epidemiology and Ageing Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Muller, Heiko" sort="Muller, Heiko" uniqKey="Muller H" first="Heiko" last="Müller">Heiko Müller</name><affiliation><nlm:aff id="aff26"><addr-line>Division of Clinical Epidemiology and Ageing Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Arndt, Volker" sort="Arndt, Volker" uniqKey="Arndt V" first="Volker" last="Arndt">Volker Arndt</name><affiliation><nlm:aff id="aff26"><addr-line>Division of Clinical Epidemiology and Ageing Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stegmaier, Christa" sort="Stegmaier, Christa" uniqKey="Stegmaier C" first="Christa" last="Stegmaier">Christa Stegmaier</name><affiliation><nlm:aff id="aff27"><addr-line>Saarland Cancer Registry, Saarbrücken, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brauch, Hiltrud" sort="Brauch, Hiltrud" uniqKey="Brauch H" first="Hiltrud" last="Brauch">Hiltrud Brauch</name><affiliation><nlm:aff id="aff28"><addr-line>Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff29"><addr-line>University of Tübingen, Tübingen, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bruning, Thomas" sort="Bruning, Thomas" uniqKey="Bruning T" first="Thomas" last="Brüning">Thomas Brüning</name><affiliation><nlm:aff id="aff30"><addr-line>Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-Universität Bochum (IPA), Bochum, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Harth, Volker" sort="Harth, Volker" uniqKey="Harth V" first="Volker" last="Harth">Volker Harth</name><affiliation><nlm:aff id="aff31"><addr-line>Institute and Outpatient Clinic of Occupational Medicine, Saarland University Medical Center and Saarland University Faculty of Medicine, Homburg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff32"><addr-line>Institute for Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mannermaa, Arto" sort="Mannermaa, Arto" uniqKey="Mannermaa A" first="Arto" last="Mannermaa">Arto Mannermaa</name><affiliation><nlm:aff id="aff36"><addr-line>School of Medicine, Institute of Clinical Medicine, Department of Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff37"><addr-line>Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kataja, Vesa" sort="Kataja, Vesa" uniqKey="Kataja V" first="Vesa" last="Kataja">Vesa Kataja</name><affiliation><nlm:aff id="aff37"><addr-line>Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff38"><addr-line>School of Medicine, Institute of Clinical Medicine, Department of Oncology, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kosma, Veli Matti" sort="Kosma, Veli Matti" uniqKey="Kosma V" first="Veli-Matti" last="Kosma">Veli-Matti Kosma</name><affiliation><nlm:aff id="aff36"><addr-line>School of Medicine, Institute of Clinical Medicine, Department of Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff37"><addr-line>Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hartikainen, Jaana M" sort="Hartikainen, Jaana M" uniqKey="Hartikainen J" first="Jaana M." last="Hartikainen">Jaana M. Hartikainen</name><affiliation><nlm:aff id="aff36"><addr-line>School of Medicine, Institute of Clinical Medicine, Department of Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff37"><addr-line>Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Group, Aocs Management" sort="Group, Aocs Management" uniqKey="Group A" first="Aocs Management" last="Group">Aocs Management Group</name><affiliation><nlm:aff id="aff12"><addr-line>Queensland Institute of Medical Research, Herston, Queensland, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff39"><addr-line>The Kathleen Cuningham Foundation for Resesarch into Familial Breast Cancer (kConFab), Peter MacCallum Cancer Centre, East Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lambrechts, Diether" sort="Lambrechts, Diether" uniqKey="Lambrechts D" first="Diether" last="Lambrechts">Diether Lambrechts</name><affiliation><nlm:aff id="aff40"><addr-line>Vesalius Research Center (VRC), VIB, Leuven, Belgium</addr-line></nlm:aff></affiliation></author><author><name sortKey="Smeets, Dominiek" sort="Smeets, Dominiek" uniqKey="Smeets D" first="Dominiek" last="Smeets">Dominiek Smeets</name><affiliation><nlm:aff id="aff40"><addr-line>Vesalius Research Center (VRC), VIB, Leuven, Belgium</addr-line></nlm:aff></affiliation></author><author><name sortKey="Neven, Patrick" sort="Neven, Patrick" uniqKey="Neven P" first="Patrick" last="Neven">Patrick Neven</name><affiliation><nlm:aff id="aff41"><addr-line>Multidisciplinary Breast Center, University Hospital Gasthuisberg, Leuven, Belgium</addr-line></nlm:aff></affiliation></author><author><name sortKey="Paridaens, Robert" sort="Paridaens, Robert" uniqKey="Paridaens R" first="Robert" last="Paridaens">Robert Paridaens</name><affiliation><nlm:aff id="aff41"><addr-line>Multidisciplinary Breast Center, University Hospital Gasthuisberg, Leuven, Belgium</addr-line></nlm:aff></affiliation></author><author><name sortKey="Flesch Janys, Dieter" sort="Flesch Janys, Dieter" uniqKey="Flesch Janys D" first="Dieter" last="Flesch-Janys">Dieter Flesch-Janys</name><affiliation><nlm:aff id="aff42"><addr-line>Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Obi, Nadia" sort="Obi, Nadia" uniqKey="Obi N" first="Nadia" last="Obi">Nadia Obi</name><affiliation><nlm:aff id="aff42"><addr-line>Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wang Gohrke, Shan" sort="Wang Gohrke, Shan" uniqKey="Wang Gohrke S" first="Shan" last="Wang-Gohrke">Shan Wang-Gohrke</name><affiliation><nlm:aff id="aff43"><addr-line>Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Couch, Fergus J" sort="Couch, Fergus J" uniqKey="Couch F" first="Fergus J." last="Couch">Fergus J. Couch</name><affiliation><nlm:aff id="aff44"><addr-line>Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Olson, Janet E" sort="Olson, Janet E" uniqKey="Olson J" first="Janet E." last="Olson">Janet E. Olson</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Vachon, Celine M" sort="Vachon, Celine M" uniqKey="Vachon C" first="Celine M." last="Vachon">Celine M. Vachon</name><affiliation><nlm:aff id="aff4"><addr-line>Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G." last="Giles">Graham G. Giles</name><affiliation><nlm:aff id="aff45"><addr-line>Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff46"><addr-line>Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, University of Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Severi, Gianluca" sort="Severi, Gianluca" uniqKey="Severi G" first="Gianluca" last="Severi">Gianluca Severi</name><affiliation><nlm:aff id="aff45"><addr-line>Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff46"><addr-line>Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, University of Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Baglietto, Laura" sort="Baglietto, Laura" uniqKey="Baglietto L" first="Laura" last="Baglietto">Laura Baglietto</name><affiliation><nlm:aff id="aff45"><addr-line>Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff46"><addr-line>Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, University of Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Offit, Kenneth" sort="Offit, Kenneth" uniqKey="Offit K" first="Kenneth" last="Offit">Kenneth Offit</name><affiliation><nlm:aff id="aff47"><addr-line>Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="John, Esther M" sort="John, Esther M" uniqKey="John E" first="Esther M." last="John">Esther M. John</name><affiliation><nlm:aff id="aff24"><addr-line>Cancer Prevention Institute of California, Fremont, California, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff25"><addr-line>Division of Epidemiology, Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Miron, Alexander" sort="Miron, Alexander" uniqKey="Miron A" first="Alexander" last="Miron">Alexander Miron</name><affiliation><nlm:aff id="aff48"><addr-line>Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Andrulis, Irene L" sort="Andrulis, Irene L" uniqKey="Andrulis I" first="Irene L." last="Andrulis">Irene L. Andrulis</name><affiliation><nlm:aff id="aff49"><addr-line>Ontario Cancer Genetics Network, Fred A. Litwin Center for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff50"><addr-line>Department of Molecular Genetics, University of Toronto, Toronto, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Knight, Julia A" sort="Knight, Julia A" uniqKey="Knight J" first="Julia A." last="Knight">Julia A. Knight</name><affiliation><nlm:aff id="aff51"><addr-line>Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff52"><addr-line>Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Glendon, Gord" sort="Glendon, Gord" uniqKey="Glendon G" first="Gord" last="Glendon">Gord Glendon</name><affiliation><nlm:aff id="aff53"><addr-line>Ontario Cancer Genetics Network, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mulligan, Anna Marie" sort="Mulligan, Anna Marie" uniqKey="Mulligan A" first="Anna Marie" last="Mulligan">Anna Marie Mulligan</name><affiliation><nlm:aff id="aff54"><addr-line>Laboratory Medicine Program, University Health Network, Toronto, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff55"><addr-line>Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chanock, Stephen J" sort="Chanock, Stephen J" uniqKey="Chanock S" first="Stephen J." last="Chanock">Stephen J. Chanock</name><affiliation><nlm:aff id="aff56"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lissowska, Jolanta" sort="Lissowska, Jolanta" uniqKey="Lissowska J" first="Jolanta" last="Lissowska">Jolanta Lissowska</name><affiliation><nlm:aff id="aff57"><addr-line>Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Liu, Jianjun" sort="Liu, Jianjun" uniqKey="Liu J" first="Jianjun" last="Liu">Jianjun Liu</name><affiliation><nlm:aff id="aff58"><addr-line>Human Genetics, Genome Institute of Singapore, Singapore, Singapore</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cox, Angela" sort="Cox, Angela" uniqKey="Cox A" first="Angela" last="Cox">Angela Cox</name><affiliation><nlm:aff id="aff59"><addr-line>Institute for Cancer Studies, Department of Oncology, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cramp, Helen" sort="Cramp, Helen" uniqKey="Cramp H" first="Helen" last="Cramp">Helen Cramp</name><affiliation><nlm:aff id="aff59"><addr-line>Institute for Cancer Studies, Department of Oncology, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Connley, Dan" sort="Connley, Dan" uniqKey="Connley D" first="Dan" last="Connley">Dan Connley</name><affiliation><nlm:aff id="aff59"><addr-line>Institute for Cancer Studies, Department of Oncology, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Balasubramanian, Sabapathy" sort="Balasubramanian, Sabapathy" uniqKey="Balasubramanian S" first="Sabapathy" last="Balasubramanian">Sabapathy Balasubramanian</name><affiliation><nlm:aff id="aff60"><addr-line>Academic Unit of Surgical Oncology, Department of Oncology, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dunning, Alison M" sort="Dunning, Alison M" uniqKey="Dunning A" first="Alison M." last="Dunning">Alison M. Dunning</name><affiliation><nlm:aff id="aff61"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Shah, Mitul" sort="Shah, Mitul" uniqKey="Shah M" first="Mitul" last="Shah">Mitul Shah</name><affiliation><nlm:aff id="aff61"><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Trentham Dietz, Amy" sort="Trentham Dietz, Amy" uniqKey="Trentham Dietz A" first="Amy" last="Trentham-Dietz">Amy Trentham-Dietz</name><affiliation><nlm:aff id="aff62"><addr-line>University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Newcomb, Polly" sort="Newcomb, Polly" uniqKey="Newcomb P" first="Polly" last="Newcomb">Polly Newcomb</name><affiliation><nlm:aff id="aff62"><addr-line>University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff63"><addr-line>Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Titus, Linda" sort="Titus, Linda" uniqKey="Titus L" first="Linda" last="Titus">Linda Titus</name><affiliation><nlm:aff id="aff64"><addr-line>Department of Community and Family Medicine, Department of Pediatrics, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Egan, Kathleen" sort="Egan, Kathleen" uniqKey="Egan K" first="Kathleen" last="Egan">Kathleen Egan</name><affiliation><nlm:aff id="aff65"><addr-line>Division of Population Sciences, Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cahoon, Elizabeth K" sort="Cahoon, Elizabeth K" uniqKey="Cahoon E" first="Elizabeth K." last="Cahoon">Elizabeth K. Cahoon</name><affiliation><nlm:aff id="aff66"><addr-line>Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rajaraman, Preetha" sort="Rajaraman, Preetha" uniqKey="Rajaraman P" first="Preetha" last="Rajaraman">Preetha Rajaraman</name><affiliation><nlm:aff id="aff66"><addr-line>Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sigurdson, Alice J" sort="Sigurdson, Alice J" uniqKey="Sigurdson A" first="Alice J." last="Sigurdson">Alice J. Sigurdson</name><affiliation><nlm:aff id="aff66"><addr-line>Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Doody, Michele M" sort="Doody, Michele M" uniqKey="Doody M" first="Michele M." last="Doody">Michele M. Doody</name><affiliation><nlm:aff id="aff66"><addr-line>Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Guenel, Pascal" sort="Guenel, Pascal" uniqKey="Guenel P" first="Pascal" last="Guénel">Pascal Guénel</name><affiliation><nlm:aff id="aff2"><addr-line>Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pharoah, Paul D P" sort="Pharoah, Paul D P" uniqKey="Pharoah P" first="Paul D. P." last="Pharoah">Paul D. P. Pharoah</name><affiliation><nlm:aff id="aff67"><addr-line>Department of Oncology and Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schmidt, Marjanka K" sort="Schmidt, Marjanka K" uniqKey="Schmidt M" first="Marjanka K." last="Schmidt">Marjanka K. Schmidt</name><affiliation><nlm:aff id="aff68"><addr-line>Division of Molecular Pathology and Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hall, Per" sort="Hall, Per" uniqKey="Hall P" first="Per" last="Hall">Per Hall</name><affiliation><nlm:aff id="aff10"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Easton, Doug F" sort="Easton, Doug F" uniqKey="Easton D" first="Doug F." last="Easton">Doug F. Easton</name><affiliation><nlm:aff id="aff19"><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Garcia Closas, Montserrat" sort="Garcia Closas, Montserrat" uniqKey="Garcia Closas M" first="Montserrat" last="Garcia-Closas">Montserrat Garcia-Closas</name><affiliation><nlm:aff id="aff56"><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff69"><addr-line>Sections of Epidemiology and Genetics, Institute of Cancer Research and Breakthrough Breast Cancer Research Centre, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Milne, Roger L" sort="Milne, Roger L" uniqKey="Milne R" first="Roger L." last="Milne">Roger L. Milne</name><affiliation><nlm:aff id="aff70"><addr-line>Genetic and Molecular Epidemiology Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chang Claude, Jenny" sort="Chang Claude, Jenny" uniqKey="Chang Claude J" first="Jenny" last="Chang-Claude">Jenny Chang-Claude</name><affiliation><nlm:aff id="aff1"><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS Genetics</title><idno type="ISSN">1553-7390</idno><idno type="eISSN">1553-7404</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene–environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between <italic>LSP1-</italic>rs3817198 and parity (P<sub>interaction</sub> = 2.4×10<sup>−6</sup>) and between <italic>CASP8</italic>-rs17468277 and alcohol consumption (P<sub>interaction</sub> = 3.1×10<sup>−4</sup>). Overall, the per-allele odds ratio (95% confidence interval) for <italic>LSP1</italic>-rs3817198 was 1.08 (1.01–1.16) in nulliparous women and ranged from 1.03 (0.96–1.10) in parous women with one birth to 1.26 (1.16–1.37) in women with at least four births. For <italic>CASP8</italic>-rs17468277, the per-allele OR was 0.91 (0.85–0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14–1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (P<sub>interaction</sub> = 5.3×10<sup>−5</sup>), with a per-allele OR of 1.14 (1.11–1.17) in parous women and 0.98 (0.92–1.05) in nulliparous women. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Genet</journal-id><journal-id journal-id-type="iso-abbrev">PLoS Genet</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosgen</journal-id><journal-title-group><journal-title>PLoS Genetics</journal-title></journal-title-group><issn pub-type="ppub">1553-7390</issn><issn pub-type="epub">1553-7404</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">23544014</article-id><article-id pub-id-type="pmc">3609648</article-id><article-id pub-id-type="publisher-id">PGENETICS-D-12-02331</article-id><article-id pub-id-type="doi">10.1371/journal.pgen.1003284</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Medicine</subject><subj-group><subject>Epidemiology</subject><subj-group><subject>Cancer Epidemiology</subject><subject>Genetic Epidemiology</subject></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Evidence of Gene–Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors</article-title><alt-title alt-title-type="running-head">Gene–Environment Interactions for Breast Cancer</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Nickels</surname><given-names>Stefan</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Truong</surname><given-names>Thérèse</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hein</surname><given-names>Rebecca</given-names></name><xref 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rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Vrieling</surname><given-names>Alina</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gaudet</surname><given-names>Mia</given-names></name><xref ref-type="aff" rid="aff9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Figueroa</surname><given-names>Jonine</given-names></name><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schoof</surname><given-names>Nils</given-names></name><xref ref-type="aff" rid="aff11"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>Spurdle</surname><given-names>Amanda B.</given-names></name><xref ref-type="aff" rid="aff12"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rudolph</surname><given-names>Anja</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fasching</surname><given-names>Peter A.</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref><xref ref-type="aff" rid="aff13"><sup>13</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hopper</surname><given-names>John L.</given-names></name><xref ref-type="aff" rid="aff14"><sup>14</sup></xref></contrib><contrib contrib-type="author"><name><surname>Makalic</surname><given-names>Enes</given-names></name><xref ref-type="aff" rid="aff14"><sup>14</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schmidt</surname><given-names>Daniel F.</given-names></name><xref ref-type="aff" rid="aff14"><sup>14</sup></xref></contrib><contrib contrib-type="author"><name><surname>Southey</surname><given-names>Melissa C.</given-names></name><xref ref-type="aff" rid="aff15"><sup>15</sup></xref></contrib><contrib contrib-type="author"><name><surname>Beckmann</surname><given-names>Matthias W.</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ekici</surname><given-names>Arif B.</given-names></name><xref ref-type="aff" rid="aff16"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fletcher</surname><given-names>Olivia</given-names></name><xref ref-type="aff" rid="aff17"><sup>17</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gibson</surname><given-names>Lorna</given-names></name><xref ref-type="aff" rid="aff18"><sup>18</sup></xref></contrib><contrib contrib-type="author"><name><surname>dos Santos Silva</surname><given-names>Isabel</given-names></name><xref ref-type="aff" rid="aff18"><sup>18</sup></xref></contrib><contrib contrib-type="author"><name><surname>Peto</surname><given-names>Julian</given-names></name><xref ref-type="aff" rid="aff18"><sup>18</sup></xref></contrib><contrib contrib-type="author"><name><surname>Humphreys</surname><given-names>Manjeet K.</given-names></name><xref ref-type="aff" rid="aff19"><sup>19</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Jean</given-names></name><xref ref-type="aff" rid="aff19"><sup>19</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cordina-Duverger</surname><given-names>Emilie</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Menegaux</surname><given-names>Florence</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nordestgaard</surname><given-names>Børge G.</given-names></name><xref ref-type="aff" rid="aff20"><sup>20</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bojesen</surname><given-names>Stig E.</given-names></name><xref ref-type="aff" rid="aff20"><sup>20</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lanng</surname><given-names>Charlotte</given-names></name><xref ref-type="aff" rid="aff21"><sup>21</sup></xref></contrib><contrib contrib-type="author"><name><surname>Anton-Culver</surname><given-names>Hoda</given-names></name><xref ref-type="aff" rid="aff22"><sup>22</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ziogas</surname><given-names>Argyrios</given-names></name><xref ref-type="aff" rid="aff22"><sup>22</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bernstein</surname><given-names>Leslie</given-names></name><xref ref-type="aff" rid="aff23"><sup>23</sup></xref></contrib><contrib contrib-type="author"><name><surname>Clarke</surname><given-names>Christina A.</given-names></name><xref ref-type="aff" rid="aff24"><sup>24</sup></xref><xref ref-type="aff" rid="aff25"><sup>25</sup></xref></contrib><contrib contrib-type="author"><name><surname>Brenner</surname><given-names>Hermann</given-names></name><xref ref-type="aff" rid="aff26"><sup>26</sup></xref></contrib><contrib contrib-type="author"><name><surname>Müller</surname><given-names>Heiko</given-names></name><xref ref-type="aff" rid="aff26"><sup>26</sup></xref></contrib><contrib contrib-type="author"><name><surname>Arndt</surname><given-names>Volker</given-names></name><xref ref-type="aff" rid="aff26"><sup>26</sup></xref></contrib><contrib contrib-type="author"><name><surname>Stegmaier</surname><given-names>Christa</given-names></name><xref ref-type="aff" rid="aff27"><sup>27</sup></xref></contrib><contrib contrib-type="author"><name><surname>Brauch</surname><given-names>Hiltrud</given-names></name><xref ref-type="aff" rid="aff28"><sup>28</sup></xref><xref ref-type="aff" rid="aff29"><sup>29</sup></xref></contrib><contrib contrib-type="author"><name><surname>Brüning</surname><given-names>Thomas</given-names></name><xref ref-type="aff" rid="aff30"><sup>30</sup></xref></contrib><contrib contrib-type="author"><name><surname>Harth</surname><given-names>Volker</given-names></name><xref ref-type="aff" rid="aff31"><sup>31</sup></xref><xref ref-type="aff" rid="aff32"><sup>32</sup></xref></contrib><contrib contrib-type="author"><name><surname>The GENICA Network</surname><given-names></given-names></name><xref ref-type="aff" rid="aff28"><sup>28</sup></xref><xref ref-type="aff" rid="aff29"><sup>29</sup></xref><xref ref-type="aff" rid="aff30"><sup>30</sup></xref><xref ref-type="aff" rid="aff31"><sup>31</sup></xref><xref ref-type="aff" rid="aff33"><sup>33</sup></xref><xref ref-type="aff" rid="aff34"><sup>34</sup></xref><xref ref-type="aff" rid="aff35"><sup>35</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mannermaa</surname><given-names>Arto</given-names></name><xref ref-type="aff" rid="aff36"><sup>36</sup></xref><xref ref-type="aff" rid="aff37"><sup>37</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kataja</surname><given-names>Vesa</given-names></name><xref ref-type="aff" rid="aff37"><sup>37</sup></xref><xref ref-type="aff" rid="aff38"><sup>38</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kosma</surname><given-names>Veli-Matti</given-names></name><xref ref-type="aff" rid="aff36"><sup>36</sup></xref><xref ref-type="aff" rid="aff37"><sup>37</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hartikainen</surname><given-names>Jaana M.</given-names></name><xref ref-type="aff" rid="aff36"><sup>36</sup></xref><xref ref-type="aff" rid="aff37"><sup>37</sup></xref></contrib><contrib contrib-type="author"><name><surname>kConFab</surname><given-names></given-names></name><xref ref-type="aff" rid="aff39"><sup>39</sup></xref></contrib><contrib contrib-type="author"><name><surname>Group</surname><given-names>AOCS Management</given-names></name><xref ref-type="aff" rid="aff12"><sup>12</sup></xref><xref ref-type="aff" rid="aff39"><sup>39</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lambrechts</surname><given-names>Diether</given-names></name><xref ref-type="aff" rid="aff40"><sup>40</sup></xref></contrib><contrib contrib-type="author"><name><surname>Smeets</surname><given-names>Dominiek</given-names></name><xref ref-type="aff" rid="aff40"><sup>40</sup></xref></contrib><contrib contrib-type="author"><name><surname>Neven</surname><given-names>Patrick</given-names></name><xref ref-type="aff" rid="aff41"><sup>41</sup></xref></contrib><contrib contrib-type="author"><name><surname>Paridaens</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="aff41"><sup>41</sup></xref></contrib><contrib contrib-type="author"><name><surname>Flesch-Janys</surname><given-names>Dieter</given-names></name><xref ref-type="aff" rid="aff42"><sup>42</sup></xref></contrib><contrib contrib-type="author"><name><surname>Obi</surname><given-names>Nadia</given-names></name><xref ref-type="aff" rid="aff42"><sup>42</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wang-Gohrke</surname><given-names>Shan</given-names></name><xref ref-type="aff" rid="aff43"><sup>43</sup></xref></contrib><contrib contrib-type="author"><name><surname>Couch</surname><given-names>Fergus J.</given-names></name><xref ref-type="aff" rid="aff44"><sup>44</sup></xref></contrib><contrib contrib-type="author"><name><surname>Olson</surname><given-names>Janet E.</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Vachon</surname><given-names>Celine M.</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Giles</surname><given-names>Graham G.</given-names></name><xref ref-type="aff" rid="aff45"><sup>45</sup></xref><xref ref-type="aff" rid="aff46"><sup>46</sup></xref></contrib><contrib contrib-type="author"><name><surname>Severi</surname><given-names>Gianluca</given-names></name><xref ref-type="aff" rid="aff45"><sup>45</sup></xref><xref ref-type="aff" rid="aff46"><sup>46</sup></xref></contrib><contrib contrib-type="author"><name><surname>Baglietto</surname><given-names>Laura</given-names></name><xref ref-type="aff" rid="aff45"><sup>45</sup></xref><xref ref-type="aff" rid="aff46"><sup>46</sup></xref></contrib><contrib contrib-type="author"><name><surname>Offit</surname><given-names>Kenneth</given-names></name><xref ref-type="aff" rid="aff47"><sup>47</sup></xref></contrib><contrib contrib-type="author"><name><surname>John</surname><given-names>Esther M.</given-names></name><xref ref-type="aff" rid="aff24"><sup>24</sup></xref><xref ref-type="aff" rid="aff25"><sup>25</sup></xref></contrib><contrib contrib-type="author"><name><surname>Miron</surname><given-names>Alexander</given-names></name><xref ref-type="aff" rid="aff48"><sup>48</sup></xref></contrib><contrib contrib-type="author"><name><surname>Andrulis</surname><given-names>Irene L.</given-names></name><xref ref-type="aff" rid="aff49"><sup>49</sup></xref><xref ref-type="aff" rid="aff50"><sup>50</sup></xref></contrib><contrib contrib-type="author"><name><surname>Knight</surname><given-names>Julia A.</given-names></name><xref ref-type="aff" rid="aff51"><sup>51</sup></xref><xref ref-type="aff" rid="aff52"><sup>52</sup></xref></contrib><contrib contrib-type="author"><name><surname>Glendon</surname><given-names>Gord</given-names></name><xref ref-type="aff" rid="aff53"><sup>53</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mulligan</surname><given-names>Anna Marie</given-names></name><xref ref-type="aff" rid="aff54"><sup>54</sup></xref><xref ref-type="aff" rid="aff55"><sup>55</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chanock</surname><given-names>Stephen J.</given-names></name><xref ref-type="aff" rid="aff56"><sup>56</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lissowska</surname><given-names>Jolanta</given-names></name><xref ref-type="aff" rid="aff57"><sup>57</sup></xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Jianjun</given-names></name><xref ref-type="aff" rid="aff58"><sup>58</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cox</surname><given-names>Angela</given-names></name><xref ref-type="aff" rid="aff59"><sup>59</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cramp</surname><given-names>Helen</given-names></name><xref ref-type="aff" rid="aff59"><sup>59</sup></xref></contrib><contrib contrib-type="author"><name><surname>Connley</surname><given-names>Dan</given-names></name><xref ref-type="aff" rid="aff59"><sup>59</sup></xref></contrib><contrib contrib-type="author"><name><surname>Balasubramanian</surname><given-names>Sabapathy</given-names></name><xref ref-type="aff" rid="aff60"><sup>60</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dunning</surname><given-names>Alison M.</given-names></name><xref ref-type="aff" rid="aff61"><sup>61</sup></xref></contrib><contrib contrib-type="author"><name><surname>Shah</surname><given-names>Mitul</given-names></name><xref ref-type="aff" rid="aff61"><sup>61</sup></xref></contrib><contrib contrib-type="author"><name><surname>Trentham-Dietz</surname><given-names>Amy</given-names></name><xref ref-type="aff" rid="aff62"><sup>62</sup></xref></contrib><contrib contrib-type="author"><name><surname>Newcomb</surname><given-names>Polly</given-names></name><xref ref-type="aff" rid="aff62"><sup>62</sup></xref><xref ref-type="aff" rid="aff63"><sup>63</sup></xref></contrib><contrib contrib-type="author"><name><surname>Titus</surname><given-names>Linda</given-names></name><xref ref-type="aff" rid="aff64"><sup>64</sup></xref></contrib><contrib contrib-type="author"><name><surname>Egan</surname><given-names>Kathleen</given-names></name><xref ref-type="aff" rid="aff65"><sup>65</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cahoon</surname><given-names>Elizabeth K.</given-names></name><xref ref-type="aff" rid="aff66"><sup>66</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rajaraman</surname><given-names>Preetha</given-names></name><xref ref-type="aff" rid="aff66"><sup>66</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sigurdson</surname><given-names>Alice J.</given-names></name><xref ref-type="aff" rid="aff66"><sup>66</sup></xref></contrib><contrib contrib-type="author"><name><surname>Doody</surname><given-names>Michele M.</given-names></name><xref ref-type="aff" rid="aff66"><sup>66</sup></xref></contrib><contrib contrib-type="author"><name><surname>Guénel</surname><given-names>Pascal</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pharoah</surname><given-names>Paul D. P.</given-names></name><xref ref-type="aff" rid="aff67"><sup>67</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schmidt</surname><given-names>Marjanka K.</given-names></name><xref ref-type="aff" rid="aff68"><sup>68</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hall</surname><given-names>Per</given-names></name><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Easton</surname><given-names>Doug F.</given-names></name><xref ref-type="aff" rid="aff19"><sup>19</sup></xref></contrib><contrib contrib-type="author"><name><surname>Garcia-Closas</surname><given-names>Montserrat</given-names></name><xref ref-type="aff" rid="aff56"><sup>56</sup></xref><xref ref-type="aff" rid="aff69"><sup>69</sup></xref></contrib><contrib contrib-type="author"><name><surname>Milne</surname><given-names>Roger L.</given-names></name><xref ref-type="aff" rid="aff70"><sup>70</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chang-Claude</surname><given-names>Jenny</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France</addr-line></aff><aff id="aff3"><label>3</label><addr-line>PMV Research Group at the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany</addr-line></aff><aff id="aff4"><label>4</label><addr-line>Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America</addr-line></aff><aff id="aff5"><label>5</label><addr-line>Department of Preventive Oncology, National Center of Tumor Diseases, Heidelberg, Germany</addr-line></aff><aff id="aff6"><label>6</label><addr-line>Unit of Environmental Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></aff><aff id="aff7"><label>7</label><addr-line>Department of Gynecology and Obstetrics, University Hospital, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany</addr-line></aff><aff id="aff8"><label>8</label><addr-line>Department for Health Evidence, Radboud University Medical Centre, Nijmegen, The Netherlands</addr-line></aff><aff id="aff9"><label>9</label><addr-line>Epidemiology Research Program, Division of Cancer Epidemiology, American Cancer Society, Atlanta, Georgia, United States of America</addr-line></aff><aff id="aff10"><label>10</label><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></aff><aff id="aff11"><label>11</label><addr-line>Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden</addr-line></aff><aff id="aff12"><label>12</label><addr-line>Queensland Institute of Medical Research, Herston, Queensland, Australia</addr-line></aff><aff id="aff13"><label>13</label><addr-line>Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America</addr-line></aff><aff id="aff14"><label>14</label><addr-line>Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia</addr-line></aff><aff id="aff15"><label>15</label><addr-line>Department of Pathology, University of Melbourne, Melbourne, Australia</addr-line></aff><aff id="aff16"><label>16</label><addr-line>Institute of Human Genetics, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany</addr-line></aff><aff id="aff17"><label>17</label><addr-line>Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom</addr-line></aff><aff id="aff18"><label>18</label><addr-line>London School of Hygiene and Tropical Medicine, London, United Kingdom</addr-line></aff><aff id="aff19"><label>19</label><addr-line>Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></aff><aff id="aff20"><label>20</label><addr-line>Copenhagen General Population Study and Department of Clinical Biochemistry, Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark</addr-line></aff><aff id="aff21"><label>21</label><addr-line>Department of Breast Surgery, Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark</addr-line></aff><aff id="aff22"><label>22</label><addr-line>Department of Epidemiology, University of California Irvine, Irvine, California, United States of America</addr-line></aff><aff id="aff23"><label>23</label><addr-line>Beckman Research Institute of the City of Hope, Duarte, California, United States of America</addr-line></aff><aff id="aff24"><label>24</label><addr-line>Cancer Prevention Institute of California, Fremont, California, United States of America</addr-line></aff><aff id="aff25"><label>25</label><addr-line>Division of Epidemiology, Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, United States of America</addr-line></aff><aff id="aff26"><label>26</label><addr-line>Division of Clinical Epidemiology and Ageing Research, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></aff><aff id="aff27"><label>27</label><addr-line>Saarland Cancer Registry, Saarbrücken, Germany</addr-line></aff><aff id="aff28"><label>28</label><addr-line>Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany</addr-line></aff><aff id="aff29"><label>29</label><addr-line>University of Tübingen, Tübingen, Germany</addr-line></aff><aff id="aff30"><label>30</label><addr-line>Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-Universität Bochum (IPA), Bochum, Germany</addr-line></aff><aff id="aff31"><label>31</label><addr-line>Institute and Outpatient Clinic of Occupational Medicine, Saarland University Medical Center and Saarland University Faculty of Medicine, Homburg, Germany</addr-line></aff><aff id="aff32"><label>32</label><addr-line>Institute for Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany</addr-line></aff><aff id="aff33"><label>33</label><addr-line>Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany</addr-line></aff><aff id="aff34"><label>34</label><addr-line>Institute of Pathology, University of Bonn, Bonn, Germany</addr-line></aff><aff id="aff35"><label>35</label><addr-line>Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany</addr-line></aff><aff id="aff36"><label>36</label><addr-line>School of Medicine, Institute of Clinical Medicine, Department of Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland</addr-line></aff><aff id="aff37"><label>37</label><addr-line>Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland</addr-line></aff><aff id="aff38"><label>38</label><addr-line>School of Medicine, Institute of Clinical Medicine, Department of Oncology, University of Eastern Finland, Kuopio, Finland</addr-line></aff><aff id="aff39"><label>39</label><addr-line>The Kathleen Cuningham Foundation for Resesarch into Familial Breast Cancer (kConFab), Peter MacCallum Cancer Centre, East Melbourne, Australia</addr-line></aff><aff id="aff40"><label>40</label><addr-line>Vesalius Research Center (VRC), VIB, Leuven, Belgium</addr-line></aff><aff id="aff41"><label>41</label><addr-line>Multidisciplinary Breast Center, University Hospital Gasthuisberg, Leuven, Belgium</addr-line></aff><aff id="aff42"><label>42</label><addr-line>Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany</addr-line></aff><aff id="aff43"><label>43</label><addr-line>Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany</addr-line></aff><aff id="aff44"><label>44</label><addr-line>Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America</addr-line></aff><aff id="aff45"><label>45</label><addr-line>Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Australia</addr-line></aff><aff id="aff46"><label>46</label><addr-line>Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, University of Melbourne, Australia</addr-line></aff><aff id="aff47"><label>47</label><addr-line>Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America</addr-line></aff><aff id="aff48"><label>48</label><addr-line>Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America</addr-line></aff><aff id="aff49"><label>49</label><addr-line>Ontario Cancer Genetics Network, Fred A. Litwin Center for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada</addr-line></aff><aff id="aff50"><label>50</label><addr-line>Department of Molecular Genetics, University of Toronto, Toronto, Canada</addr-line></aff><aff id="aff51"><label>51</label><addr-line>Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada</addr-line></aff><aff id="aff52"><label>52</label><addr-line>Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Canada</addr-line></aff><aff id="aff53"><label>53</label><addr-line>Ontario Cancer Genetics Network, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada</addr-line></aff><aff id="aff54"><label>54</label><addr-line>Laboratory Medicine Program, University Health Network, Toronto, Canada</addr-line></aff><aff id="aff55"><label>55</label><addr-line>Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada</addr-line></aff><aff id="aff56"><label>56</label><addr-line>Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></aff><aff id="aff57"><label>57</label><addr-line>Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland</addr-line></aff><aff id="aff58"><label>58</label><addr-line>Human Genetics, Genome Institute of Singapore, Singapore, Singapore</addr-line></aff><aff id="aff59"><label>59</label><addr-line>Institute for Cancer Studies, Department of Oncology, University of Sheffield, Sheffield, United Kingdom</addr-line></aff><aff id="aff60"><label>60</label><addr-line>Academic Unit of Surgical Oncology, Department of Oncology, University of Sheffield, Sheffield, United Kingdom</addr-line></aff><aff id="aff61"><label>61</label><addr-line>Department of Oncology, University of Cambridge, Cambridge, United Kingdom</addr-line></aff><aff id="aff62"><label>62</label><addr-line>University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, United States of America</addr-line></aff><aff id="aff63"><label>63</label><addr-line>Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America</addr-line></aff><aff id="aff64"><label>64</label><addr-line>Department of Community and Family Medicine, Department of Pediatrics, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, United States of America</addr-line></aff><aff id="aff65"><label>65</label><addr-line>Division of Population Sciences, Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America</addr-line></aff><aff id="aff66"><label>66</label><addr-line>Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, United States of America</addr-line></aff><aff id="aff67"><label>67</label><addr-line>Department of Oncology and Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom</addr-line></aff><aff id="aff68"><label>68</label><addr-line>Division of Molecular Pathology and Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands</addr-line></aff><aff id="aff69"><label>69</label><addr-line>Sections of Epidemiology and Genetics, Institute of Cancer Research and Breakthrough Breast Cancer Research Centre, London, United Kingdom</addr-line></aff><aff id="aff70"><label>70</label><addr-line>Genetic and Molecular Epidemiology Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Horwitz</surname><given-names>Marshall S.</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>University of Washington, United States of America</addr-line></aff><author-notes><corresp id="cor1">* E-mail: <email>j.chang-claude@dkfz.de</email></corresp><fn fn-type="COI-statement"><p>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con"><p>Conceived and designed the experiments: P Guénel, PDP Pharoah, MK Schmidt, P Hall, DF Easton, M Garcia-Closas, RL Milne, J Chang-Claude. Performed the experiments: AM Dunning. Analyzed the data: S Nickels, T Truong, R Hein, K Stevens, K Buck, S Behrens, U Eilber, M Schmidt, L Häberle, A Vrieling, M Gaudet, J Figueroa, N Schoof, AB Spurdle, A Rudolph, PA Fasching, J Chang-Claude. Contributed reagents/materials/analysis tools: JL Hopper, E Makalic, DF Schmidt, MC Southey, MW Beckman, AB Ekici, O Fletcher, L Gibson, I dos Santo Silva, J Peto, MK Humphreys, J Wang, E Cordina-Duverger, F Menegaux, BG Nordestgaard, SE Bojeson, C Lanng, H Anton-Culver, A Ziogas, L Bernstein, CA Clarke, H Brenner, H Müller, V Arndt, C Stegmaier, H Brauch, T Brüning, V Harth, A Mannermaa, V Kataj, V-M Kosma, JM Hartikainen, D Lambrechts, D Smeets, P Neven, R Paridaens, D Flesch-Janys, N Obi, S Wang-Gohrke, FJ Couch, JE Olson, CM Vachon, GG Giles, G Severi, L Baglietto, K Offit, EM John, A Miron, IL Andrulis, JA Knight, G Glendon, AM Mulligan, SJ Chanock, J Lissowska, J Liu, A Cox, H Cramp, D Connley, S Balasubramanian, AM Dunning, M Shah, A Trentham-Dietz, P Newcomb, L Titus, K Egan, EK Cahoon, P Rajaraman, AJ Sigurdson, MM Doody, P Guénel, PDP Pharoah, MK Schmidt, P Hall, DF Easton, M Garcia-Closas, RL Milne, J Chang-Claude. Wrote the paper: S Nickels, T Truong, P Hall, DF Easton, M Garcia-Closas, RL Milne, J Chang-Claude.</p></fn></author-notes><pub-date pub-type="collection"><month>3</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>27</day><month>3</month><year>2013</year></pub-date><volume>9</volume><issue>3</issue><elocation-id>e1003284</elocation-id><history><date date-type="received"><day>17</day><month>9</month><year>2012</year></date><date date-type="accepted"><day>13</day><month>12</month><year>2012</year></date></history><permissions><copyright-year>2013</copyright-year><license xlink:href="https://creativecommons.org/publicdomain/zero/1.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.</license-p></license></permissions><related-article id="RA1" related-article-type="companion" vol="" page="e1003173" ext-link-type="pmc"><pmc-comment>related-article was converted to @ext-link-type="pmc" and original @xlink:href value
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<article-title>Identification of a BRCA2-specific Modifier Locus at 6p24 Related to Breast Cancer Risk</article-title></related-article><related-article id="RA2" related-article-type="companion" vol="" page="e1003212" ext-link-type="pmc"><pmc-comment>related-article was converted to @ext-link-type="pmc" and original @xlink:href value
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<article-title>Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk</article-title></related-article><abstract><p>Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene–environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between <italic>LSP1-</italic>rs3817198 and parity (P<sub>interaction</sub> = 2.4×10<sup>−6</sup>) and between <italic>CASP8</italic>-rs17468277 and alcohol consumption (P<sub>interaction</sub> = 3.1×10<sup>−4</sup>). Overall, the per-allele odds ratio (95% confidence interval) for <italic>LSP1</italic>-rs3817198 was 1.08 (1.01–1.16) in nulliparous women and ranged from 1.03 (0.96–1.10) in parous women with one birth to 1.26 (1.16–1.37) in women with at least four births. For <italic>CASP8</italic>-rs17468277, the per-allele OR was 0.91 (0.85–0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14–1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (P<sub>interaction</sub> = 5.3×10<sup>−5</sup>), with a per-allele OR of 1.14 (1.11–1.17) in parous women and 0.98 (0.92–1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.</p></abstract><abstract abstract-type="summary"><title>Author Summary</title><p>Breast cancer involves combined effects of numerous genetic, environmental, and behavioral risk factors that are unique to each individual. High risk genes, such as <italic>BRCA1</italic> and <italic>BRCA2</italic>, account for only a small proportion of disease occurrence. Recent genome-wide research has identified more than 20 common genetic variants, which individually alter breast cancer risk very moderately. We undertook an international collaborative study to determine whether the effect of these genetic variants vary with environmental factors, such as parity, body mass index (BMI), height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, and physical activity, which are known to affect risk of developing breast cancer. Using pooled data from 24 studies of the Breast Cancer Association Consortium (BCAC), we provide first convincing evidence that the breast cancer risk associated with a genetic variant in <italic>LSP1</italic> differs with the number of births and that the risk associated with a <italic>CASP8</italic> variant is altered by high alcohol consumption. The effect of an additional genetic variant might also be modified by reproductive factors. This knowledge will stimulate new research towards a better understanding of breast cancer development.</p></abstract><funding-group><funding-statement>BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme [BM0606]. DF Easton is a Principal Research Fellow of CR-UK. RL Milne is supported by Fondo de Investigación Sanitario (PI11/00923). The Australian Breast Cancer Family Registry (ABCFR; 1992-1995) was supported by the Australian NHMRC, the New South Wales Cancer Council, and the Victorian Health Promotion Foundation (Australia). The Breast Cancer Family Registry (BCFR) was supported by the National Cancer Institute, National Institutes of Health, under RFA # CA-06-503, and through cooperative agreements with members of the BCFR and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), Cancer Prevention Institute of California (U01 CA69417), University of Melbourne (U01 CA69638), and Georgetown University Medical Center Informatics Support Center (HHSN261200900010C). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating BCFR centres, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government or the BCFR. JL Hopper is an Australia Fellow and MC Southey is a Senior Research Fellow of the National Health and Medical Research Council (NHMRC) of Australia. MC Southey and JL Hopper are Group Leaders of the Victorian Breast Cancer Research Consortium. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The CECILE study was funded by the Fondation de France, the French National Institute of Cancer (INCa), The National League against Cancer, the National Agency for Environmental and Occupational Health and Food Safety (ANSES), the National Agency for Research (ANR), and the Association for Research against Cancer (ARC). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Herlev Hospital. The CTS was supported by the California Breast Cancer Act of 1993, National Institutes of Health (grants R01 CA77398 and the Lon V Smith Foundation [LVS39420]), and the California Breast Cancer Research Fund (contract 97-10500). Collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. The ESTHER study was supportd by a grant from the Baden Württemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which was supported by a grant from the German Cancer Aid (Deutsche Krebshilfe). The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0, and 01KW0114; the Robert Bosch Foundation, Stuttgart; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum; as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany. The GESBC was supported by the Deutsche Krebshilfe e. V. [70492] and genotyping in part by the state of Baden-Württemberg through the Medical Faculty of the University of Ulm [P.685]. The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland, and by the strategic funding of the University of Eastern Finland. kConFab is supported by grants from the National Breast Cancer Foundation; the NHMRC; the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. The kConFab Clinical Follow Up Study was funded by the NHMRC [145684, 288704, 454508]. Financial support for the AOCS was provided by the United States Army Medical Research and Materiel Command [DAMD17-01-1-0729], the Cancer Council of Tasmania and Cancer Foundation of Western Australia and the NHMRC [199600]. AB Spurdle is supported by an NHMRC Senior Research Fellowship. LMBC is supported by the “Stichting tegen Kanker” (232-2008 and 196-2010). The MARIE study was supported by the Deutsche Krebshilfe e.V. [70-2892-BR I], the Hamburg Cancer Society, the German Cancer Research Center, and genotype work in part by the Federal Ministry of Education and Research (BMBF) Germany [01KH0402]. The MCBCS was supported by the NIH grants [CA122340, CA128978] and a Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria. The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The Singapore and Swedish Breast Cancer Study (SASBAC) was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR); the U.S. National Institute of Health (NIH); the Susan G. Komen Breast Cancer Foundation; and Märit and Hans Rausings Initiative Against Breast Cancer. The SBCS was supported by Yorkshire Cancer Research and the Breast Cancer Campaign. SEARCH is funded by grants from Cancer Research UK [C490/A6187, C490/A10119, C490/A10124] and the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The US3SS study was supported by Massachusetts (KME, R01CA47305), Wisconsin (PAN, R01 CA47147), and New Hampshire (LT-E, R01CA69664) centers and by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA. The USRT study was funded by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><page-count count="14"></page-count></counts></article-meta></front><body><sec id="s1"><title>Introduction</title><p>Both genetic and non-genetic factors are involved in the etiology of breast cancer. Known susceptibility variants include rare high-risk mutations, principally in <italic>BRCA1</italic> and <italic>BRCA2</italic>, more moderate susceptibility variants in genes such as <italic>PALB2</italic>, <italic>CHEK2</italic> and <italic>ATM</italic>, and more than 20 common genetic susceptibility variants conferring modest increased risks, principally identified through genome-wide association studies. Taken together, the known susceptibility variants have been estimated to explain about 20–25% of the observed familial breast cancer risk <xref rid="pgen.1003284-Mavaddat1" ref-type="bibr">[1]</xref>. There is still limited knowledge about how the relative risks of common susceptibility loci might be modified by the established reproductive and lifestyle risk factors (referred to as environmental risk factors) for breast cancer. Such knowledge could provide insights into common biological pathways for cancer development and further our understanding of breast cancer etiology for specific tumor subtypes. Previous reports of a possible interaction between variants in <italic>FGFR2</italic> and use of menopausal hormone therapy (MHT) were not confirmed <xref rid="pgen.1003284-Campa1" ref-type="bibr">[2]</xref>–<xref rid="pgen.1003284-Travis1" ref-type="bibr">[6]</xref>. All recent large studies found no statistically significant evidence of multiplicative gene-environment interaction between several common susceptibility loci and established risk factors for breast cancer after allowing for multiple comparisons <xref rid="pgen.1003284-Campa1" ref-type="bibr">[2]</xref>, <xref rid="pgen.1003284-Travis1" ref-type="bibr">[6]</xref>, <xref rid="pgen.1003284-Milne1" ref-type="bibr">[7]</xref>. The strongest previously reported findings were for an interaction between <italic>LSP1</italic>-rs3817198 and number of births (P-value = 0.002), between <italic>CASP8</italic>-rs104585 and alcohol consumption (P-value = 0.003), and between 5p12-rs10941679 and use of estrogen-only MHT (P-value = 0.007) <xref rid="pgen.1003284-Campa1" ref-type="bibr">[2]</xref>, <xref rid="pgen.1003284-Travis1" ref-type="bibr">[6]</xref>, <xref rid="pgen.1003284-Milne1" ref-type="bibr">[7]</xref>. This lack of statistical evidence of interaction beyond that expected by chance may be partly due to limited power to detect weak gene-environment interactions and not having considered specific subtypes of breast cancer. We used pooled data from 24 studies participating in the Breast Cancer Association Consortium (BCAC) to evaluate whether the relative risks of single nucleotide polymorphisms (SNPs) at 23 published loci vary according to levels of 10 established environmental risk factors <xref rid="pgen.1003284-Breast1" ref-type="bibr">[8]</xref>. Since there is etiologic heterogeneity by subtypes of breast cancer, we also carried out these assessments for breast cancer with positive and negative estrogen receptor (ER) status <xref rid="pgen.1003284-Yang1" ref-type="bibr">[9]</xref>.</p></sec><sec id="s2"><title>Results</title><p>Up to 34,793 invasive cases and 41,099 controls of self-reported European ancestry were included in these analyses (<xref ref-type="table" rid="pgen-1003284-t001">Table 1</xref>). Based on 18,532 cases and 25,341 controls from 16 population-based studies, we found the expected associations between the environmental risk factors and breast cancer risk (<xref ref-type="table" rid="pgen-1003284-t002">Table 2</xref>). As expected, significant effect heterogeneity by age (as a surrogate for menopausal status) was observed only for body mass index (BMI) (P-value = 0.007).</p><table-wrap id="pgen-1003284-t001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pgen.1003284.t001</object-id><label>Table 1</label><caption><title>List of participating studies and number of Caucasian subjects included in at least one GxE analysis.</title></caption><alternatives><graphic id="pgen-1003284-t001-1" xlink:href="pgen.1003284.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1">Study acronym</td><td align="left" rowspan="1" colspan="1">Study Name</td><td align="left" rowspan="1" colspan="1">Country</td><td align="left" rowspan="1" colspan="1">Design category</td><td align="left" rowspan="1" colspan="1">Cases/controls used for GxE</td><td align="left" rowspan="1" colspan="1">ER+ cases</td><td align="left" rowspan="1" colspan="1">ER−cases</td><td align="left" rowspan="1" colspan="1">Mean age (range) in cases</td><td align="left" rowspan="1" colspan="1">Mean age (range) in controls</td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">ABCFS</td><td align="left" rowspan="1" colspan="1">Australian Breast Cancer Family Study</td><td align="left" rowspan="1" colspan="1">Australia</td><td align="left" rowspan="1" colspan="1">Population-based<xref ref-type="table-fn" rid="nt101">1</xref></td><td align="left" rowspan="1" colspan="1">1335/687</td><td align="left" rowspan="1" colspan="1">754</td><td align="left" rowspan="1" colspan="1">392</td><td align="left" rowspan="1" colspan="1">42.4 (23–69)</td><td align="left" rowspan="1" colspan="1">41.6 (20–68)</td></tr><tr><td align="left" rowspan="1" colspan="1">CECILE</td><td align="left" rowspan="1" colspan="1">CECILE Breast Cancer Study</td><td align="left" rowspan="1" colspan="1">France</td><td align="left" rowspan="1" colspan="1">Population-based</td><td align="left" rowspan="1" colspan="1">938/1026</td><td align="left" rowspan="1" colspan="1">768</td><td align="left" rowspan="1" colspan="1">143</td><td align="left" rowspan="1" colspan="1">54.4 (25–74)</td><td align="left" rowspan="1" colspan="1">54.7 (25–74)</td></tr><tr><td align="left" rowspan="1" colspan="1">CGPS</td><td align="left" rowspan="1" colspan="1">Copenhagen General Population Study</td><td align="left" rowspan="1" colspan="1">Denmark</td><td align="left" rowspan="1" colspan="1">Population-based</td><td align="left" rowspan="1" colspan="1">2388/6704</td><td align="left" rowspan="1" colspan="1">1800</td><td align="left" rowspan="1" colspan="1">357</td><td align="left" rowspan="1" colspan="1">62.0 (27–95)</td><td align="left" rowspan="1" colspan="1">55.7 (20–91)</td></tr><tr><td align="left" rowspan="1" colspan="1">CTS</td><td align="left" rowspan="1" colspan="1">California Teachers Study</td><td align="left" rowspan="1" colspan="1">USA</td><td align="left" rowspan="1" colspan="1">Prospective cohort<xref ref-type="table-fn" rid="nt101">1</xref></td><td align="left" rowspan="1" colspan="1">1252/1226</td><td align="left" rowspan="1" colspan="1">No Info</td><td align="left" rowspan="1" colspan="1">No Info</td><td align="left" rowspan="1" colspan="1">61.8 (32–83)</td><td align="left" rowspan="1" colspan="1">56.2 (26–77)</td></tr><tr><td align="left" rowspan="1" colspan="1">ESTHER</td><td align="left" rowspan="1" colspan="1">ESTHER Breast Cancer Study</td><td align="left" rowspan="1" colspan="1">Germany</td><td align="left" rowspan="1" colspan="1">Population-based</td><td align="left" rowspan="1" colspan="1">433/511</td><td align="left" rowspan="1" colspan="1">293</td><td align="left" rowspan="1" colspan="1">85</td><td align="left" rowspan="1" colspan="1">60.3 (30–79)</td><td align="left" rowspan="1" colspan="1">62.3 (49–75)</td></tr><tr><td align="left" rowspan="1" colspan="1">GENICA</td><td align="left" rowspan="1" colspan="1">Gene Environment Interaction and Breast Cancer in Germany</td><td align="left" rowspan="1" colspan="1">Germany</td><td align="left" rowspan="1" colspan="1">Population-based</td><td align="left" rowspan="1" colspan="1">1021/1015</td><td align="left" rowspan="1" colspan="1">755</td><td align="left" rowspan="1" colspan="1">216</td><td align="left" rowspan="1" colspan="1">58.2 (23–80)</td><td align="left" rowspan="1" colspan="1">58.2 (24–80)</td></tr><tr><td align="left" rowspan="1" colspan="1">GESBC</td><td align="left" rowspan="1" colspan="1">Genetic Epidemiology Study of Breast Cancer by Age 50</td><td align="left" rowspan="1" colspan="1">Germany</td><td align="left" rowspan="1" colspan="1">Population-based</td><td align="left" rowspan="1" colspan="1">586/869</td><td align="left" rowspan="1" colspan="1">248</td><td align="left" rowspan="1" colspan="1">155</td><td align="left" rowspan="1" colspan="1">42.6 (20–50)</td><td align="left" rowspan="1" colspan="1">42.7 (24–52)</td></tr><tr><td align="left" rowspan="1" colspan="1">KBCP</td><td align="left" rowspan="1" colspan="1">Kuopio Breast Cancer Project</td><td align="left" rowspan="1" colspan="1">Finland</td><td align="left" rowspan="1" colspan="1">Population-based</td><td align="left" rowspan="1" colspan="1">466/523</td><td align="left" rowspan="1" colspan="1">328</td><td align="left" rowspan="1" colspan="1">98</td><td align="left" rowspan="1" colspan="1">59.0 (23–92)</td><td align="left" rowspan="1" colspan="1">52.9 (17–77)</td></tr><tr><td align="left" rowspan="1" colspan="1">MARIE</td><td align="left" rowspan="1" colspan="1">Mammary Carcinoma Risk Factor Investigation</td><td align="left" rowspan="1" colspan="1">Germany</td><td align="left" rowspan="1" colspan="1">Population-based</td><td align="left" rowspan="1" colspan="1">2583/5309</td><td align="left" rowspan="1" colspan="1">2008</td><td align="left" rowspan="1" colspan="1">533</td><td align="left" rowspan="1" colspan="1">62.5 (50–75)</td><td align="left" rowspan="1" colspan="1">61.9 (49–75)</td></tr><tr><td align="left" rowspan="1" colspan="1">MCCS</td><td align="left" rowspan="1" colspan="1">Melbourne Collaborative Cohort Study</td><td align="left" rowspan="1" colspan="1">Australia</td><td align="left" rowspan="1" colspan="1">Prospective cohort</td><td align="left" rowspan="1" colspan="1">703/766</td><td align="left" rowspan="1" colspan="1">424</td><td align="left" rowspan="1" colspan="1">141</td><td align="left" rowspan="1" colspan="1">61.4 (37–80)</td><td align="left" rowspan="1" colspan="1">57.2 (38–70)</td></tr><tr><td align="left" rowspan="1" colspan="1">NC-BCFR</td><td align="left" rowspan="1" colspan="1">Northern California Breast Cancer Family Registry</td><td align="left" rowspan="1" colspan="1">USA</td><td align="left" rowspan="1" colspan="1">Population-based</td><td align="left" rowspan="1" colspan="1">268/154</td><td align="left" rowspan="1" colspan="1">203</td><td align="left" rowspan="1" colspan="1">35</td><td align="left" rowspan="1" colspan="1">56.9 (26–65)</td><td align="left" rowspan="1" colspan="1">56.9 (51–65)</td></tr><tr><td align="left" rowspan="1" colspan="1">OFBCR</td><td align="left" rowspan="1" colspan="1">Ontario Familial Breast Cancer Registry</td><td align="left" rowspan="1" colspan="1">Canada</td><td align="left" rowspan="1" colspan="1">Population-based</td><td align="left" rowspan="1" colspan="1">1135/328</td><td align="left" rowspan="1" colspan="1">634</td><td align="left" rowspan="1" colspan="1">260</td><td align="left" rowspan="1" colspan="1">53.8 (22–81)</td><td align="left" rowspan="1" colspan="1">57.4 (40–69)</td></tr><tr><td align="left" rowspan="1" colspan="1">PBCS</td><td align="left" rowspan="1" colspan="1">NCI Polish Breast Cancer Study</td><td align="left" rowspan="1" colspan="1">Poland</td><td align="left" rowspan="1" colspan="1">Population-based</td><td align="left" rowspan="1" colspan="1">2009/2381</td><td align="left" rowspan="1" colspan="1">1204</td><td align="left" rowspan="1" colspan="1">622</td><td align="left" rowspan="1" colspan="1">55.7 (27–75)</td><td align="left" rowspan="1" colspan="1">55.7 (24–75)</td></tr><tr><td align="left" rowspan="1" colspan="1">SASBAC</td><td align="left" rowspan="1" colspan="1">Singapore and Sweden Breast Cancer Study</td><td align="left" rowspan="1" colspan="1">Sweden</td><td align="left" rowspan="1" colspan="1">Population-based</td><td align="left" rowspan="1" colspan="1">1246/1515</td><td align="left" rowspan="1" colspan="1">711</td><td align="left" rowspan="1" colspan="1">160</td><td align="left" rowspan="1" colspan="1">63.0 (50–75)</td><td align="left" rowspan="1" colspan="1">63.4 (49–76)</td></tr><tr><td align="left" rowspan="1" colspan="1">US3SS</td><td align="left" rowspan="1" colspan="1">US Three State Study</td><td align="left" rowspan="1" colspan="1">USA</td><td align="left" rowspan="1" colspan="1">Population-based</td><td align="left" rowspan="1" colspan="1">1444/1274</td><td align="left" rowspan="1" colspan="1">No Info</td><td align="left" rowspan="1" colspan="1">No Info</td><td align="left" rowspan="1" colspan="1">54.3 (29–69)</td><td align="left" rowspan="1" colspan="1">54.3 (27–75)</td></tr><tr><td align="left" rowspan="1" colspan="1">USRT</td><td align="left" rowspan="1" colspan="1">US Radiologic Technologists Study</td><td align="left" rowspan="1" colspan="1">USA</td><td align="left" rowspan="1" colspan="1">Population-based</td><td align="left" rowspan="1" colspan="1">725/1053</td><td align="left" rowspan="1" colspan="1">No Info</td><td align="left" rowspan="1" colspan="1">No info</td><td align="left" rowspan="1" colspan="1">48.9 (22–82)</td><td align="left" rowspan="1" colspan="1">62.8 (42–94)</td></tr><tr><td align="left" rowspan="1" colspan="1">BBCC</td><td align="left" rowspan="1" colspan="1">Bavarian Breast Cancer Cases and Controls</td><td align="left" rowspan="1" colspan="1">Germany</td><td align="left" rowspan="1" colspan="1">Mixed<xref ref-type="table-fn" rid="nt102">2</xref></td><td align="left" rowspan="1" colspan="1">1432/1002</td><td align="left" rowspan="1" colspan="1">967</td><td align="left" rowspan="1" colspan="1">375</td><td align="left" rowspan="1" colspan="1">55.4 (22–96)</td><td align="left" rowspan="1" colspan="1">57.2 (18–100)</td></tr><tr><td align="left" rowspan="1" colspan="1">BBCS</td><td align="left" rowspan="1" colspan="1">British Breast Cancer Study</td><td align="left" rowspan="1" colspan="1">UK</td><td align="left" rowspan="1" colspan="1">Mixed</td><td align="left" rowspan="1" colspan="1">1381/1297</td><td align="left" rowspan="1" colspan="1">No Info</td><td align="left" rowspan="1" colspan="1">No Info</td><td align="left" rowspan="1" colspan="1">53.9 (25–77)</td><td align="left" rowspan="1" colspan="1">51.4 (21–81)</td></tr><tr><td align="left" rowspan="1" colspan="1">kConFab/AOCS</td><td align="left" rowspan="1" colspan="1">Kathleen Cuningham Foundation Consortium for research into Familial Breast Cancer/Australian Ovarian Cancer Study</td><td align="left" rowspan="1" colspan="1">Australia/New Zealand</td><td align="left" rowspan="1" colspan="1">Mixed</td><td align="left" rowspan="1" colspan="1">499/962</td><td align="left" rowspan="1" colspan="1">156</td><td align="left" rowspan="1" colspan="1">65</td><td align="left" rowspan="1" colspan="1">45.0 (20–76)</td><td align="left" rowspan="1" colspan="1">58.3 (20–83)</td></tr><tr><td align="left" rowspan="1" colspan="1">LMBC</td><td align="left" rowspan="1" colspan="1">Leuven Multidisciplinary Breast Centre</td><td align="left" rowspan="1" colspan="1">Belgium</td><td align="left" rowspan="1" colspan="1">Mixed</td><td align="left" rowspan="1" colspan="1">2890/1625</td><td align="left" rowspan="1" colspan="1">2290</td><td align="left" rowspan="1" colspan="1">416</td><td align="left" rowspan="1" colspan="1">56.6 (21–94)</td><td align="left" rowspan="1" colspan="1">44.1 (19–66)</td></tr><tr><td align="left" rowspan="1" colspan="1">MCBCS</td><td align="left" rowspan="1" colspan="1">Mayo Clinic Breast Cancer Study</td><td align="left" rowspan="1" colspan="1">USA</td><td align="left" rowspan="1" colspan="1">Mixed</td><td align="left" rowspan="1" colspan="1">1803/2452</td><td align="left" rowspan="1" colspan="1">1475</td><td align="left" rowspan="1" colspan="1">292</td><td align="left" rowspan="1" colspan="1">56.8 (22–93)</td><td align="left" rowspan="1" colspan="1">56.6 (19–91)</td></tr><tr><td align="left" rowspan="1" colspan="1">MSKCC</td><td align="left" rowspan="1" colspan="1">Memorial Sloan-Kettering Cancer Center Study</td><td align="left" rowspan="1" colspan="1">USA</td><td align="left" rowspan="1" colspan="1">Hospital-based<xref ref-type="table-fn" rid="nt103">3</xref></td><td align="left" rowspan="1" colspan="1">425/455</td><td align="left" rowspan="1" colspan="1">256</td><td align="left" rowspan="1" colspan="1">66</td><td align="left" rowspan="1" colspan="1">47.1 (23–85)</td><td align="left" rowspan="1" colspan="1">47.0 (24–86)</td></tr><tr><td align="left" rowspan="1" colspan="1">SBCS</td><td align="left" rowspan="1" colspan="1">Sheffield Breast Cancer Study</td><td align="left" rowspan="1" colspan="1">UK</td><td align="left" rowspan="1" colspan="1">Mixed</td><td align="left" rowspan="1" colspan="1">1111/1283</td><td align="left" rowspan="1" colspan="1">533</td><td align="left" rowspan="1" colspan="1">175</td><td align="left" rowspan="1" colspan="1">59.0 (28–92)</td><td align="left" rowspan="1" colspan="1">57.7 (45–80)</td></tr><tr><td align="left" rowspan="1" colspan="1">SEARCH</td><td align="left" rowspan="1" colspan="1">Study of Epidemiology and Risk factors in Cancer Heredity</td><td align="left" rowspan="1" colspan="1">UK</td><td align="left" rowspan="1" colspan="1">Mixed</td><td align="left" rowspan="1" colspan="1">6720/6682</td><td align="left" rowspan="1" colspan="1">3758</td><td align="left" rowspan="1" colspan="1">977</td><td align="left" rowspan="1" colspan="1">53.3 (23–88)</td><td align="left" rowspan="1" colspan="1">58.4 (26–81)</td></tr><tr><td align="left" rowspan="1" colspan="1">Total</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">34793/41099</td><td align="left" rowspan="1" colspan="1">19565</td><td align="left" rowspan="1" colspan="1">5563</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt101"><label>1</label><p>Studies that included all, or a random sample of all cases occurring in a geographically defined population during a specified period of time, and controls that were a random sample of the same source population as cases, recruited during the same period of time.</p></fn><fn id="nt102"><label>2</label><p>Studies not strictly population-based or hospital-based.</p></fn><fn id="nt103"><label>3</label><p>Cases diagnosed in a given hospital or hospitals during a specified period of time, and controls that were selected from the recruitment area as the cases during the same period of time.</p></fn></table-wrap-foot></table-wrap><table-wrap id="pgen-1003284-t002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pgen.1003284.t002</object-id><label>Table 2</label><caption><title>Main effects for the epidemiologic variables included in the analyses, derived from population-based studies only<xref ref-type="table-fn" rid="nt104">1</xref>.</title></caption><alternatives><graphic id="pgen-1003284-t002-2" xlink:href="pgen.1003284.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1"></td><td colspan="3" align="left" rowspan="1">All</td><td colspan="3" align="left" rowspan="1"><54 years</td><td colspan="3" align="left" rowspan="1">> = 54 years</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">n (cases/controls)</td><td align="left" rowspan="1" colspan="1">OR (95% CI)</td><td align="left" rowspan="1" colspan="1">p-value</td><td align="left" rowspan="1" colspan="1">n (ca/co)</td><td align="left" rowspan="1" colspan="1">OR (95% CI)</td><td align="left" rowspan="1" colspan="1">p-value</td><td align="left" rowspan="1" colspan="1">n (ca/co)</td><td align="left" rowspan="1" colspan="1">OR (95% CI)</td><td align="left" rowspan="1" colspan="1">p-value</td><td align="left" rowspan="1" colspan="1">Studies included</td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Age at menarche (per 2 years)</td><td align="left" rowspan="1" colspan="1">17185/24136</td><td align="left" rowspan="1" colspan="1">0.93 (0.90–0.95)</td><td align="left" rowspan="1" colspan="1">7.8×10<sup>−9</sup></td><td align="left" rowspan="1" colspan="1">6511/8987</td><td align="left" rowspan="1" colspan="1">0.90 (0.86–0.94)</td><td align="left" rowspan="1" colspan="1">1.0×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">10674/15149</td><td align="left" rowspan="1" colspan="1">0.93 (0.90–0.96)</td><td align="left" rowspan="1" colspan="1">3.3×10<sup>−6</sup></td><td align="left" rowspan="1" colspan="1">ABCFS CECILE CGPS CTS ESTHER GENICA GESBC KBCP MARIE MCCS NC-BCFR OFBCR PBCS SASBAC US3SS USRTS</td></tr><tr><td align="left" rowspan="1" colspan="1">Parous (yes/no)</td><td align="left" rowspan="1" colspan="1">18265/25241</td><td align="left" rowspan="1" colspan="1">0.80 (0.76–0.85)</td><td align="left" rowspan="1" colspan="1">3.9×10<sup>−15</sup></td><td align="left" rowspan="1" colspan="1">6807/9128</td><td align="left" rowspan="1" colspan="1">0.85 (0.78–0.93)</td><td align="left" rowspan="1" colspan="1">0.00051</td><td align="left" rowspan="1" colspan="1">11458/16113</td><td align="left" rowspan="1" colspan="1">0.77 (0.71–0.82)</td><td align="left" rowspan="1" colspan="1">3.7×10<sup>−13</sup></td><td align="left" rowspan="1" colspan="1">ABCFS CECILE CGPS CTS ESTHER GENICA GESBC KBCP MARIE MCCS NC-BCFR OFBCR PBCS SASBAC US3SS USRTS</td></tr><tr><td align="left" rowspan="1" colspan="1">Number of births (among parous)</td><td align="left" rowspan="1" colspan="1">15046/21771</td><td align="left" rowspan="1" colspan="1">0.90 (0.88–0.92)</td><td align="left" rowspan="1" colspan="1">7.9×10<sup>−24</sup></td><td align="left" rowspan="1" colspan="1">5397/7635</td><td align="left" rowspan="1" colspan="1">0.92 (0.89–0.96)</td><td align="left" rowspan="1" colspan="1">0.00023</td><td align="left" rowspan="1" colspan="1">9649/14136</td><td align="left" rowspan="1" colspan="1">0.89 (0.87–0.91)</td><td align="left" rowspan="1" colspan="1">6.5×10<sup>−21</sup></td><td align="left" rowspan="1" colspan="1">ABCFS CECILE CGPS CTS ESTHER GENICA GESBC KBCP MARIE MCCS NC-BCFR OFBCR PBCS SASBAC US3SS USRTS</td></tr><tr><td align="left" rowspan="1" colspan="1">Age at first birth (per 5 years)</td><td align="left" rowspan="1" colspan="1">14671/21322</td><td align="left" rowspan="1" colspan="1">1.08 (1.06–1.11)</td><td align="left" rowspan="1" colspan="1">4.6×10<sup>−11</sup></td><td align="left" rowspan="1" colspan="1">5327/7550</td><td align="left" rowspan="1" colspan="1">1.06 (1.02–1.11)</td><td align="left" rowspan="1" colspan="1">0.0031</td><td align="left" rowspan="1" colspan="1">9344/13772</td><td align="left" rowspan="1" colspan="1">1.10 (1.07–1.14)</td><td align="left" rowspan="1" colspan="1">3.4×10<sup>−10</sup></td><td align="left" rowspan="1" colspan="1">ABCFS CECILE CGPS CTS GENICA GESBC KBCP MARIE MCCS NC-BCFR OFBCR PBCS SASBAC US3SS USRTS</td></tr><tr><td align="left" rowspan="1" colspan="1">Ever breastfed (yes/no)</td><td align="left" rowspan="1" colspan="1">11022/13182</td><td align="left" rowspan="1" colspan="1">0.90 (0.85–0.96)</td><td align="left" rowspan="1" colspan="1">0.0013</td><td align="left" rowspan="1" colspan="1">4174/4267</td><td align="left" rowspan="1" colspan="1">0.87 (0.79–0.97)</td><td align="left" rowspan="1" colspan="1">0.011</td><td align="left" rowspan="1" colspan="1">6848/8915</td><td align="left" rowspan="1" colspan="1">0.90 (0.83–0.97)</td><td align="left" rowspan="1" colspan="1">0.0073</td><td align="left" rowspan="1" colspan="1">ABCFS CECILE GENICA GESBC KBCP MARIE MCCS NC-BCFR OFBCR PBCS SASBAC US3SS</td></tr><tr><td align="left" rowspan="1" colspan="1">Usual adult BMI (per 5 units)</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">5051/4905</td><td align="left" rowspan="1" colspan="1">0.92 (0.88–0.97)</td><td align="left" rowspan="1" colspan="1">0.0010</td><td align="left" rowspan="1" colspan="1">7557/9832</td><td align="left" rowspan="1" colspan="1">1.01 (0.97–1.05)</td><td align="left" rowspan="1" colspan="1">0.550</td><td align="left" rowspan="1" colspan="1"><54: ABCFS CECILE GENICA GESBC KBCP MARIE NC-BCFR OFBCR PBCS SASBAC US3SS/> = 54: ABCFS CECILE GENICA KBCP MARIE NC-BCFR OFBCR PBCS SASBAC US3SS</td></tr><tr><td align="left" rowspan="1" colspan="1">Usual adult height (per 5 cm)</td><td align="left" rowspan="1" colspan="1">15861/18464</td><td align="left" rowspan="1" colspan="1">1.07 (1.05–1.09)</td><td align="left" rowspan="1" colspan="1">4.1×10<sup>−13</sup></td><td align="left" rowspan="1" colspan="1">6096/5990</td><td align="left" rowspan="1" colspan="1">1.05 (1.02–1.08)</td><td align="left" rowspan="1" colspan="1">0.0017</td><td align="left" rowspan="1" colspan="1">9765/12474</td><td align="left" rowspan="1" colspan="1">1.08 (1.06–1.11)</td><td align="left" rowspan="1" colspan="1">3.4×10<sup>−12</sup></td><td align="left" rowspan="1" colspan="1">ABCFS CECILE CTS ESTHER GENICA GESBC KBCP MARIE MCCS NC-BCFR OFBCR PBCS SASBAC US3SS USRTS</td></tr><tr><td align="left" rowspan="1" colspan="1">Ever use of oral contraceptives(yes/no)</td><td align="left" rowspan="1" colspan="1">12812/15667</td><td align="left" rowspan="1" colspan="1">0.99 (0.93–1.05)</td><td align="left" rowspan="1" colspan="1">0.687</td><td align="left" rowspan="1" colspan="1">4762/4961</td><td align="left" rowspan="1" colspan="1">1.01 (0.91–1.13)</td><td align="left" rowspan="1" colspan="1">0.831</td><td align="left" rowspan="1" colspan="1">8050/10706</td><td align="left" rowspan="1" colspan="1">0.99 (0.92–1.06)</td><td align="left" rowspan="1" colspan="1">0.688</td><td align="left" rowspan="1" colspan="1">ABCFS CECILE ESTHER GENICA GESBC KBCP MARIE MCCS NC-BCFR PBCS SASBAC US3SS</td></tr><tr><td align="left" rowspan="1" colspan="1">Duration of oral contraceptive use (per 5 years)</td><td align="left" rowspan="1" colspan="1">12671/15478</td><td align="left" rowspan="1" colspan="1">1.02 (1.00–1.04)</td><td align="left" rowspan="1" colspan="1">0.021</td><td align="left" rowspan="1" colspan="1">4714/4914</td><td align="left" rowspan="1" colspan="1">1.05</td><td align="left" rowspan="1" colspan="1">(1.01–1.08)</td><td align="left" rowspan="1" colspan="1">0.0067</td><td align="left" rowspan="1" colspan="1">7957/10564</td><td align="left" rowspan="1" colspan="1">1.01 (0.99–1.04) 0.336</td><td align="left" rowspan="1" colspan="1">ABCFS CECILE ESTHER GENICA GESBC KBCP MARIE MCCS NC-BCFR PBCS SASBAC US3SS</td></tr><tr><td align="left" rowspan="1" colspan="1">Current use of combined estrogen-progestagen therapy</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">6425/9225</td><td align="left" rowspan="1" colspan="1">1.76(1.61–1.94)</td><td align="left" rowspan="1" colspan="1">6.9×10<sup>−33</sup></td><td align="left" rowspan="1" colspan="1">CECILE GENICA MARIE PBCS SASBAC US3SS</td></tr><tr><td align="left" rowspan="1" colspan="1">Current use of estrogen-only therapy</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">6689/9457</td><td align="left" rowspan="1" colspan="1">1.19 (1.07–1.33)</td><td align="left" rowspan="1" colspan="1">0.001</td><td align="left" rowspan="1" colspan="1">CECILE GENICA MARIE PBCS SASBAC US3SS</td></tr><tr><td align="left" rowspan="1" colspan="1">Duration of combined estrogen-progestagen therapy in current users (per 5 years)</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">6337/9130</td><td align="left" rowspan="1" colspan="1">1.25 (1.20–1.30)</td><td align="left" rowspan="1" colspan="1">9.6×10<sup>−27</sup></td><td align="left" rowspan="1" colspan="1">CECILE GENICA MARIE PBCS SASBAC US3SS</td></tr><tr><td align="left" rowspan="1" colspan="1">Duration of estrogen-only therapy in current users (per 5 years)</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">6596/9332</td><td align="left" rowspan="1" colspan="1">1.07 (1.03–1.12)</td><td align="left" rowspan="1" colspan="1">9.8×10<sup>−4</sup></td><td align="left" rowspan="1" colspan="1">CECILE GENICA MARIE PBCS SASBAC US3SS</td></tr><tr><td align="left" rowspan="1" colspan="1">Lifetime intake of alcohol<xref ref-type="table-fn" rid="nt105">2</xref> (per 10 g/day)</td><td align="left" rowspan="1" colspan="1">6763/10273</td><td align="left" rowspan="1" colspan="1">1.03 (1.00–1.05)</td><td align="left" rowspan="1" colspan="1">0.035</td><td align="left" rowspan="1" colspan="1">2280/3162</td><td align="left" rowspan="1" colspan="1">1.05 (1.00–1.09)</td><td align="left" rowspan="1" colspan="1">0.0443</td><td align="left" rowspan="1" colspan="1">4483/7111</td><td align="left" rowspan="1" colspan="1">1.02 (0.99–1.05)</td><td align="left" rowspan="1" colspan="1">0.167</td><td align="left" rowspan="1" colspan="1">CECILE GESBC MARIE MCCS PBCS</td></tr><tr><td align="left" rowspan="1" colspan="1">Smoking (ever/never)</td><td align="left" rowspan="1" colspan="1">13725/16189</td><td align="left" rowspan="1" colspan="1">1.02 (0.98–1.07)</td><td align="left" rowspan="1" colspan="1">0.344</td><td align="left" rowspan="1" colspan="1">5292/5284</td><td align="left" rowspan="1" colspan="1">1.05 (0.97–1.14)</td><td align="left" rowspan="1" colspan="1">0.237</td><td align="left" rowspan="1" colspan="1">8433/10905</td><td align="left" rowspan="1" colspan="1">1.02 (0.96–1.08)</td><td align="left" rowspan="1" colspan="1">0.571</td><td align="left" rowspan="1" colspan="1">ABCFS CECILE ESTHER GENICA GESBC KBCP MARIE MCCS OFBCR PBCS SASBAC US3SS</td></tr><tr><td align="left" rowspan="1" colspan="1">Smoking amount(per 10 pack-years)</td><td align="left" rowspan="1" colspan="1">11890/14044</td><td align="left" rowspan="1" colspan="1">1.01 (0.99–1.03)</td><td align="left" rowspan="1" colspan="1">0.447</td><td align="left" rowspan="1" colspan="1">5030/5045</td><td align="left" rowspan="1" colspan="1">1.04 (1.00–1.08)</td><td align="left" rowspan="1" colspan="1">0.032</td><td align="left" rowspan="1" colspan="1">6860/8999</td><td align="left" rowspan="1" colspan="1">1.00 (0.98–1.03)</td><td align="left" rowspan="1" colspan="1">0.837</td><td align="left" rowspan="1" colspan="1">ABCFS CECILE GENICA GESBC KBCP MARIE MCCS OFBCR PBCS US3SS</td></tr><tr><td align="left" rowspan="1" colspan="1">Physical activity in year before reference date (square root of h/week)<xref ref-type="table-fn" rid="nt106">3</xref></td><td align="left" rowspan="1" colspan="1">7211/1052</td><td align="left" rowspan="1" colspan="1">0.92 (0.87–0.97)</td><td align="left" rowspan="1" colspan="1">0.005</td><td align="left" rowspan="1" colspan="1">1759/1996</td><td align="left" rowspan="1" colspan="1">0.96 (0.89–1.02)</td><td align="left" rowspan="1" colspan="1">0.189</td><td align="left" rowspan="1" colspan="1">5452/8056</td><td align="left" rowspan="1" colspan="1">0.96 (0.93–1.00)</td><td align="left" rowspan="1" colspan="1">0.032</td><td align="left" rowspan="1" colspan="1">CECILE GENICA MARIE SASBAC US3SS</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt104"><label>1</label><p>Model used for the assessment of epidemiologic main effects: logit(Pr(breast cancer|risk factor)) = β<sub>0</sub>+β<sub>1</sub>*study + β<sub>2</sub>*reference_age + β<sub>3</sub>*risk_factor.</p></fn><fn id="nt105"><label>2</label><p>Mean lifetime alcohol intake derived from duration and amount of alcohol intake in g/day at different age periods.</p></fn><fn id="nt106"><label>3</label><p>For physical activity, square root (hours/week) was used since this model gave the highest likelihood when modeling the marginal association using fractional polynomials (Royston P, Ambler G, Sauerbrei W. The use of fractional polynomials to model continuous risk variables in epidemiology. Int J Epidemiol 1999;28(5):964-74.) and was further adjusted for menopausal status.</p></fn></table-wrap-foot></table-wrap><p>Except for <italic>TGFB1</italic>-rs1982073, all SNPs showed highly significant associations with breast cancer overall (<xref ref-type="table" rid="pgen-1003284-t003">Table 3</xref>). Eleven SNPs showed evidence of heterogeneity in the OR by ER status at p<0.01. The per-allele OR overall and for subsets of women with information available for the risk factors considered were very similar to those previously published and provided no evidence of bias in OR estimates related to data availability (data not shown).</p><table-wrap id="pgen-1003284-t003" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pgen.1003284.t003</object-id><label>Table 3</label><caption><title>Associations between selected SNPs and breast cancer risk in Caucasians, overall and by ER status (estimated per-allele odds ratios and 95% confidence intervals)<xref ref-type="table-fn" rid="nt107">1</xref>.</title></caption><alternatives><graphic id="pgen-1003284-t003-3" xlink:href="pgen.1003284.t003"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1">SNP</td><td align="left" rowspan="1" colspan="1">Locus</td><td align="left" rowspan="1" colspan="1">Gene</td><td align="left" rowspan="1" colspan="1">Allele</td><td align="left" rowspan="1" colspan="1">MAF<xref ref-type="table-fn" rid="nt111">5</xref></td><td align="left" rowspan="1" colspan="1">N Cases/Controls</td><td align="left" rowspan="1" colspan="1">OR per allele (95%CI)</td><td align="left" rowspan="1" colspan="1">P trend</td><td align="left" rowspan="1" colspan="1">P het ER status<xref ref-type="table-fn" rid="nt112">6</xref></td><td align="left" rowspan="1" colspan="1">ER+n (ca)</td><td align="left" rowspan="1" colspan="1">ER+OR (95%CI)</td><td align="left" rowspan="1" colspan="1">P trend</td><td align="left" rowspan="1" colspan="1">ER-n (ca)</td><td align="left" rowspan="1" colspan="1">ER-OR (95%CI)</td><td align="left" rowspan="1" colspan="1">P trend</td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">rs11249433</td><td align="left" rowspan="1" colspan="1">1p11</td><td align="left" rowspan="1" colspan="1">-</td><td align="left" rowspan="1" colspan="1">T/C</td><td align="left" rowspan="1" colspan="1">0.401</td><td align="left" rowspan="1" colspan="1">29502/31361</td><td align="left" rowspan="1" colspan="1">1.11 (1.09–1.14)</td><td align="left" rowspan="1" colspan="1">5.5×10<sup>−19</sup></td><td align="left" rowspan="1" colspan="1">3.6×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">17670</td><td align="left" rowspan="1" colspan="1">1.13 (1.10–1.16)</td><td align="left" rowspan="1" colspan="1">7.8×10<sup>−18</sup></td><td align="left" rowspan="1" colspan="1">5030</td><td align="left" rowspan="1" colspan="1">1.03 (0.98–1.07)</td><td align="left" rowspan="1" colspan="1">0.223</td></tr><tr><td align="left" rowspan="1" colspan="1">rs17468277<xref ref-type="table-fn" rid="nt108">2</xref></td><td align="left" rowspan="1" colspan="1">2q33</td><td align="left" rowspan="1" colspan="1"><italic>CASP8</italic></td><td align="left" rowspan="1" colspan="1">C/T</td><td align="left" rowspan="1" colspan="1">0.127</td><td align="left" rowspan="1" colspan="1">29884/35245</td><td align="left" rowspan="1" colspan="1">0.94 (0.91–0.97)</td><td align="left" rowspan="1" colspan="1">0.00022</td><td align="left" rowspan="1" colspan="1">0.019</td><td align="left" rowspan="1" colspan="1">17589</td><td align="left" rowspan="1" colspan="1">0.97 (0.93–1.01)</td><td align="left" rowspan="1" colspan="1">0.090</td><td align="left" rowspan="1" colspan="1">4956</td><td align="left" rowspan="1" colspan="1">0.88 (0.83–0.94)</td><td align="left" rowspan="1" colspan="1">0.0025</td></tr><tr><td align="left" rowspan="1" colspan="1">rs13387042</td><td align="left" rowspan="1" colspan="1">2q35</td><td align="left" rowspan="1" colspan="1"><italic>-</italic></td><td align="left" rowspan="1" colspan="1">A/G</td><td align="left" rowspan="1" colspan="1">0.484</td><td align="left" rowspan="1" colspan="1">29732/34911</td><td align="left" rowspan="1" colspan="1">0.88 (0.86–0.90)</td><td align="left" rowspan="1" colspan="1">1.3×10<sup>−26</sup></td><td align="left" rowspan="1" colspan="1">0.00030</td><td align="left" rowspan="1" colspan="1">17859</td><td align="left" rowspan="1" colspan="1">0.87 (0.85–0.90)</td><td align="left" rowspan="1" colspan="1">1.8×10<sup>−23</sup></td><td align="left" rowspan="1" colspan="1">5085</td><td align="left" rowspan="1" colspan="1">0.94 (0.90–0.98)</td><td align="left" rowspan="1" colspan="1">0.0053</td></tr><tr><td align="left" rowspan="1" colspan="1">rs4973768</td><td align="left" rowspan="1" colspan="1">3p24</td><td align="left" rowspan="1" colspan="1"><italic>SLC4A7</italic></td><td align="left" rowspan="1" colspan="1">C/T</td><td align="left" rowspan="1" colspan="1">0.466</td><td align="left" rowspan="1" colspan="1">29300/33940</td><td align="left" rowspan="1" colspan="1">1.10 (1.08–1.13)</td><td align="left" rowspan="1" colspan="1">5.8×10<sup>−17</sup></td><td align="left" rowspan="1" colspan="1">0.005</td><td align="left" rowspan="1" colspan="1">17643</td><td align="left" rowspan="1" colspan="1">1.11 (1.08–1.14)</td><td align="left" rowspan="1" colspan="1">5.7×10<sup>−15</sup></td><td align="left" rowspan="1" colspan="1">5037</td><td align="left" rowspan="1" colspan="1">1.04 (1.00–1.09)</td><td align="left" rowspan="1" colspan="1">0.057</td></tr><tr><td align="left" rowspan="1" colspan="1">rs10941679</td><td align="left" rowspan="1" colspan="1">5p12</td><td align="left" rowspan="1" colspan="1"><italic>-</italic></td><td align="left" rowspan="1" colspan="1">A/G</td><td align="left" rowspan="1" colspan="1">0.256</td><td align="left" rowspan="1" colspan="1">29511/34613</td><td align="left" rowspan="1" colspan="1">1.12 (1.09–1.15)</td><td align="left" rowspan="1" colspan="1">1.3×10<sup>−18</sup></td><td align="left" rowspan="1" colspan="1">8.8×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">17688</td><td align="left" rowspan="1" colspan="1">1.14 (1.11–1.18)</td><td align="left" rowspan="1" colspan="1">7.2×10<sup>−18</sup></td><td align="left" rowspan="1" colspan="1">5110</td><td align="left" rowspan="1" colspan="1">1.03 (0.98–1.08)</td><td align="left" rowspan="1" colspan="1">0.288</td></tr><tr><td align="left" rowspan="1" colspan="1">rs889312</td><td align="left" rowspan="1" colspan="1">5q11</td><td align="left" rowspan="1" colspan="1"><italic>MAP3K1</italic></td><td align="left" rowspan="1" colspan="1">A/C</td><td align="left" rowspan="1" colspan="1">0.278</td><td align="left" rowspan="1" colspan="1">28387/29030</td><td align="left" rowspan="1" colspan="1">1.11 (1.08–1.14)</td><td align="left" rowspan="1" colspan="1">4.1×10<sup>−15</sup></td><td align="left" rowspan="1" colspan="1">0.038</td><td align="left" rowspan="1" colspan="1">16446</td><td align="left" rowspan="1" colspan="1">1.12 (1.09–1.16)</td><td align="left" rowspan="1" colspan="1">1.7×10<sup>−13</sup></td><td align="left" rowspan="1" colspan="1">4740</td><td align="left" rowspan="1" colspan="1">1.06 (1.01–1.11)</td><td align="left" rowspan="1" colspan="1">0.025</td></tr><tr><td align="left" rowspan="1" colspan="1">rs12662670</td><td align="left" rowspan="1" colspan="1">6q25</td><td align="left" rowspan="1" colspan="1"><italic>ESR1</italic></td><td align="left" rowspan="1" colspan="1">T/G</td><td align="left" rowspan="1" colspan="1">0.076</td><td align="left" rowspan="1" colspan="1">16518/15659</td><td align="left" rowspan="1" colspan="1">1.16 (1.09–1.23)</td><td align="left" rowspan="1" colspan="1">4.8×10<sup>−7</sup></td><td align="left" rowspan="1" colspan="1">0.073</td><td align="left" rowspan="1" colspan="1">10810</td><td align="left" rowspan="1" colspan="1">1.12 (1.05–1.20)</td><td align="left" rowspan="1" colspan="1">0.00061</td><td align="left" rowspan="1" colspan="1">2705</td><td align="left" rowspan="1" colspan="1">1.22 (1.10–1.35)</td><td align="left" rowspan="1" colspan="1">0.00023</td></tr><tr><td align="left" rowspan="1" colspan="1">rs2046210</td><td align="left" rowspan="1" colspan="1">6q25</td><td align="left" rowspan="1" colspan="1"><italic>ESR1</italic></td><td align="left" rowspan="1" colspan="1">C/T</td><td align="left" rowspan="1" colspan="1">0.341</td><td align="left" rowspan="1" colspan="1">28196/29938</td><td align="left" rowspan="1" colspan="1">1.09 (1.06–1.12)</td><td align="left" rowspan="1" colspan="1">1.4×10<sup>−11</sup></td><td align="left" rowspan="1" colspan="1">6.4×10<sup>−7</sup></td><td align="left" rowspan="1" colspan="1">16713</td><td align="left" rowspan="1" colspan="1">1.06 (1.03–1.09)</td><td align="left" rowspan="1" colspan="1">6.42×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">4667</td><td align="left" rowspan="1" colspan="1">1.21 (1.16–1.27)</td><td align="left" rowspan="1" colspan="1">1.2×10<sup>−15</sup></td></tr><tr><td align="left" rowspan="1" colspan="1">rs13281615</td><td align="left" rowspan="1" colspan="1">8q24</td><td align="left" rowspan="1" colspan="1"><italic>-</italic></td><td align="left" rowspan="1" colspan="1">A/G</td><td align="left" rowspan="1" colspan="1">0.406</td><td align="left" rowspan="1" colspan="1">27252/26610</td><td align="left" rowspan="1" colspan="1">1.13 (1.10–1.16)</td><td align="left" rowspan="1" colspan="1">7.5×10<sup>−23</sup></td><td align="left" rowspan="1" colspan="1">0.100</td><td align="left" rowspan="1" colspan="1">16067</td><td align="left" rowspan="1" colspan="1">1.14 (1.11–1.17)</td><td align="left" rowspan="1" colspan="1">1.2×10<sup>−18</sup></td><td align="left" rowspan="1" colspan="1">4635</td><td align="left" rowspan="1" colspan="1">1.08 (1.03–1.13)</td><td align="left" rowspan="1" colspan="1">0.016</td></tr><tr><td align="left" rowspan="1" colspan="1">rs1011970</td><td align="left" rowspan="1" colspan="1">9p21</td><td align="left" rowspan="1" colspan="1"><italic>CDKN2A/B</italic></td><td align="left" rowspan="1" colspan="1">G/T</td><td align="left" rowspan="1" colspan="1">0.162</td><td align="left" rowspan="1" colspan="1">23531/28641</td><td align="left" rowspan="1" colspan="1">1.09 (1.05–1.12)</td><td align="left" rowspan="1" colspan="1">2.2×10<sup>−6</sup></td><td align="left" rowspan="1" colspan="1">0.073</td><td align="left" rowspan="1" colspan="1">14565</td><td align="left" rowspan="1" colspan="1">1.07 (1.03–1.11)</td><td align="left" rowspan="1" colspan="1">0.00010</td><td align="left" rowspan="1" colspan="1">4141</td><td align="left" rowspan="1" colspan="1">1.13 (1.06–1.21)</td><td align="left" rowspan="1" colspan="1">9.5×10<sup>−5</sup></td></tr><tr><td align="left" rowspan="1" colspan="1">rs865686</td><td align="left" rowspan="1" colspan="1">9q31</td><td align="left" rowspan="1" colspan="1"><italic>-</italic></td><td align="left" rowspan="1" colspan="1">T/G</td><td align="left" rowspan="1" colspan="1">0.381</td><td align="left" rowspan="1" colspan="1">28077/31963</td><td align="left" rowspan="1" colspan="1">0.90 (0.88–0.92)</td><td align="left" rowspan="1" colspan="1">1.2×10<sup>−17</sup></td><td align="left" rowspan="1" colspan="1">6.1×10<sup>−6</sup></td><td align="left" rowspan="1" colspan="1">17037</td><td align="left" rowspan="1" colspan="1">0.88 (0.86–0.91)</td><td align="left" rowspan="1" colspan="1">4.9×10<sup>−17</sup></td><td align="left" rowspan="1" colspan="1">4505</td><td align="left" rowspan="1" colspan="1">0.99 (0.94–1.03)</td><td align="left" rowspan="1" colspan="1">0.541</td></tr><tr><td align="left" rowspan="1" colspan="1">rs10995190</td><td align="left" rowspan="1" colspan="1">10q21</td><td align="left" rowspan="1" colspan="1"><italic>ZNF365</italic></td><td align="left" rowspan="1" colspan="1">G/A</td><td align="left" rowspan="1" colspan="1">0.159</td><td align="left" rowspan="1" colspan="1">22672/28655</td><td align="left" rowspan="1" colspan="1">0.88 (0.85–0.91)</td><td align="left" rowspan="1" colspan="1">1.6×10<sup>−12</sup></td><td align="left" rowspan="1" colspan="1">0.218</td><td align="left" rowspan="1" colspan="1">13876</td><td align="left" rowspan="1" colspan="1">0.88 (0.84–0.91)</td><td align="left" rowspan="1" colspan="1">7.5×10<sup>−10</sup></td><td align="left" rowspan="1" colspan="1">4028</td><td align="left" rowspan="1" colspan="1">0.91 (0.85–0.98)</td><td align="left" rowspan="1" colspan="1">0.0081</td></tr><tr><td align="left" rowspan="1" colspan="1">rs704010</td><td align="left" rowspan="1" colspan="1">10q22</td><td align="left" rowspan="1" colspan="1"><italic>ZMIZ1</italic></td><td align="left" rowspan="1" colspan="1">G/A</td><td align="left" rowspan="1" colspan="1">0.383</td><td align="left" rowspan="1" colspan="1">23456/28651</td><td align="left" rowspan="1" colspan="1">1.06 (1.03–1.09)</td><td align="left" rowspan="1" colspan="1">2.4×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">0.150</td><td align="left" rowspan="1" colspan="1">14528</td><td align="left" rowspan="1" colspan="1">1.05 (1.02–1.09)</td><td align="left" rowspan="1" colspan="1">0.00079</td><td align="left" rowspan="1" colspan="1">4132</td><td align="left" rowspan="1" colspan="1">1.02 (0.97–1.07)</td><td align="left" rowspan="1" colspan="1">0.468</td></tr><tr><td align="left" rowspan="1" colspan="1">rs2981582</td><td align="left" rowspan="1" colspan="1">10q26</td><td align="left" rowspan="1" colspan="1"><italic>FGFR2</italic></td><td align="left" rowspan="1" colspan="1">C/T</td><td align="left" rowspan="1" colspan="1">0.383</td><td align="left" rowspan="1" colspan="1">31807/33940</td><td align="left" rowspan="1" colspan="1">1.23 (1.20–1.26)</td><td align="left" rowspan="1" colspan="1">7.2×10<sup>−73</sup></td><td align="left" rowspan="1" colspan="1">2.0×10<sup>−18</sup></td><td align="left" rowspan="1" colspan="1">17973</td><td align="left" rowspan="1" colspan="1">1.28 (1.25–1.32)</td><td align="left" rowspan="1" colspan="1">2.1×10<sup>−70</sup></td><td align="left" rowspan="1" colspan="1">5141</td><td align="left" rowspan="1" colspan="1">1.04 (1.00–1.09</td><td align="left" rowspan="1" colspan="1">0.053</td></tr><tr><td align="left" rowspan="1" colspan="1">rs614367</td><td align="left" rowspan="1" colspan="1">11q13</td><td align="left" rowspan="1" colspan="1"><italic>-</italic></td><td align="left" rowspan="1" colspan="1">C/T</td><td align="left" rowspan="1" colspan="1">0.152</td><td align="left" rowspan="1" colspan="1">21068/22008</td><td align="left" rowspan="1" colspan="1">1.21 (1.16–1.25)</td><td align="left" rowspan="1" colspan="1">4.8×10<sup>−23</sup></td><td align="left" rowspan="1" colspan="1">1.4×10<sup>−9</sup></td><td align="left" rowspan="1" colspan="1">12749</td><td align="left" rowspan="1" colspan="1">1.26 (1.21–1.32)</td><td align="left" rowspan="1" colspan="1">8.0×10<sup>−26</sup></td><td align="left" rowspan="1" colspan="1">3777</td><td align="left" rowspan="1" colspan="1">1.02 (0.96–1.10)</td><td align="left" rowspan="1" colspan="1">0.509</td></tr><tr><td align="left" rowspan="1" colspan="1">rs3817198</td><td align="left" rowspan="1" colspan="1">11p15</td><td align="left" rowspan="1" colspan="1"><italic>LSP1</italic></td><td align="left" rowspan="1" colspan="1">T/C</td><td align="left" rowspan="1" colspan="1">0.312</td><td align="left" rowspan="1" colspan="1">28404/28438</td><td align="left" rowspan="1" colspan="1">1.09 (1.06–1.12)</td><td align="left" rowspan="1" colspan="1">5.6×10<sup>−11</sup></td><td align="left" rowspan="1" colspan="1">0.543</td><td align="left" rowspan="1" colspan="1">16395</td><td align="left" rowspan="1" colspan="1">1.08 (1.04–1.11)</td><td align="left" rowspan="1" colspan="1">3.1×10<sup>−6</sup></td><td align="left" rowspan="1" colspan="1">4743</td><td align="left" rowspan="1" colspan="1">1.07 (1.02–1.12)</td><td align="left" rowspan="1" colspan="1">0.0076</td></tr><tr><td align="left" rowspan="1" colspan="1">rs10771399<xref ref-type="table-fn" rid="nt109">3</xref></td><td align="left" rowspan="1" colspan="1">12p11</td><td align="left" rowspan="1" colspan="1"><italic>PTHLH</italic></td><td align="left" rowspan="1" colspan="1">T/C</td><td align="left" rowspan="1" colspan="1">0.117</td><td align="left" rowspan="1" colspan="1">21182/18129</td><td align="left" rowspan="1" colspan="1">0.84 (0.80–0.88)</td><td align="left" rowspan="1" colspan="1">1.4×10<sup>−12</sup></td><td align="left" rowspan="1" colspan="1">0.590</td><td align="left" rowspan="1" colspan="1">14392</td><td align="left" rowspan="1" colspan="1">0.86 (0.82–0.91)</td><td align="left" rowspan="1" colspan="1">3.3×10<sup>−8</sup></td><td align="left" rowspan="1" colspan="1">3455</td><td align="left" rowspan="1" colspan="1">0.82 (0.75–0.90)</td><td align="left" rowspan="1" colspan="1">3.08×10<sup>−5</sup></td></tr><tr><td align="left" rowspan="1" colspan="1">rs1292011</td><td align="left" rowspan="1" colspan="1">12q24</td><td align="left" rowspan="1" colspan="1"><italic>-</italic></td><td align="left" rowspan="1" colspan="1">T/C</td><td align="left" rowspan="1" colspan="1">0.415</td><td align="left" rowspan="1" colspan="1">17780/14298</td><td align="left" rowspan="1" colspan="1">0.94 (0.91–0.97)</td><td align="left" rowspan="1" colspan="1">0.00026</td><td align="left" rowspan="1" colspan="1">0.0056</td><td align="left" rowspan="1" colspan="1">12424</td><td align="left" rowspan="1" colspan="1">0.92 (0.89–0.96)</td><td align="left" rowspan="1" colspan="1">2.6×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">2935</td><td align="left" rowspan="1" colspan="1">1.00 (0.94–1.06)</td><td align="left" rowspan="1" colspan="1">0.887</td></tr><tr><td align="left" rowspan="1" colspan="1">rs999737<xref ref-type="table-fn" rid="nt110">4</xref></td><td align="left" rowspan="1" colspan="1">14q24</td><td align="left" rowspan="1" colspan="1"><italic>RAD51L1</italic></td><td align="left" rowspan="1" colspan="1">T/A</td><td align="left" rowspan="1" colspan="1">0.230</td><td align="left" rowspan="1" colspan="1">29189/31066</td><td align="left" rowspan="1" colspan="1">0.93 (0.91–0.96)</td><td align="left" rowspan="1" colspan="1">1.3×10<sup>−6</sup></td><td align="left" rowspan="1" colspan="1">0.475</td><td align="left" rowspan="1" colspan="1">17493</td><td align="left" rowspan="1" colspan="1">0.93 (0.90–0.96)</td><td align="left" rowspan="1" colspan="1">1.8×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">4985</td><td align="left" rowspan="1" colspan="1">0.95 (0.90–1.00)</td><td align="left" rowspan="1" colspan="1">0.062</td></tr><tr><td align="left" rowspan="1" colspan="1">rs3803662</td><td align="left" rowspan="1" colspan="1">16q12</td><td align="left" rowspan="1" colspan="1"><italic>TOX3</italic></td><td align="left" rowspan="1" colspan="1">C/T</td><td align="left" rowspan="1" colspan="1">0.262</td><td align="left" rowspan="1" colspan="1">27700/29192</td><td align="left" rowspan="1" colspan="1">1.24 (1.21–1.27)</td><td align="left" rowspan="1" colspan="1">8.3×10<sup>−58</sup></td><td align="left" rowspan="1" colspan="1">0.0036</td><td align="left" rowspan="1" colspan="1">15802</td><td align="left" rowspan="1" colspan="1">1.26 (1.22–1.30)</td><td align="left" rowspan="1" colspan="1">1.0×10<sup>−45</sup></td><td align="left" rowspan="1" colspan="1">4659</td><td align="left" rowspan="1" colspan="1">1.17 (1.12–1.23)</td><td align="left" rowspan="1" colspan="1">3.6×10<sup>−10</sup></td></tr><tr><td align="left" rowspan="1" colspan="1">rs6504950</td><td align="left" rowspan="1" colspan="1">17q23</td><td align="left" rowspan="1" colspan="1"><italic>COX11</italic></td><td align="left" rowspan="1" colspan="1">G/A</td><td align="left" rowspan="1" colspan="1">0.276</td><td align="left" rowspan="1" colspan="1">29787/34101</td><td align="left" rowspan="1" colspan="1">0.93 (0.91–0.96)</td><td align="left" rowspan="1" colspan="1">2.2×10<sup>−7</sup></td><td align="left" rowspan="1" colspan="1">0.00057</td><td align="left" rowspan="1" colspan="1">18028</td><td align="left" rowspan="1" colspan="1">0.92 (0.89–0.95)</td><td align="left" rowspan="1" colspan="1">1.3×10<sup>−7</sup></td><td align="left" rowspan="1" colspan="1">5100</td><td align="left" rowspan="1" colspan="1">1.01 (0.96–1.06)</td><td align="left" rowspan="1" colspan="1">0.791</td></tr><tr><td align="left" rowspan="1" colspan="1">rs1982073</td><td align="left" rowspan="1" colspan="1">19q13</td><td align="left" rowspan="1" colspan="1"><italic>TGFB1</italic></td><td align="left" rowspan="1" colspan="1">T/C</td><td align="left" rowspan="1" colspan="1">0.376</td><td align="left" rowspan="1" colspan="1">17012/22985</td><td align="left" rowspan="1" colspan="1">1.04 (1.01–1.07)</td><td align="left" rowspan="1" colspan="1">0.020</td><td align="left" rowspan="1" colspan="1">0.314</td><td align="left" rowspan="1" colspan="1">9889</td><td align="left" rowspan="1" colspan="1">1.03 (1.00–1.07)</td><td align="left" rowspan="1" colspan="1">0.082</td><td align="left" rowspan="1" colspan="1">3032</td><td align="left" rowspan="1" colspan="1">1.07 (1.01–1.13)</td><td align="left" rowspan="1" colspan="1">0.018</td></tr><tr><td align="left" rowspan="1" colspan="1">rs2823093</td><td align="left" rowspan="1" colspan="1">21q21</td><td align="left" rowspan="1" colspan="1"><italic>NRIP1</italic></td><td align="left" rowspan="1" colspan="1">G/A</td><td align="left" rowspan="1" colspan="1">0.267</td><td align="left" rowspan="1" colspan="1">18655/16443</td><td align="left" rowspan="1" colspan="1">0.95 (0.92–0.98)</td><td align="left" rowspan="1" colspan="1">0.0038</td><td align="left" rowspan="1" colspan="1">0.121</td><td align="left" rowspan="1" colspan="1">12927</td><td align="left" rowspan="1" colspan="1">0.94 (0.91–0.98)</td><td align="left" rowspan="1" colspan="1">0.0031</td><td align="left" rowspan="1" colspan="1">2972</td><td align="left" rowspan="1" colspan="1">1.00 (0.93–1.06)</td><td align="left" rowspan="1" colspan="1">0.898</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt107"><label>1</label><p>model used for the assessment of SNP main effects: logit(Pr(breast cancer|SNP)) = β<sub>0</sub>+β<sub>1</sub>*study + β<sub>2</sub>*SNP.</p></fn><fn id="nt108"><label>2</label><p>or the highly correlated SNP rs1045485 (<italic>r<sup>2</sup></italic> = 1 in HapMap CEU).</p></fn><fn id="nt109"><label>3</label><p>or the highly correlated SNP rs1975930 (<italic>r<sup>2</sup></italic> = 1 in HapMap CEU).</p></fn><fn id="nt110"><label>4</label><p>or the highly correlated SNP rs10483813 (<italic>r<sup>2</sup></italic> = 1 in HapMap CEU).</p></fn><fn id="nt111"><label>5</label><p>MAF: minor allele frequency among controls.</p></fn><fn id="nt112"><label>6</label><p>P-value for heterogeneity by ER-status: from case-case analysis.</p></fn></table-wrap-foot></table-wrap><p>The strongest evidence was found for modification of the association with <italic>LSP1-</italic>rs3817198 by number of births in parous women (P<sub>interaction</sub> per birth increase in parous women = 2.4×10<sup>−6</sup>) (<xref ref-type="table" rid="pgen-1003284-t004">Table 4</xref>; <xref ref-type="fig" rid="pgen-1003284-g001">Figure 1</xref> showing individual study results). Since this interaction was previously assessed in BCAC, we reassessed the interaction in 6266 cases and 3899 controls not included in the previous report <xref rid="pgen.1003284-Milne1" ref-type="bibr">[7]</xref>. The SNP association still varied significantly with number of births in parous women (P<sub>interaction</sub> = 1.6×10<sup>−3</sup>), thus independently replicating the previous finding. The results were consistent across studies (P<sub>heterogeneity</sub> = 0.37) (<xref ref-type="fig" rid="pgen-1003284-g001">Figure 1B</xref>). In the overall dataset, the per-allele OR (95% confidence interval) for rs3817198 ranged from 1.03 (0.96–1.10) in parous women with one birth to 1.26 (1.16–1.37) in women with four or more births (<xref ref-type="fig" rid="pgen-1003284-g002">Figure 2</xref>) and in comparison was 1.08 (1.01–1.16) in nulliparous women (<xref ref-type="supplementary-material" rid="pgen.1003284.s004">Table S4</xref>).</p><fig id="pgen-1003284-g001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pgen.1003284.g001</object-id><label>Figure 1</label><caption><title>Odds ratios of gene-environment interaction for risk of breast cancer with p-value<10<sup>−3</sup> by study.</title><p>(A) <italic>LSP1</italic>-rs3817198 x Number of full-term births (among parous), (B) <italic>LSP1</italic>-rs3817198 x Number of full-term births (among parous), restricted to subjects not included in previous BCAC report, (C) 1p11-rs11249433 x Parous (yes/no), (D) <italic>CASP8</italic>-rs17468277 x mean lifetime intake of alcohol (<20 g/day versus > = 20 g/day).</p></caption><graphic xlink:href="pgen.1003284.g001"></graphic></fig><fig id="pgen-1003284-g002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pgen.1003284.g002</object-id><label>Figure 2</label><caption><title>Per-allele SNP odds ratios and 95% confidence intervals stratified by environmental risk factors of breast cancer, and combined SNP main effect.</title><p>(A) <italic>LSP1</italic>-rs3817198 x Number of full-term births (among parous), (B) 1p11-rs11249433 x Parous (yes/no), (C) <italic>CASP8</italic>-rs17468277 x mean lifetime intake of alcohol (<20 g/day versus > = 20 g/day).</p></caption><graphic xlink:href="pgen.1003284.g002"></graphic></fig><table-wrap id="pgen-1003284-t004" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pgen.1003284.t004</object-id><label>Table 4</label><caption><title>Per-allele odds ratios and 95% confidence intervals for SNPs by environmental risk factors of breast cancer showing interaction P-value<10<sup>−3</sup>, overall and by estrogen receptor status.</title></caption><alternatives><graphic id="pgen-1003284-t004-4" xlink:href="pgen.1003284.t004"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td colspan="4" align="left" rowspan="1">All</td><td colspan="3" align="left" rowspan="1">Estrogen receptor-positive</td><td colspan="3" align="left" rowspan="1">Estrogen receptor-negative</td></tr><tr><td align="left" rowspan="1" colspan="1">SNP (Gene)</td><td align="left" rowspan="1" colspan="1">Variable</td><td align="left" rowspan="1" colspan="1">Category</td><td align="left" rowspan="1" colspan="1">N Cases/Controls</td><td align="left" rowspan="1" colspan="1">OR (95%CI)</td><td align="left" rowspan="1" colspan="1">P<sub>interaction</sub><xref ref-type="table-fn" rid="nt113">1</xref></td><td align="left" rowspan="1" colspan="1">P<sub>het</sub><xref ref-type="table-fn" rid="nt114">2</xref></td><td align="left" rowspan="1" colspan="1">N Cases</td><td align="left" rowspan="1" colspan="1">OR (95%CI)</td><td align="left" rowspan="1" colspan="1">P<sub>interaction</sub><xref ref-type="table-fn" rid="nt113">1</xref></td><td align="left" rowspan="1" colspan="1">N Cases</td><td align="left" rowspan="1" colspan="1">OR (95%CI)</td><td align="left" rowspan="1" colspan="1">P<sub>interaction</sub><xref ref-type="table-fn" rid="nt113">1</xref></td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">rs3817198 (<italic>LSP1</italic>)</td><td align="left" rowspan="1" colspan="1">Number of births (among parous women)</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">4957/4464</td><td align="left" rowspan="1" colspan="1">1.03 (0.96–1.10)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2970</td><td align="left" rowspan="1" colspan="1">1.02 (0.95–1.10)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">936</td><td align="left" rowspan="1" colspan="1">0.98 (0.87–1.10)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">10549/10234</td><td align="left" rowspan="1" colspan="1">1.07 (1.02–1.11)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">6044</td><td align="left" rowspan="1" colspan="1">1.05 (1.00–1.11)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1800</td><td align="left" rowspan="1" colspan="1">1.05 (0.97–1.14)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">3</td><td align="left" rowspan="1" colspan="1">4970/4821</td><td align="left" rowspan="1" colspan="1">1.16 (1.09–1.23)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2871</td><td align="left" rowspan="1" colspan="1">1.15 (1.07–1.24)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">780</td><td align="left" rowspan="1" colspan="1">1.13 (1.00–1.27)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">> = 4</td><td align="left" rowspan="1" colspan="1">2588/2632</td><td align="left" rowspan="1" colspan="1">1.26 (1.16–1.37)</td><td align="left" rowspan="1" colspan="1">2.4×10<sup>−6</sup></td><td align="left" rowspan="1" colspan="1">0.33</td><td align="left" rowspan="1" colspan="1">1453</td><td align="left" rowspan="1" colspan="1">1.26 (1.13–1.40)</td><td align="left" rowspan="1" colspan="1">5.6×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">416</td><td align="left" rowspan="1" colspan="1">1.26 (1.06–1.49)</td><td align="left" rowspan="1" colspan="1">5.7×10<sup>−3</sup></td></tr><tr><td align="left" rowspan="1" colspan="1">rs11249433(1p11)</td><td align="left" rowspan="1" colspan="1">Parous</td><td align="left" rowspan="1" colspan="1">No</td><td align="left" rowspan="1" colspan="1">4243/3796</td><td align="left" rowspan="1" colspan="1">0.98 (0.92–1.05)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">2543</td><td align="left" rowspan="1" colspan="1">0.97 (0.90–1.04)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">720</td><td align="left" rowspan="1" colspan="1">0.96 (0.85–1.08)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">Yes</td><td align="left" rowspan="1" colspan="1">24226/25432</td><td align="left" rowspan="1" colspan="1">1.14 (1.11–1.17)</td><td align="left" rowspan="1" colspan="1">5.3×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">0.15</td><td align="left" rowspan="1" colspan="1">14443</td><td align="left" rowspan="1" colspan="1">1.16 (1.13–1.20)</td><td align="left" rowspan="1" colspan="1">1.6×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">4203</td><td align="left" rowspan="1" colspan="1">1.04 (0.99–1.10)</td><td align="left" rowspan="1" colspan="1">0.19</td></tr><tr><td align="left" rowspan="1" colspan="1">rs17468277<xref ref-type="table-fn" rid="nt115">3</xref>(<italic>CASP8</italic>)</td><td align="left" rowspan="1" colspan="1">Mean lifetime intake of alcohol<xref ref-type="table-fn" rid="nt116">4</xref> (g/day)</td><td align="left" rowspan="1" colspan="1"><20</td><td align="left" rowspan="1" colspan="1">5630/8547</td><td align="left" rowspan="1" colspan="1">0.91 (0.85–0.98)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">3965</td><td align="left" rowspan="1" colspan="1">0.94 (0.87–1.02)</td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">1315</td><td align="left" rowspan="1" colspan="1">0.88 (0.78–1.00)</td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1">> = 20</td><td align="left" rowspan="1" colspan="1">451/758</td><td align="left" rowspan="1" colspan="1">1.45 (1.14–1.85)</td><td align="left" rowspan="1" colspan="1">3.1×10<sup>−4</sup></td><td align="left" rowspan="1" colspan="1">0.30</td><td align="left" rowspan="1" colspan="1">345</td><td align="left" rowspan="1" colspan="1">1.48 (1.14–1.91)</td><td align="left" rowspan="1" colspan="1">0.001</td><td align="left" rowspan="1" colspan="1">83</td><td align="left" rowspan="1" colspan="1">1.22 (0.77–1.94)</td><td align="left" rowspan="1" colspan="1">0.18</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt113"><label>1</label><p>P-value for GxE interaction from logistic regression analysis stratified by study and adjusted for reference age. The interaction term was the product between the continuous SNP variable (number of risk alleles) and the risk factor variable (continuous for number of births and dichotomized for ever being parous and for mean alcohol intake): logit(Pr(breast cancer|risk factor, study, SNP)) = β<sub>0</sub>+β<sub>1</sub>* reference_age + β<sub>2</sub>*SNP + β<sub>3</sub>*risk_factor + β<sub>4</sub>*SNP* risk_factor.</p></fn><fn id="nt114"><label>2</label><p>P-value for study heterogeneity from fixed effects meta-analysis of case-control analyses per study.</p></fn><fn id="nt115"><label>3</label><p>or the highly correlated SNP rs1045485 (<italic>r<sup>2</sup></italic> = 1 in HapMap CEU).</p></fn><fn id="nt116"><label>4</label><p>mean lifetime alcohol intake derived from duration and amount of alcohol intake in g/day at different age periods.</p></fn></table-wrap-foot></table-wrap><p>The polymorphism 1p11.2-rs11249433 was associated with breast cancer in parous (1.14, 1.11–1.17) but not nulliparous women (0.98, 0.92–1.05) (P<sub>interaction</sub> = 5.3×10<sup>−5</sup>). The interaction was non-significantly stronger for risk of ER-positive than ER-negative tumours (P<sub>heterogeneity</sub> = 0.13, <xref ref-type="supplementary-material" rid="pgen.1003284.s005">Table S5</xref>, <xref ref-type="supplementary-material" rid="pgen.1003284.s006">Table S6</xref>), corresponding to this SNP being more strongly associated with ER-positive disease (<xref ref-type="table" rid="pgen-1003284-t003">Table 3</xref>). When restricted to ER-positive breast cancer, the per-allele OR for rs11249433 was 1.16 (1.13–1.20) in parous women and 0.97 (0.90–1.04) in nulliparous women (P<sub>interaction</sub> = 1.6×10<sup>−5</sup>) (<xref ref-type="table" rid="pgen-1003284-t004">Table 4</xref>). There was no significant heterogeneity in the interaction ORs by study (<xref ref-type="fig" rid="pgen-1003284-g001">Figure 1C</xref>).</p><p>For the previously reported potential interaction between <italic>CASP8</italic>-rs1045485 (in complete LD with rs17468277) and alcohol consumption (<1 versus ≥1 drink/day) <xref rid="pgen.1003284-Travis1" ref-type="bibr">[6]</xref>, we found moderate evidence when assessing effect modification by alcohol intake per 10 g/day increase (P<sub>interaction</sub> per 10 g/day = 3.0×10<sup>−3</sup>) (<xref ref-type="supplementary-material" rid="pgen.1003284.s004">Table S4</xref>). However, when alcohol intake was dichotomized at 20 g/day (approximately 2 drinks/day), the estimated per-allele OR for <italic>CASP8</italic>-rs17468277 was 0.91 (0.84–0.98) in those who drank <20 g/day and 1.45 (1.14–1.85) in those who drank ≥20 g/day (P<sub>interaction</sub> = 3.1×10<sup>−4</sup>) (<xref ref-type="table" rid="pgen-1003284-t004">Table 4</xref>, <xref ref-type="fig" rid="pgen-1003284-g001">Figure 1D</xref>).</p><p>We observed weaker evidence of differences in the associations with breast cancer for three further SNPs according to use of MHT and for one SNP according to age at first birth. These included rs13387042 and current use of combined estrogen/progestagen MHT (yes/no) (P<sub>interaction</sub> = 2.4×10<sup>−3</sup>), rs2823093 and current use of estrogen only MHT (yes/no) (P<sub>interaction</sub> = 6.6×10<sup>−3</sup>), rs999737 and duration of estrogen only MHT among current users (P<sub>interaction</sub> = 4.0×10<sup>−3</sup>), and rs614367 and age at first birth among parous women (P<sub>interaction</sub> = 9.1×10<sup>−3</sup>) (<xref ref-type="supplementary-material" rid="pgen.1003284.s004">Table S4</xref>).</p><p>The observed SNP-environmental interaction ORs were not altered substantially (less than 8% change in the interaction ORs) when adjusting for additional covariates. These additional covariates included (when not the potentially effect-modifying variable of interest) ever parous (yes/no), number of births, BMI, age surrogate for postmenopausal status (≥54 years), interaction of BMI and postmenopausal status (≥54 years), current use of MHT, past use of MHT, duration of oral contraceptives (OC) use, lifetime alcohol intake, smoking (pack-years) (<xref ref-type="supplementary-material" rid="pgen.1003284.s007">Table S7</xref>). Subjects with missing covariable information were excluded from these analyses, leading to considerably reduced sample sizes. Restricting the analyses to only 16 population-based studies did not change the results substantially (i.e., less than 3%) (<xref ref-type="supplementary-material" rid="pgen.1003284.s008">Table S8</xref>).</p><p>The false-positive report probability (FPRP) was below 0.2 at a prior probability greater than 0.001 for the replicated effect modification of <italic>LSP1-</italic>rs3817198 by number of births and 1p11.2-rs11249433 and being ever parous. For the effect modification of <italic>CASP8</italic>-rs17468277 by alcohol intake ≥20 g/day, the FPRP was below 0.2 at a prior probability greater than 0.01. For the four potential interactions reported above, the FPRP was only below 0.2 at a prior probability greater than 0.05. (<xref ref-type="supplementary-material" rid="pgen.1003284.s009">Table S9</xref>).</p></sec><sec id="s3"><title>Discussion</title><p>We carried out a comprehensive evaluation of potential gene-environment interactions between 23 established common susceptibility variants for breast cancer and 10 established environmental risk factors, using 18 variables. Compared to the previous analysis, the present dataset from BCAC included 5 new population-based studies as well as additional study participants from some studies <xref rid="pgen.1003284-Milne1" ref-type="bibr">[7]</xref>. We examined additional environmental risk factors (14 variables), and 11 additional recently identified common susceptibility loci.</p><p>In our previous report, the strongest evidence of effect modification (P-value = 0.002) was observed for <italic>LSP1-</italic>rs3817198 by number of births <xref rid="pgen.1003284-Milne1" ref-type="bibr">[7]</xref>. The highly consistent and significant finding based on the present analysis of only additional cases and controls provided clear independent replication. We also show that the interaction holds for both ER-positive and ER-negative disease. This lack of heterogeneity is biologically plausible since neither the SNP nor number of births show heterogeneity by ER status in association with breast cancer risk <xref rid="pgen.1003284-Yang1" ref-type="bibr">[9]</xref>, <xref rid="pgen.1003284-Broeks1" ref-type="bibr">[10]</xref>. Only ever parous versus nulliparous but not the number of births in parous women was assessed for gene-environment interaction in two previous studies <xref rid="pgen.1003284-Campa1" ref-type="bibr">[2]</xref>, <xref rid="pgen.1003284-Travis1" ref-type="bibr">[6]</xref>. Consistent with our data indicating no differential effects by ever parous compared to never parous, they did not find evidence of interaction between <italic>LSP1</italic>-rs3817198 and ever being parous. The rs3817198 SNP is located on the short arm of chromosome 11 and lies within <italic>LSP1</italic>, encoding lymphocyte-specific protein 1, an intracellular F-actin binding protein, although the gene underlying the association has not been definitively identified. The SNP lies close to the H19/IGF2 imprinted region, and the association of breast cancer with rs3817198 has been reported to be restricted to the paternally inherited allele <xref rid="pgen.1003284-Kong1" ref-type="bibr">[11]</xref>. The effect heterogeneity of <italic>LSP1</italic>-rs3817198 by number of births appears to be partly due to a significant negative correlation between number of rs3817198 C alleles and number of births in parous women (P-value = 0.002), which was found both in the data of our previous report as well as the additional data for the present analysis. Although not statistically significant, the mean number of children was also reported to be lower in women carrying the CC genotype in the Million Women Study <xref rid="pgen.1003284-Travis1" ref-type="bibr">[6]</xref>. Also of interest is that <italic>LSP1</italic>-rs3817198 has been associated with mammographic density, consistent with the direction of the breast cancer association <xref rid="pgen.1003284-Vachon1" ref-type="bibr">[12]</xref>. Mammographic density has also been found to be reduced after a full-term pregnancy, particularly with greater number of births <xref rid="pgen.1003284-Butler1" ref-type="bibr">[13]</xref>, <xref rid="pgen.1003284-Loehberg1" ref-type="bibr">[14]</xref>.</p><p>We also replicated the strongest finding reported in the Million Women Study based on 7,610 cases and 10,196 controls <xref rid="pgen.1003284-Travis1" ref-type="bibr">[6]</xref>. In that study, the per-allele OR of <italic>CASP8</italic>-rs1045485 (or rs17468277 in our dataset) was 0.99 (0.92–1.07) in those who reported <1 drink/day and 1.23 (1.09–1.38) in those who reported ≥1 drink/day (P-value = 0.003). Our observation of an increased per-allele OR of 1.45 (1.14–1.85) for those who reported high alcohol intake ≥20 g/day and 0.91 (0.84–0.98) for those who consume less provides independent replication of this SNP-environmental interaction. Although one drink corresponds to an intake of approximately 10 g alcohol, the Million Women study reported the strongest risk increase in breast cancer for women consuming at least 15 drinks per week (RR 1.29 (1.23–1.35)) <xref rid="pgen.1003284-Allen1" ref-type="bibr">[15]</xref>, corresponding to approximately to 2 drinks per day (20 g alcohol). There is no known functional effect of <italic>CASP8</italic>-rs1045485, however, it is associated with a risk haplotype in <italic>CASP8</italic>, which is more strongly associated with breast cancer risk <xref rid="pgen.1003284-Camp1" ref-type="bibr">[16]</xref>, <xref rid="pgen.1003284-Cox1" ref-type="bibr">[17]</xref>. Caspase 8 is an important initiator of apoptosis and is activated in response to DNA damage that can be caused by alcohol consumption through ethanol-related oxidative stress <xref rid="pgen.1003284-Dumitrescu1" ref-type="bibr">[18]</xref>.</p><p>Ever being parous, but not number of births, was found to modify the effect of a different SNP, 1p11.2-rs11249433, in particular for ER-positive breast cancer. This SNP shows significantly stronger association with risk of ER-positive tumors than of ER-negative tumors <xref rid="pgen.1003284-Figueroa1" ref-type="bibr">[19]</xref>. In nulliparous women, rs11249433 was not associated with risk of ER-positive disease, whereas in parous women, the per-allele OR of 1.14 was slightly greater than the overall OR of 1.12. The Breast and Prostate Cancer Cohort Consortium evaluated interactions between 13 of the 23 genetic loci and 9 risk factors, including 1p11.2-rs11249433 and ever parous. They found no evidence for this interaction (P-value = 0.79), with per-allele OR of 1.09 (1.04–1.14) in parous and 1.11 (0.99–1.24) in nulliparous women <xref rid="pgen.1003284-Campa1" ref-type="bibr">[2]</xref>. These ORs are not in the same relative direction as our finding with respect to ever being parous. This may be in part due to misclassification of parity if information on parity for participants of the cohort studies was only available at time of recruitment and therefore incomplete with reference to the diagnosis of breast cancer. Their analysis was based on 8,576 cases and 11,892 controls, which had considerably lower statistical power than the present study. The SNP rs11249433 is located on the short arm of chromosome 1 close to the centromere, which makes it hard to map. The nearest known genes are <italic>FCGR1B</italic> (low-affinity Fc gamma receptor family) and <italic>NOTCH2</italic> (coding a transmembrane receptor protein). Recently, a study reported a positive association of <italic>NOTCH2</italic> mRNA expression with the breast cancer risk allele of rs11249433 <xref rid="pgen.1003284-Fu1" ref-type="bibr">[20]</xref>. This association was strongest with the subgroup of ER-positive breast tumors without TP53 mutation, providing some evidence that the increased risk of ER-positive breast cancer might be due to differences in <italic>NOTCH2</italic> expression <xref rid="pgen.1003284-Fu1" ref-type="bibr">[20]</xref>.</p><p>The evidence for the other four potential interactions mentioned in the results was considerably weaker and confirmation of these findings in further studies is therefore required. Three of these involved effect modification by use of MHT. The effect modification of <italic>RAD51L1</italic>-rs999737 by duration of estrogen only MHT in current users is particularly interesting because this polymorphism has been associated with mammographic density in the same direction as the breast cancer association <xref rid="pgen.1003284-Vachon1" ref-type="bibr">[12]</xref>. Mammographic density has also been found to be increased in postmenopausal women among users of MHT <xref rid="pgen.1003284-Boyd1" ref-type="bibr">[21]</xref>.</p><p><italic>RAD51L1</italic> is a member of the Rad51-like proteins that play a crucial role in homologous recombinational repair <xref rid="pgen.1003284-Lio1" ref-type="bibr">[22]</xref>. Rare deleterious mutations in other genes of this pathway, including <italic>BRCA1</italic> and <italic>BRCA2</italic>, confer a high risk of breast cancer <xref rid="pgen.1003284-Mavaddat1" ref-type="bibr">[1]</xref>, <xref rid="pgen.1003284-Meindl1" ref-type="bibr">[23]</xref>. Menopausal hormone therapy has been suggested to alter breast cancer risk in <italic>BRCA1</italic> mutation carriers although the evidence is still limited <xref rid="pgen.1003284-Chlebowski1" ref-type="bibr">[24]</xref>. It is thus plausible that estrogen only MHT modifies the relative risk for genetic variants in <italic>RAD51L1</italic> on breast cancer risk.</p><p><italic>NRIP1</italic> (nuclear receptor–interacting protein 1), also called <italic>RIP140</italic> (receptor-interacting protein 140), is known to interact with ERα, repress ER signaling and inhibit its mitogenic effects <xref rid="pgen.1003284-Ghoussaini1" ref-type="bibr">[25]</xref>. Exposure to exogenous estrogens through MHT, which stimulate ER signalling, could therefore alter the association of <italic>NRIP1</italic> rs2823093 with breast cancer.</p><p>It is less clear how 2q35-rs13387042 might be modified by current combined estrogen/progestagen MHT use since the gene involved at this locus is still unknown. The SNP is located on the short arm of chromosome 2 and lies in a linkage disequilibrium (LD) block containing no known gene(s) or non-coding RNAs. The closest known genes are <italic>TNP1</italic> (transition protein 1), <italic>IGFBP5</italic> (insulin-like growth factor binding protein 5), <italic>IGFBP2</italic> (insulin-like growth factor binding protein 2) and <italic>TNS1</italic> (tensin 1/matrix-remodelling-associated protein 6) <xref rid="pgen.1003284-Stacey1" ref-type="bibr">[26]</xref>. The observed effect modification would suggest that the gene involved may be responsive to steroid hormones.</p><p>Both Campa et al. and the Million Women Study investigated potential interactions with MHT (overall use) <xref rid="pgen.1003284-Campa1" ref-type="bibr">[2]</xref>, <xref rid="pgen.1003284-Travis1" ref-type="bibr">[6]</xref>. Neither study reported evidence for interaction between 2q35-rs13387042 or <italic>RAD51L1</italic>-rs999737 with MHT and breast cancer risk. However, neither study considered current use of MHT even though elevated risks for breast cancer have been clearly established for current use and not for past use <xref rid="pgen.1003284-Travis1" ref-type="bibr">[6]</xref>, <xref rid="pgen.1003284-Beral1" ref-type="bibr">[27]</xref>, <xref rid="pgen.1003284-FleschJanys1" ref-type="bibr">[28]</xref>. Yet Campa et al. found differences in OR estimates for 2q35-rs13387042 by ever use of combined estrogen/progestagen MHT in the same direction as our results for current combined estrogen/progestagen MHT use, with a per-allele OR of 0.83 (0.78–0.89) in non-users and 0.77 (0.69–0.86) in ever combined estrogen/progestagen MHT users (P-value = 0.26) (in their Supplementary Table 5). We were not able to confirm the previously suggested possible interaction of 5p12-rs10941679 or <italic>FGFR2</italic> variants with MHT and other factors <xref rid="pgen.1003284-Campa1" ref-type="bibr">[2]</xref>–<xref rid="pgen.1003284-Rebbeck1" ref-type="bibr">[5]</xref>. Our data suggest that age at first birth in parous women may modify the effect of 11q13-rs614367, which is located in a region containing no known genes <xref rid="pgen.1003284-Turnbull1" ref-type="bibr">[29]</xref>. This newly identified SNP has not been previously assessed for interaction with environmental risk factors.</p><p>One of the strengths of our study is the large sample size, required for assessing weak to moderate gene-environment interactions, particularly when marker SNPs instead of causal variants are used <xref rid="pgen.1003284-Hein1" ref-type="bibr">[30]</xref>. We assessed gene-environment interaction separately for ER-positive and ER-negative disease, thereby accounting for heterogeneity by ER status in risk associated with both genetic and environmental factors. However, statistical power was still limited to detect interactions in susceptibility to ER-negative disease. Although selection bias is likely to affect estimates of environmental main effects, under reasonable assumptions, it should not influence the assessment of multiplicative gene-environment interactions or estimates of SNP relative risks <xref rid="pgen.1003284-Morimoto1" ref-type="bibr">[31]</xref>. Furthermore, both non-differential and differential misclassification of exposure tend to underestimate the multiplicative interaction parameter rather than yield spurious evidence of interaction <xref rid="pgen.1003284-GarciaClosas1" ref-type="bibr">[32]</xref>. To reduce potential bias due to population stratification, we restricted our analyses to subjects of European ancestry and stratified by study in all analyses. The robustness of our findings to differences in study design was supported by sensitivity analyses considering only data from population-based studies. The interaction estimates also did not change substantially when adjusting for further covariates: the p-values were however higher due to the considerably reduced sample sizes. The absence of study heterogeneity in the estimates of gene-environment interactions provides further reassurance of the robustness of the findings.</p><p>The effect modifications identified in our study are relatively weak and should result in small differences in risk estimates of joint effects compared to those based on models assuming multiplicative effects. However, most of the SNPs investigated are only markers of the underlying causal variants and underestimate the effects of the causal variants if linkage disequilibrium is incomplete <xref rid="pgen.1003284-Zondervan1" ref-type="bibr">[33]</xref>. Thus, gene-environment interactions with the underlying causal variant could have a greater modifying effect on the relative risk <xref rid="pgen.1003284-Hein1" ref-type="bibr">[30]</xref>. These findings also underline the importance of investigating interactions separately for causally distinct subtypes of breast cancer in future assessments of gene-environment interaction.</p><p>In summary, we provide strong evidence of effect modification of <italic>LSP1-</italic>rs3817198 by number of births and of <italic>CASP8</italic>-rs1045485 by alcohol consumption. For some additional common genetic variants, the associations with breast cancer risk may vary with environmental factors. However, there is little evidence for multiplicative gene-environment interactions for most susceptibility loci and environmental risk factors. Understanding the biological implications of the observed interactions could provide further insight into the etiology of breast cancer. The potential impact of these results on risk prediction for breast cancer needs to be considered in future studies.</p></sec><sec sec-type="methods" id="s4"><title>Methods</title><sec id="s4a"><title>Study participants and risk factor data</title><p>We used primary data from the studies in BCAC. All studies had approval from the relevant ethics committees and all participants gave informed consent. A centralized BCAC database of information about common risk factors and tumor characteristics was constructed to facilitate studies of potential modifications of SNP associations by other risk factors. A multi-step data harmonization procedure was used to reconcile differences in individual study questionnaires. The reference age for cohort studies was calculated at time of enrollment and for case-control studies at date of diagnosis for cases and at date of interview for controls. All time-dependent variables were assessed at reference age. This analysis included only subjects of European ancestry that had genotype data for at least 3 SNPs and provided information on at least one of the established risk factors. Relevant data were available from 24 studies, including 16 population-based studies (14 case-control and 2 prospective cohort studies) and 8 non-population-based studies (<xref ref-type="table" rid="pgen-1003284-t001">Table 1</xref>, <xref ref-type="supplementary-material" rid="pgen.1003284.s001">Table S1</xref>, <xref ref-type="supplementary-material" rid="pgen.1003284.s002">Table S2</xref>). Subsets of data from 19 studies (with 11 population-based) were included in a previous report that assessed interactions between 12 susceptibility variants, reproductive history, BMI and breast cancer risk <xref rid="pgen.1003284-Milne1" ref-type="bibr">[7]</xref>.</p></sec><sec id="s4b"><title>SNP selection and genotyping</title><p>We included 21 SNPs found to be associated with overall breast cancer risk at genome-wide statistical significance (p<5×10<sup>−7</sup>) <xref rid="pgen.1003284-Broeks1" ref-type="bibr">[10]</xref>, <xref rid="pgen.1003284-Ghoussaini1" ref-type="bibr">[25]</xref>, <xref rid="pgen.1003284-Fletcher1" ref-type="bibr">[34]</xref> and SNPs for <italic>TGFB1</italic> and <italic>CASP8</italic> from candidate gene studies <xref rid="pgen.1003284-Cox1" ref-type="bibr">[17]</xref> (<xref ref-type="supplementary-material" rid="pgen.1003284.s003">Table S3</xref>). For three loci, 14q24.1/<italic>RAD51L1</italic>, 12p11, <italic>CASP8</italic>, a surrogate SNP in high linkage disequilibrium (LD) (<italic>r<sup>2</sup></italic> = 1 in HapMap CEU) was genotyped in a subset (<xref ref-type="table" rid="pgen-1003284-t003">Table 3</xref> footnote) <xref rid="pgen.1003284-Figueroa1" ref-type="bibr">[19]</xref>, <xref rid="pgen.1003284-Ghoussaini1" ref-type="bibr">[25]</xref>, <xref rid="pgen.1003284-Thomas1" ref-type="bibr">[35]</xref>.</p><p>Genotyping was performed in the framework of BCAC by Taqman and iPlex assays and underwent quality control as described previously <xref rid="pgen.1003284-Broeks1" ref-type="bibr">[10]</xref>, <xref rid="pgen.1003284-Figueroa1" ref-type="bibr">[19]</xref>, <xref rid="pgen.1003284-Ghoussaini1" ref-type="bibr">[25]</xref>, <xref rid="pgen.1003284-Fletcher1" ref-type="bibr">[34]</xref>, <xref rid="pgen.1003284-Milne2" ref-type="bibr">[36]</xref>, <xref rid="pgen.1003284-Milne3" ref-type="bibr">[37]</xref>. Genotype data were excluded from analysis on a study-by-study basis according to the following BCAC quality control (QC) guidelines: 1) any sample that consistently failed for >20% of the SNPs within a genotyping round, 2) all samples on any one plate that had a call rate <90% for any one SNP, 3) all genotype data for any SNP where overall call rate was <95%, 4) all genotype data for any SNP where duplicate concordance was <98%. In addition, for any SNP where the P-value for departure from Hardy-Weinberg proportions for controls was <0.005, clustering of the intensity plots was reviewed manually and the data excluded if clustering was judged to be poor.</p></sec><sec id="s4c"><title>Statistical methods</title><p>We used logistic regression to assess the main effects of the SNP and environmental risk factors on invasive breast cancer risk. Analyses were adjusted for study as a categorical variable and reference age as a continuous variable. Odds ratios (OR) and their 95% confidence intervals (CI) were calculated for the SNP associations assuming a log-additive model and tested for association with a one degree of freedom trend test. All statistical tests were two-sided.</p><p>The assessment of associations with the environmental risk factors was based on data only from the 16 population-based studies to ensure unbiased estimates for comparison with established effect sizes. The variables considered were analyzed as continuous (age at menarche, number of births in parous women, age at first birth, usual BMI, height, duration of oral contraceptive use, duration of current use of estrogen-progestagen combined therapy, duration of current use of estrogen-only therapy, pack-years of cigarette smoking, mean lifetime daily grams of alcohol intake, recent physical activity in hours per week), or as dichotomous (ever parous, ever breastfed, ever OC use, ever smoked, current EPT use, current ET use) (<xref ref-type="table" rid="pgen-1003284-t002">Table 2</xref>). Analyses were performed for all women as well as separately for women aged <54 years and ≥54 years, considering the age groups as surrogates of pre- and postmenopausal status, Differential effects by menopausal status were assessed by adding an interaction term. For all categorical variables, the lowest level of exposure (or no use) was used as the reference. For evaluating current use of MHT by type, we used never use of MHT as the reference category and additionally adjusted for former use of MHT and other MHT type, as appropriate.</p><p>To test for interactions between SNPs and environmental risk factors, we fitted for each SNP two logistic models, a model with terms for the SNP and the risk factor of interest and another model with additionally an interaction term for the product between the SNP (number of risk alleles) and the risk factor variable. We modeled the interaction based on the risk factor variable definitions employed for the main effects. All analyses were stratified by study and adjusted for age as a continuous variable. The likelihood ratio test was used to compare the difference between the two models and departure from independent multiplicative effects of the SNP and the risk factor. BMI was the only variable found to show differential effects by menopausal status, which is consistent with the literature <xref rid="pgen.1003284-vandenBrandt1" ref-type="bibr">[38]</xref>. Therefore, interaction between SNPs and BMI was assessed separately for pre- and postmenopausal women whereas all other risk factors were evaluated regardless of menopausal status. To assess study heterogeneity, we calculated odds ratios for interaction for each individual study, adjusting for age, and reported P-values for heterogeneity using a Q-test. Subjects with missing data for a particular SNP or environmental factor were excluded from the respective analysis. We also calculated stratum specific per-allele ORs for each SNP: age at menarche (≤11, 12–13, ≥14 years), number of births (1,2,3, ≥4), age at first birth (<20, 20–24, 25–29, ≥30 years), usual BMI (<25, 25–29, ≥30), height (<160, 160–164, 165–169, ≥170 cm), duration of oral contraceptive use and of menopausal hormone use (0, >0–<5, 5–<10, ≥10 years), mean lifetime alcohol intake (0, 0–<10, 10–<20, ≥20 g/day), pack-years of smoking (0, 1–<10, 10–<20, ≥20), and physical activity (0, >0–<3.5, ≥3.5–<7, ≥7 h/week).</p><p>For SNP-environment interactions with associated P-value<10<sup>−3</sup>, we also compared results after adjusting for additional covariates. We performed a total of 414 (23 SNPs x 18 risk variables) tests. To account for chance findings due to multiple comparisons, we calculated the false positive report probability (FPRP) for SNP-environment interactions with associated P-value<10<sup>−3</sup><xref rid="pgen.1003284-Wacholder1" ref-type="bibr">[39]</xref>. The FPRP depends on the prior probability that the association between the SNP and breast cancer is modified by the environmental risk factor, the power of the present study, and the observed P-value. Since the prior probability of the assessed multiplicative interactions varies depending on subjective evaluation of existing evidence, we calculated the FPRPs for prior probabilities ranging from 0.05 to 0.0001. We considered findings with FPRP below 0.2 to be noteworthy results, as previously proposed <xref rid="pgen.1003284-Wacholder1" ref-type="bibr">[39]</xref>.</p><p>In secondary analyses, we examined associations and effect modifications separately for women with ER-positive tumors and ER-negative tumors, each compared to all controls. Effect heterogeneity by ER status was tested using case-case analysis.</p><p>Data harmonization was performed using an ACCESS database and transformation of the data elements was performed using SAS (Release 9.2). All other data analyses were conducted using SAS (Release 9.2) and the R programming language <xref rid="pgen.1003284-R1" ref-type="bibr">[40]</xref>.</p></sec></sec><sec sec-type="supplementary-material" id="s5"><title>Supporting Information</title><supplementary-material content-type="local-data" id="pgen.1003284.s001"><label>Table S1</label><caption><p>Description of BCAC studies included in the analysis of gene–environment interaction.</p><p>(PDF)</p></caption><media xlink:href="pgen.1003284.s001.pdf"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1003284.s002"><label>Table S2</label><caption><p>Description of environmental risk factors by study.</p><p>(PDF)</p></caption><media xlink:href="pgen.1003284.s002.pdf"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1003284.s003"><label>Table S3</label><caption><p>SNPs previously reported to be associated with breast cancer risk.</p><p>(PDF)</p></caption><media xlink:href="pgen.1003284.s003.pdf"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1003284.s004"><label>Table S4</label><caption><p>Per-allele odds ratios (OR) and 95% confidence intervals (CI) for SNPs by environmental risk factors of breast cancer, overall.</p><p>(PDF)</p></caption><media xlink:href="pgen.1003284.s004.pdf"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1003284.s005"><label>Table S5</label><caption><p>Per-allele odds ratios (OR) and 95% confidence intervals (CI) for SNPs by environmental risk factors of breast cancer, estrogen receptor positive.</p><p>(PDF)</p></caption><media xlink:href="pgen.1003284.s005.pdf"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1003284.s006"><label>Table S6</label><caption><p>Per-allele odds ratios (OR) and 95% confidence intervals (CI) for SNPs by environmental risk factors of breast cancer, estrogen receptor negative.</p><p>(PDF)</p></caption><media xlink:href="pgen.1003284.s006.pdf"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1003284.s007"><label>Table S7</label><caption><p>Gene-environment interactions between SNPs and breast cancer risk factors in Caucasians with interaction p-value<10<sup>−4</sup>, overall and by ER status, adjusted for additional covariates.</p><p>(PDF)</p></caption><media xlink:href="pgen.1003284.s007.pdf"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1003284.s008"><label>Table S8</label><caption><p>Gene-environment interactions between SNPs and breast cancer risk factors in Caucasians with interaction p-value<10<sup>−4</sup>, overall and by ER status, restricted to population-based studies.</p><p>(PDF)</p></caption><media xlink:href="pgen.1003284.s008.pdf"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1003284.s009"><label>Table S9</label><caption><p>False-positive reporting probability (FPRP) for interactions of SNPs and environmental risk factors of breast cancer showing interaction p-value<10<sup>−2</sup>.</p><p>(PDF)</p></caption><media xlink:href="pgen.1003284.s009.pdf"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></sec></body><back><ack><p>We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians, and administrative staff who have enabled this work to be carried out. In particular, we thank: Maggie Angelakos, Judi Maskiell, Gillian Dite, Sonja Oeser, Silke Landrith, Eileen Williams, Elaine Ryder-Mills, Kara Sargus, The GENICA network: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Germany [Christina Justenhoven, HB]; Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany [Yon-Dschun Ko, Christian Baisch]; Institute of Pathology, University of Bonn, Bonn, Germany [Hans-Peter Fischer]; Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany [Ute Hamann]; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Bochum, Germany [TB, Beate Pesch, Sylvia Rabstein, Anne Lotz] and Institute and Outpatient Clinic of Occupational Medicine, Saarland University Medical Center and Saarland University Faculty of Medicine, Homburg, Germany [VH], Eija Myöhänen, Helena Kemiläinen, Heather Thorne, Eveline Niedermayr and the kConFab Clinical Follow-Up Study, the AOCS Management Group (D Bowtell, G Chenevix-Trench, A deFazio, D Gertig, A Green, P Webb), the ACS Management Group (A Green, P Parsons, N Hayward, P Webb, D Whiteman); The Australian Cancer Study Management Group (A. Green, P. Parsons, N. Hayward, P.M.Webb, and D. Whiteman), Margaret McCredie for key role in the establishment and leadership of the ABCFR in Sydney, Australia, and the families who donated their time, information, and biospecimens, Gilian Peuteman, Dominiek Smeets, Thomas Van Brussel and Kathleen Corthouts, Muhabbet Celik, Teresa Selander, Nayana Weerasooriya, Louise Brinton, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, Michael Stagner, Sue Higham, Simon S. Cross, Malcolm W. R. 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