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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">No Evidence for Genome-Wide Interactions on Plasma Fibrinogen by Smoking, Alcohol Consumption and Body Mass Index: Results from Meta-Analyses of 80,607 Subjects</title><author><name sortKey="Baumert, Jens" sort="Baumert, Jens" uniqKey="Baumert J" first="Jens" last="Baumert">Jens Baumert</name><affiliation><nlm:aff id="aff1"><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Huang, Jie" sort="Huang, Jie" uniqKey="Huang J" first="Jie" last="Huang">Jie Huang</name><affiliation><nlm:aff id="aff2"><addr-line>National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>National Heart, Lung and Blood Institute Division of Intramural Research, Bethesda, Maryland, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><addr-line>Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mcknight, Barbara" sort="Mcknight, Barbara" uniqKey="Mcknight B" first="Barbara" last="Mcknight">Barbara Mcknight</name><affiliation><nlm:aff id="aff5"><addr-line>Department of Biostatistics, University of Washington, Seattle, Washington, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sabater Lleal, Maria" sort="Sabater Lleal, Maria" uniqKey="Sabater Lleal M" first="Maria" last="Sabater-Lleal">Maria Sabater-Lleal</name><affiliation><nlm:aff id="aff6"><addr-line>Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Steri, Maristella" sort="Steri, Maristella" uniqKey="Steri M" first="Maristella" last="Steri">Maristella Steri</name><affiliation><nlm:aff id="aff7"><addr-line>Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chu, Audrey Y" sort="Chu, Audrey Y" uniqKey="Chu A" first="Audrey Y." last="Chu">Audrey Y. Chu</name><affiliation><nlm:aff id="aff8"><addr-line>Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Trompet, Stella" sort="Trompet, Stella" uniqKey="Trompet S" first="Stella" last="Trompet">Stella Trompet</name><affiliation><nlm:aff id="aff9"><addr-line>Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><addr-line>Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lopez, Lorna M" sort="Lopez, Lorna M" uniqKey="Lopez L" first="Lorna M." last="Lopez">Lorna M. Lopez</name><affiliation><nlm:aff id="aff11"><addr-line>Department of Psychology, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff12"><addr-line>Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fornage, Myriam" sort="Fornage, Myriam" uniqKey="Fornage M" first="Myriam" last="Fornage">Myriam Fornage</name><affiliation><nlm:aff id="aff13"><addr-line>Brown Foundation Institute of Molecular Medicine, Division of Epidemiology, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Teumer, Alexander" sort="Teumer, Alexander" uniqKey="Teumer A" first="Alexander" last="Teumer">Alexander Teumer</name><affiliation><nlm:aff id="aff14"><addr-line>Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tang, Weihong" sort="Tang, Weihong" uniqKey="Tang W" first="Weihong" last="Tang">Weihong Tang</name><affiliation><nlm:aff id="aff15"><addr-line>Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rudnicka, Alicja R" sort="Rudnicka, Alicja R" uniqKey="Rudnicka A" first="Alicja R." last="Rudnicka">Alicja R. Rudnicka</name><affiliation><nlm:aff id="aff16"><addr-line>Division of Population Health Sciences & Education, St George's, University of London, Cranmer Terrace, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="M Larstig, Anders" sort="M Larstig, Anders" uniqKey="M Larstig A" first="Anders" last="M Larstig">Anders M Larstig</name><affiliation><nlm:aff id="aff6"><addr-line>Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hottenga, Jouke Jan" sort="Hottenga, Jouke Jan" uniqKey="Hottenga J" first="Jouke-Jan" last="Hottenga">Jouke-Jan Hottenga</name><affiliation><nlm:aff id="aff17"><addr-line>Department of Biological Psychology, VU University & EMGO+ institute, VU Medical Centre, Amsterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kavousi, Maryam" sort="Kavousi, Maryam" uniqKey="Kavousi M" first="Maryam" last="Kavousi">Maryam Kavousi</name><affiliation><nlm:aff id="aff18"><addr-line>Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><addr-line>Netherlands Genomics Initiative (NGI)-Sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lahti, Jari" sort="Lahti, Jari" uniqKey="Lahti J" first="Jari" last="Lahti">Jari Lahti</name><affiliation><nlm:aff id="aff20"><addr-line>Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff21"><addr-line>Folkhalsan Research Centre, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tanaka, Toshiko" sort="Tanaka, Toshiko" uniqKey="Tanaka T" first="Toshiko" last="Tanaka">Toshiko Tanaka</name><affiliation><nlm:aff id="aff22"><addr-line>Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hayward, Caroline" sort="Hayward, Caroline" uniqKey="Hayward C" first="Caroline" last="Hayward">Caroline Hayward</name><affiliation><nlm:aff id="aff23"><addr-line>MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Huffman, Jennifer E" sort="Huffman, Jennifer E" uniqKey="Huffman J" first="Jennifer E." last="Huffman">Jennifer E. Huffman</name><affiliation><nlm:aff id="aff23"><addr-line>MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Morange, Pierre Emmanuel" sort="Morange, Pierre Emmanuel" uniqKey="Morange P" first="Pierre-Emmanuel" last="Morange">Pierre-Emmanuel Morange</name><affiliation><nlm:aff id="aff24"><addr-line>INSERM UMR_S 1062, Aix-Marseille Université, Marseille, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rose, Lynda M" sort="Rose, Lynda M" uniqKey="Rose L" first="Lynda M." last="Rose">Lynda M. Rose</name><affiliation><nlm:aff id="aff8"><addr-line>Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Basu, Saonli" sort="Basu, Saonli" uniqKey="Basu S" first="Saonli" last="Basu">Saonli Basu</name><affiliation><nlm:aff id="aff25"><addr-line>Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rumley, Ann" sort="Rumley, Ann" uniqKey="Rumley A" first="Ann" last="Rumley">Ann Rumley</name><affiliation><nlm:aff id="aff26"><addr-line>Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stott, David J" sort="Stott, David J" uniqKey="Stott D" first="David J." last="Stott">David J. Stott</name><affiliation><nlm:aff id="aff27"><addr-line>Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Buckley, Brendan M" sort="Buckley, Brendan M" uniqKey="Buckley B" first="Brendan M." last="Buckley">Brendan M. Buckley</name><affiliation><nlm:aff id="aff28"><addr-line>Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland</addr-line></nlm:aff></affiliation></author><author><name sortKey="De Craen, Anton J M" sort="De Craen, Anton J M" uniqKey="De Craen A" first="Anton J. M." last="De Craen">Anton J. M. De Craen</name><affiliation><nlm:aff id="aff10"><addr-line>Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sanna, Serena" sort="Sanna, Serena" uniqKey="Sanna S" first="Serena" last="Sanna">Serena Sanna</name><affiliation><nlm:aff id="aff7"><addr-line>Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Masala, Marco" sort="Masala, Marco" uniqKey="Masala M" first="Marco" last="Masala">Marco Masala</name><affiliation><nlm:aff id="aff7"><addr-line>Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Biffar, Reiner" sort="Biffar, Reiner" uniqKey="Biffar R" first="Reiner" last="Biffar">Reiner Biffar</name><affiliation><nlm:aff id="aff29"><addr-line>Department of Prosthetic Dentistry, Gerostomatology and Dental Materials, University Medicine Greifswald, Greifswald, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Homuth, Georg" sort="Homuth, Georg" uniqKey="Homuth G" first="Georg" last="Homuth">Georg Homuth</name><affiliation><nlm:aff id="aff14"><addr-line>Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Silveira, Angela" sort="Silveira, Angela" uniqKey="Silveira A" first="Angela" last="Silveira">Angela Silveira</name><affiliation><nlm:aff id="aff6"><addr-line>Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sennblad, Bengt" sort="Sennblad, Bengt" uniqKey="Sennblad B" first="Bengt" last="Sennblad">Bengt Sennblad</name><affiliation><nlm:aff id="aff6"><addr-line>Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff30"><addr-line>Science for Life Laboratory, Karolinska Insitutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Goel, Anuj" sort="Goel, Anuj" uniqKey="Goel A" first="Anuj" last="Goel">Anuj Goel</name><affiliation><nlm:aff id="aff31"><addr-line>Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff32"><addr-line>Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Watkins, Hugh" sort="Watkins, Hugh" uniqKey="Watkins H" first="Hugh" last="Watkins">Hugh Watkins</name><affiliation><nlm:aff id="aff31"><addr-line>Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff32"><addr-line>Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Muller Nurasyid, Martina" sort="Muller Nurasyid, Martina" uniqKey="Muller Nurasyid M" first="Martina" last="Müller-Nurasyid">Martina Müller-Nurasyid</name><affiliation><nlm:aff id="aff33"><addr-line>Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff34"><addr-line>Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff35"><addr-line>Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität München, Munich, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ruckerl, Regina" sort="Ruckerl, Regina" uniqKey="Ruckerl R" first="Regina" last="Rückerl">Regina Rückerl</name><affiliation><nlm:aff id="aff1"><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff36"><addr-line>ESC-Environmental Science Center, University of Augsburg, Augsburg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Taylor, Kent" sort="Taylor, Kent" uniqKey="Taylor K" first="Kent" last="Taylor">Kent Taylor</name><affiliation><nlm:aff id="aff37"><addr-line>Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chen, Ming Huei" sort="Chen, Ming Huei" uniqKey="Chen M" first="Ming-Huei" last="Chen">Ming-Huei Chen</name><affiliation><nlm:aff id="aff38"><addr-line>Department of Biostatistics, Boston University, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="De Geus, Eco J C" sort="De Geus, Eco J C" uniqKey="De Geus E" first="Eco J. C." last="De Geus">Eco J. C. De Geus</name><affiliation><nlm:aff id="aff39"><addr-line>Department of Haematology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hofman, Albert" sort="Hofman, Albert" uniqKey="Hofman A" first="Albert" last="Hofman">Albert Hofman</name><affiliation><nlm:aff id="aff18"><addr-line>Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><addr-line>Netherlands Genomics Initiative (NGI)-Sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Witteman, Jacqueline C M" sort="Witteman, Jacqueline C M" uniqKey="Witteman J" first="Jacqueline C. M." last="Witteman">Jacqueline C. M. Witteman</name><affiliation><nlm:aff id="aff18"><addr-line>Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><addr-line>Netherlands Genomics Initiative (NGI)-Sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="De Maat, Moniek P M" sort="De Maat, Moniek P M" uniqKey="De Maat M" first="Moniek P. M." last="De Maat">Moniek P. M. De Maat</name><affiliation><nlm:aff id="aff39"><addr-line>Department of Haematology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Palotie, Aarno" sort="Palotie, Aarno" uniqKey="Palotie A" first="Aarno" last="Palotie">Aarno Palotie</name><affiliation><nlm:aff id="aff40"><addr-line>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff41"><addr-line>Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff42"><addr-line>Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Davies, Gail" sort="Davies, Gail" uniqKey="Davies G" first="Gail" last="Davies">Gail Davies</name><affiliation><nlm:aff id="aff11"><addr-line>Department of Psychology, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff12"><addr-line>Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Siscovick, David S" sort="Siscovick, David S" uniqKey="Siscovick D" first="David S." last="Siscovick">David S. Siscovick</name><affiliation><nlm:aff id="aff43"><addr-line>Department of Epidemiology, University of Washington, Seattle, Washington, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kolcic, Ivana" sort="Kolcic, Ivana" uniqKey="Kolcic I" first="Ivana" last="Kolcic">Ivana Kolcic</name><affiliation><nlm:aff id="aff44"><addr-line>Department of Public Health, University of Split Medical School, Split, Croatia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wild, Sarah H" sort="Wild, Sarah H" uniqKey="Wild S" first="Sarah H." last="Wild">Sarah H. Wild</name><affiliation><nlm:aff id="aff45"><addr-line>Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, Scotland, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Song, Jaejoon" sort="Song, Jaejoon" uniqKey="Song J" first="Jaejoon" last="Song">Jaejoon Song</name><affiliation><nlm:aff id="aff25"><addr-line>Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mcardle, Wendy L" sort="Mcardle, Wendy L" uniqKey="Mcardle W" first="Wendy L." last="Mcardle">Wendy L. Mcardle</name><affiliation><nlm:aff id="aff46"><addr-line>School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ford, Ian" sort="Ford, Ian" uniqKey="Ford I" first="Ian" last="Ford">Ian Ford</name><affiliation><nlm:aff id="aff47"><addr-line>Robertson Center for Biostatistics, University of Glasgow, Glasgow, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sattar, Naveed" sort="Sattar, Naveed" uniqKey="Sattar N" first="Naveed" last="Sattar">Naveed Sattar</name><affiliation><nlm:aff id="aff48"><addr-line>BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schlessinger, David" sort="Schlessinger, David" uniqKey="Schlessinger D" first="David" last="Schlessinger">David Schlessinger</name><affiliation><nlm:aff id="aff49"><addr-line>Intramural Research Program, National Institute on Aging, Baltimore, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Grotevendt, Anne" sort="Grotevendt, Anne" uniqKey="Grotevendt A" first="Anne" last="Grotevendt">Anne Grotevendt</name><affiliation><nlm:aff id="aff50"><addr-line>Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Franzosi, Maria Grazia" sort="Franzosi, Maria Grazia" uniqKey="Franzosi M" first="Maria Grazia" last="Franzosi">Maria Grazia Franzosi</name><affiliation><nlm:aff id="aff51"><addr-line>Department of Cardiovascular Research, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Illig, Thomas" sort="Illig, Thomas" uniqKey="Illig T" first="Thomas" last="Illig">Thomas Illig</name><affiliation><nlm:aff id="aff52"><addr-line>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff53"><addr-line>Hannover Unified Biobank, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Waldenberger, Melanie" sort="Waldenberger, Melanie" uniqKey="Waldenberger M" first="Melanie" last="Waldenberger">Melanie Waldenberger</name><affiliation><nlm:aff id="aff52"><addr-line>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lumley, Thomas" sort="Lumley, Thomas" uniqKey="Lumley T" first="Thomas" last="Lumley">Thomas Lumley</name><affiliation><nlm:aff id="aff54"><addr-line>Department of Statistics, University of Auckland, Auckland, New Zealand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tofler, Geoffrey H" sort="Tofler, Geoffrey H" uniqKey="Tofler G" first="Geoffrey H." last="Tofler">Geoffrey H. Tofler</name><affiliation><nlm:aff id="aff55"><addr-line>Royal North Shore Hospital, University of Sydney, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Willemsen, Gonneke" sort="Willemsen, Gonneke" uniqKey="Willemsen G" first="Gonneke" last="Willemsen">Gonneke Willemsen</name><affiliation><nlm:aff id="aff17"><addr-line>Department of Biological Psychology, VU University & EMGO+ institute, VU Medical Centre, Amsterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Uitterlinden, Andre G" sort="Uitterlinden, Andre G" uniqKey="Uitterlinden A" first="André G." last="Uitterlinden">André G. Uitterlinden</name><affiliation><nlm:aff id="aff18"><addr-line>Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><addr-line>Netherlands Genomics Initiative (NGI)-Sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff56"><addr-line>Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rivadeneira, Fernando" sort="Rivadeneira, Fernando" uniqKey="Rivadeneira F" first="Fernando" last="Rivadeneira">Fernando Rivadeneira</name><affiliation><nlm:aff id="aff57"><addr-line>Division of Preventive Medicine, Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="R Ikkonen, Katri" sort="R Ikkonen, Katri" uniqKey="R Ikkonen K" first="Katri" last="R Ikkönen">Katri R Ikkönen</name><affiliation><nlm:aff id="aff20"><addr-line>Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chasman, Daniel I" sort="Chasman, Daniel I" uniqKey="Chasman D" first="Daniel I." last="Chasman">Daniel I. Chasman</name><affiliation><nlm:aff id="aff57"><addr-line>Division of Preventive Medicine, Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Folsom, Aaron R" sort="Folsom, Aaron R" uniqKey="Folsom A" first="Aaron R." last="Folsom">Aaron R. Folsom</name><affiliation><nlm:aff id="aff15"><addr-line>Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lowe, Gordon D" sort="Lowe, Gordon D" uniqKey="Lowe G" first="Gordon D." last="Lowe">Gordon D. Lowe</name><affiliation><nlm:aff id="aff58"><addr-line>Institute of Cardiovascular & Medical Sciences, University of Glasgow, Glasgow, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Westendorp, Rudi G J" sort="Westendorp, Rudi G J" uniqKey="Westendorp R" first="Rudi G. J." last="Westendorp">Rudi G. J. Westendorp</name><affiliation><nlm:aff id="aff10"><addr-line>Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Slagboom, P Eline" sort="Slagboom, P Eline" uniqKey="Slagboom P" first="P. Eline" last="Slagboom">P. Eline Slagboom</name><affiliation><nlm:aff id="aff59"><addr-line>Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cucca, Francesco" sort="Cucca, Francesco" uniqKey="Cucca F" first="Francesco" last="Cucca">Francesco Cucca</name><affiliation><nlm:aff id="aff7"><addr-line>Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wallaschofski, Henri" sort="Wallaschofski, Henri" uniqKey="Wallaschofski H" first="Henri" last="Wallaschofski">Henri Wallaschofski</name><affiliation><nlm:aff id="aff49"><addr-line>Intramural Research Program, National Institute on Aging, Baltimore, Maryland, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff60"><addr-line>DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Strawbridge, Rona J" sort="Strawbridge, Rona J" uniqKey="Strawbridge R" first="Rona J." last="Strawbridge">Rona J. Strawbridge</name><affiliation><nlm:aff id="aff6"><addr-line>Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Seedorf, Udo" sort="Seedorf, Udo" uniqKey="Seedorf U" first="Udo" last="Seedorf">Udo Seedorf</name><affiliation><nlm:aff id="aff61"><addr-line>Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Koenig, Wolfgang" sort="Koenig, Wolfgang" uniqKey="Koenig W" first="Wolfgang" last="Koenig">Wolfgang Koenig</name><affiliation><nlm:aff id="aff62"><addr-line>Department of Internal Medicine II - Cardiology, University of Ulm Medical Center, Ulm, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bis, Joshua C" sort="Bis, Joshua C" uniqKey="Bis J" first="Joshua C." last="Bis">Joshua C. Bis</name><affiliation><nlm:aff id="aff63"><addr-line>Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mukamal, Kenneth J" sort="Mukamal, Kenneth J" uniqKey="Mukamal K" first="Kenneth J." last="Mukamal">Kenneth J. Mukamal</name><affiliation><nlm:aff id="aff64"><addr-line>Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff65"><addr-line>Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Van Dongen, Jenny" sort="Van Dongen, Jenny" uniqKey="Van Dongen J" first="Jenny" last="Van Dongen">Jenny Van Dongen</name><affiliation><nlm:aff id="aff17"><addr-line>Department of Biological Psychology, VU University & EMGO+ institute, VU Medical Centre, Amsterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Widen, Elisabeth" sort="Widen, Elisabeth" uniqKey="Widen E" first="Elisabeth" last="Widen">Elisabeth Widen</name><affiliation><nlm:aff id="aff40"><addr-line>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Franco, Oscar H" sort="Franco, Oscar H" uniqKey="Franco O" first="Oscar H." last="Franco">Oscar H. Franco</name><affiliation><nlm:aff id="aff18"><addr-line>Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><addr-line>Netherlands Genomics Initiative (NGI)-Sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Starr, John M" sort="Starr, John M" uniqKey="Starr J" first="John M." last="Starr">John M. Starr</name><affiliation><nlm:aff id="aff12"><addr-line>Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff66"><addr-line>Alzheimer Scotland Dementia Research Centre, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Liu, Kiang" sort="Liu, Kiang" uniqKey="Liu K" first="Kiang" last="Liu">Kiang Liu</name><affiliation><nlm:aff id="aff67"><addr-line>Department of Preventive Medicine, Northwestern University Medical School, Chicago, Illinois, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ferrucci, Luigi" sort="Ferrucci, Luigi" uniqKey="Ferrucci L" first="Luigi" last="Ferrucci">Luigi Ferrucci</name><affiliation><nlm:aff id="aff22"><addr-line>Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Polasek, Ozren" sort="Polasek, Ozren" uniqKey="Polasek O" first="Ozren" last="Polasek">Ozren Polasek</name><affiliation><nlm:aff id="aff43"><addr-line>Department of Epidemiology, University of Washington, Seattle, Washington, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wilson, James F" sort="Wilson, James F" uniqKey="Wilson J" first="James F." last="Wilson">James F. Wilson</name><affiliation><nlm:aff id="aff44"><addr-line>Department of Public Health, University of Split Medical School, Split, Croatia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Oudot Mellakh, Tiphaine" sort="Oudot Mellakh, Tiphaine" uniqKey="Oudot Mellakh T" first="Tiphaine" last="Oudot-Mellakh">Tiphaine Oudot-Mellakh</name><affiliation><nlm:aff id="aff68"><addr-line>INSERM, UMR_S 1166, Paris, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff69"><addr-line>Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff70"><addr-line>ICAN Institute for Cardiometabolism and Nutrition, Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Campbell, Harry" sort="Campbell, Harry" uniqKey="Campbell H" first="Harry" last="Campbell">Harry Campbell</name><affiliation><nlm:aff id="aff44"><addr-line>Department of Public Health, University of Split Medical School, Split, Croatia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Navarro, Pau" sort="Navarro, Pau" uniqKey="Navarro P" first="Pau" last="Navarro">Pau Navarro</name><affiliation><nlm:aff id="aff23"><addr-line>MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bandinelli, Stefania" sort="Bandinelli, Stefania" uniqKey="Bandinelli S" first="Stefania" last="Bandinelli">Stefania Bandinelli</name><affiliation><nlm:aff id="aff71"><addr-line>Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Eriksson, Johan" sort="Eriksson, Johan" uniqKey="Eriksson J" first="Johan" last="Eriksson">Johan Eriksson</name><affiliation><nlm:aff id="aff21"><addr-line>Folkhalsan Research Centre, Helsinki, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff72"><addr-line>National Institute for Health and Welfare, Helsinki, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff73"><addr-line>Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff74"><addr-line>Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Boomsma, Dorret I" sort="Boomsma, Dorret I" uniqKey="Boomsma D" first="Dorret I." last="Boomsma">Dorret I. Boomsma</name><affiliation><nlm:aff id="aff17"><addr-line>Department of Biological Psychology, VU University & EMGO+ institute, VU Medical Centre, Amsterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dehghan, Abbas" sort="Dehghan, Abbas" uniqKey="Dehghan A" first="Abbas" last="Dehghan">Abbas Dehghan</name><affiliation><nlm:aff id="aff18"><addr-line>Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><addr-line>Netherlands Genomics Initiative (NGI)-Sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Clarke, Robert" sort="Clarke, Robert" uniqKey="Clarke R" first="Robert" last="Clarke">Robert Clarke</name><affiliation><nlm:aff id="aff75"><addr-line>Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hamsten, Anders" sort="Hamsten, Anders" uniqKey="Hamsten A" first="Anders" last="Hamsten">Anders Hamsten</name><affiliation><nlm:aff id="aff6"><addr-line>Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Boerwinkle, Eric" sort="Boerwinkle, Eric" uniqKey="Boerwinkle E" first="Eric" last="Boerwinkle">Eric Boerwinkle</name><affiliation><nlm:aff id="aff76"><addr-line>Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jukema, J Wouter" sort="Jukema, J Wouter" uniqKey="Jukema J" first="J. Wouter" last="Jukema">J. Wouter Jukema</name><affiliation><nlm:aff id="aff9"><addr-line>Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff77"><addr-line>Durrer Center for Cardiogenetic Research, Amsterdam, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff78"><addr-line>Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Naitza, Silvia" sort="Naitza, Silvia" uniqKey="Naitza S" first="Silvia" last="Naitza">Silvia Naitza</name><affiliation><nlm:aff id="aff7"><addr-line>Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ridker, Paul M" sort="Ridker, Paul M" uniqKey="Ridker P" first="Paul M." last="Ridker">Paul M. Ridker</name><affiliation><nlm:aff id="aff79"><addr-line>Division of Preventive Medicine, Division of Cardiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Volzke, Henry" sort="Volzke, Henry" uniqKey="Volzke H" first="Henry" last="Völzke">Henry Völzke</name><affiliation><nlm:aff id="aff80"><addr-line>Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Deary, Ian J" sort="Deary, Ian J" uniqKey="Deary I" first="Ian J." last="Deary">Ian J. Deary</name><affiliation><nlm:aff id="aff11"><addr-line>Department of Psychology, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff12"><addr-line>Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Reiner, Alexander P" sort="Reiner, Alexander P" uniqKey="Reiner A" first="Alexander P." last="Reiner">Alexander P. Reiner</name><affiliation><nlm:aff id="aff42"><addr-line>Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tregouet, David Alexandre" sort="Tregouet, David Alexandre" uniqKey="Tregouet D" first="David-Alexandre" last="Trégouët">David-Alexandre Trégouët</name><affiliation><nlm:aff id="aff68"><addr-line>INSERM, UMR_S 1166, Paris, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff69"><addr-line>Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff70"><addr-line>ICAN Institute for Cardiometabolism and Nutrition, Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="O Donnell, Christopher J" sort="O Donnell, Christopher J" uniqKey="O Donnell C" first="Christopher J." last="O'Donnell">Christopher J. O'Donnell</name><affiliation><nlm:aff id="aff2"><addr-line>National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>National Heart, Lung and Blood Institute Division of Intramural Research, Bethesda, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Strachan, David P" sort="Strachan, David P" uniqKey="Strachan D" first="David P." last="Strachan">David P. Strachan</name><affiliation><nlm:aff id="aff16"><addr-line>Division of Population Health Sciences & Education, St George's, University of London, Cranmer Terrace, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Peters, Annette" sort="Peters, Annette" uniqKey="Peters A" first="Annette" last="Peters">Annette Peters</name><affiliation><nlm:aff id="aff1"><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff81"><addr-line>DZHK (German Centre for Cardiovascular Research), partner site Munich, Munich, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Smith, Nicholas L" sort="Smith, Nicholas L" uniqKey="Smith N" first="Nicholas L." last="Smith">Nicholas L. Smith</name><affiliation><nlm:aff id="aff42"><addr-line>Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff82"><addr-line>Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff83"><addr-line>Seattle Epidemiologic Research & Information Center, Veterans Affairs Office of Research & Development, Seattle, Washington, United States of America</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25551457</idno><idno type="pmc">4281156</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281156</idno><idno type="RBID">PMC:4281156</idno><idno type="doi">10.1371/journal.pone.0111156</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">002B79</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002B79</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">No Evidence for Genome-Wide Interactions on Plasma Fibrinogen by Smoking, Alcohol Consumption and Body Mass Index: Results from Meta-Analyses of 80,607 Subjects</title><author><name sortKey="Baumert, Jens" sort="Baumert, Jens" uniqKey="Baumert J" first="Jens" last="Baumert">Jens Baumert</name><affiliation><nlm:aff id="aff1"><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Huang, Jie" sort="Huang, Jie" uniqKey="Huang J" first="Jie" last="Huang">Jie Huang</name><affiliation><nlm:aff id="aff2"><addr-line>National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>National Heart, Lung and Blood Institute Division of Intramural Research, Bethesda, Maryland, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"><addr-line>Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mcknight, Barbara" sort="Mcknight, Barbara" uniqKey="Mcknight B" first="Barbara" last="Mcknight">Barbara Mcknight</name><affiliation><nlm:aff id="aff5"><addr-line>Department of Biostatistics, University of Washington, Seattle, Washington, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sabater Lleal, Maria" sort="Sabater Lleal, Maria" uniqKey="Sabater Lleal M" first="Maria" last="Sabater-Lleal">Maria Sabater-Lleal</name><affiliation><nlm:aff id="aff6"><addr-line>Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Steri, Maristella" sort="Steri, Maristella" uniqKey="Steri M" first="Maristella" last="Steri">Maristella Steri</name><affiliation><nlm:aff id="aff7"><addr-line>Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chu, Audrey Y" sort="Chu, Audrey Y" uniqKey="Chu A" first="Audrey Y." last="Chu">Audrey Y. Chu</name><affiliation><nlm:aff id="aff8"><addr-line>Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Trompet, Stella" sort="Trompet, Stella" uniqKey="Trompet S" first="Stella" last="Trompet">Stella Trompet</name><affiliation><nlm:aff id="aff9"><addr-line>Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff10"><addr-line>Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lopez, Lorna M" sort="Lopez, Lorna M" uniqKey="Lopez L" first="Lorna M." last="Lopez">Lorna M. Lopez</name><affiliation><nlm:aff id="aff11"><addr-line>Department of Psychology, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff12"><addr-line>Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fornage, Myriam" sort="Fornage, Myriam" uniqKey="Fornage M" first="Myriam" last="Fornage">Myriam Fornage</name><affiliation><nlm:aff id="aff13"><addr-line>Brown Foundation Institute of Molecular Medicine, Division of Epidemiology, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Teumer, Alexander" sort="Teumer, Alexander" uniqKey="Teumer A" first="Alexander" last="Teumer">Alexander Teumer</name><affiliation><nlm:aff id="aff14"><addr-line>Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tang, Weihong" sort="Tang, Weihong" uniqKey="Tang W" first="Weihong" last="Tang">Weihong Tang</name><affiliation><nlm:aff id="aff15"><addr-line>Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rudnicka, Alicja R" sort="Rudnicka, Alicja R" uniqKey="Rudnicka A" first="Alicja R." last="Rudnicka">Alicja R. Rudnicka</name><affiliation><nlm:aff id="aff16"><addr-line>Division of Population Health Sciences & Education, St George's, University of London, Cranmer Terrace, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="M Larstig, Anders" sort="M Larstig, Anders" uniqKey="M Larstig A" first="Anders" last="M Larstig">Anders M Larstig</name><affiliation><nlm:aff id="aff6"><addr-line>Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hottenga, Jouke Jan" sort="Hottenga, Jouke Jan" uniqKey="Hottenga J" first="Jouke-Jan" last="Hottenga">Jouke-Jan Hottenga</name><affiliation><nlm:aff id="aff17"><addr-line>Department of Biological Psychology, VU University & EMGO+ institute, VU Medical Centre, Amsterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kavousi, Maryam" sort="Kavousi, Maryam" uniqKey="Kavousi M" first="Maryam" last="Kavousi">Maryam Kavousi</name><affiliation><nlm:aff id="aff18"><addr-line>Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><addr-line>Netherlands Genomics Initiative (NGI)-Sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lahti, Jari" sort="Lahti, Jari" uniqKey="Lahti J" first="Jari" last="Lahti">Jari Lahti</name><affiliation><nlm:aff id="aff20"><addr-line>Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff21"><addr-line>Folkhalsan Research Centre, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tanaka, Toshiko" sort="Tanaka, Toshiko" uniqKey="Tanaka T" first="Toshiko" last="Tanaka">Toshiko Tanaka</name><affiliation><nlm:aff id="aff22"><addr-line>Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hayward, Caroline" sort="Hayward, Caroline" uniqKey="Hayward C" first="Caroline" last="Hayward">Caroline Hayward</name><affiliation><nlm:aff id="aff23"><addr-line>MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Huffman, Jennifer E" sort="Huffman, Jennifer E" uniqKey="Huffman J" first="Jennifer E." last="Huffman">Jennifer E. Huffman</name><affiliation><nlm:aff id="aff23"><addr-line>MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Morange, Pierre Emmanuel" sort="Morange, Pierre Emmanuel" uniqKey="Morange P" first="Pierre-Emmanuel" last="Morange">Pierre-Emmanuel Morange</name><affiliation><nlm:aff id="aff24"><addr-line>INSERM UMR_S 1062, Aix-Marseille Université, Marseille, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rose, Lynda M" sort="Rose, Lynda M" uniqKey="Rose L" first="Lynda M." last="Rose">Lynda M. Rose</name><affiliation><nlm:aff id="aff8"><addr-line>Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Basu, Saonli" sort="Basu, Saonli" uniqKey="Basu S" first="Saonli" last="Basu">Saonli Basu</name><affiliation><nlm:aff id="aff25"><addr-line>Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rumley, Ann" sort="Rumley, Ann" uniqKey="Rumley A" first="Ann" last="Rumley">Ann Rumley</name><affiliation><nlm:aff id="aff26"><addr-line>Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stott, David J" sort="Stott, David J" uniqKey="Stott D" first="David J." last="Stott">David J. Stott</name><affiliation><nlm:aff id="aff27"><addr-line>Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Buckley, Brendan M" sort="Buckley, Brendan M" uniqKey="Buckley B" first="Brendan M." last="Buckley">Brendan M. Buckley</name><affiliation><nlm:aff id="aff28"><addr-line>Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland</addr-line></nlm:aff></affiliation></author><author><name sortKey="De Craen, Anton J M" sort="De Craen, Anton J M" uniqKey="De Craen A" first="Anton J. M." last="De Craen">Anton J. M. De Craen</name><affiliation><nlm:aff id="aff10"><addr-line>Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sanna, Serena" sort="Sanna, Serena" uniqKey="Sanna S" first="Serena" last="Sanna">Serena Sanna</name><affiliation><nlm:aff id="aff7"><addr-line>Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Masala, Marco" sort="Masala, Marco" uniqKey="Masala M" first="Marco" last="Masala">Marco Masala</name><affiliation><nlm:aff id="aff7"><addr-line>Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Biffar, Reiner" sort="Biffar, Reiner" uniqKey="Biffar R" first="Reiner" last="Biffar">Reiner Biffar</name><affiliation><nlm:aff id="aff29"><addr-line>Department of Prosthetic Dentistry, Gerostomatology and Dental Materials, University Medicine Greifswald, Greifswald, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Homuth, Georg" sort="Homuth, Georg" uniqKey="Homuth G" first="Georg" last="Homuth">Georg Homuth</name><affiliation><nlm:aff id="aff14"><addr-line>Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Silveira, Angela" sort="Silveira, Angela" uniqKey="Silveira A" first="Angela" last="Silveira">Angela Silveira</name><affiliation><nlm:aff id="aff6"><addr-line>Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sennblad, Bengt" sort="Sennblad, Bengt" uniqKey="Sennblad B" first="Bengt" last="Sennblad">Bengt Sennblad</name><affiliation><nlm:aff id="aff6"><addr-line>Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff30"><addr-line>Science for Life Laboratory, Karolinska Insitutet, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Goel, Anuj" sort="Goel, Anuj" uniqKey="Goel A" first="Anuj" last="Goel">Anuj Goel</name><affiliation><nlm:aff id="aff31"><addr-line>Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff32"><addr-line>Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Watkins, Hugh" sort="Watkins, Hugh" uniqKey="Watkins H" first="Hugh" last="Watkins">Hugh Watkins</name><affiliation><nlm:aff id="aff31"><addr-line>Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff32"><addr-line>Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Muller Nurasyid, Martina" sort="Muller Nurasyid, Martina" uniqKey="Muller Nurasyid M" first="Martina" last="Müller-Nurasyid">Martina Müller-Nurasyid</name><affiliation><nlm:aff id="aff33"><addr-line>Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff34"><addr-line>Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff35"><addr-line>Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität München, Munich, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ruckerl, Regina" sort="Ruckerl, Regina" uniqKey="Ruckerl R" first="Regina" last="Rückerl">Regina Rückerl</name><affiliation><nlm:aff id="aff1"><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff36"><addr-line>ESC-Environmental Science Center, University of Augsburg, Augsburg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Taylor, Kent" sort="Taylor, Kent" uniqKey="Taylor K" first="Kent" last="Taylor">Kent Taylor</name><affiliation><nlm:aff id="aff37"><addr-line>Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chen, Ming Huei" sort="Chen, Ming Huei" uniqKey="Chen M" first="Ming-Huei" last="Chen">Ming-Huei Chen</name><affiliation><nlm:aff id="aff38"><addr-line>Department of Biostatistics, Boston University, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="De Geus, Eco J C" sort="De Geus, Eco J C" uniqKey="De Geus E" first="Eco J. C." last="De Geus">Eco J. C. De Geus</name><affiliation><nlm:aff id="aff39"><addr-line>Department of Haematology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hofman, Albert" sort="Hofman, Albert" uniqKey="Hofman A" first="Albert" last="Hofman">Albert Hofman</name><affiliation><nlm:aff id="aff18"><addr-line>Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><addr-line>Netherlands Genomics Initiative (NGI)-Sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Witteman, Jacqueline C M" sort="Witteman, Jacqueline C M" uniqKey="Witteman J" first="Jacqueline C. M." last="Witteman">Jacqueline C. M. Witteman</name><affiliation><nlm:aff id="aff18"><addr-line>Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><addr-line>Netherlands Genomics Initiative (NGI)-Sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="De Maat, Moniek P M" sort="De Maat, Moniek P M" uniqKey="De Maat M" first="Moniek P. M." last="De Maat">Moniek P. M. De Maat</name><affiliation><nlm:aff id="aff39"><addr-line>Department of Haematology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Palotie, Aarno" sort="Palotie, Aarno" uniqKey="Palotie A" first="Aarno" last="Palotie">Aarno Palotie</name><affiliation><nlm:aff id="aff40"><addr-line>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff41"><addr-line>Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff42"><addr-line>Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Davies, Gail" sort="Davies, Gail" uniqKey="Davies G" first="Gail" last="Davies">Gail Davies</name><affiliation><nlm:aff id="aff11"><addr-line>Department of Psychology, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff12"><addr-line>Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Siscovick, David S" sort="Siscovick, David S" uniqKey="Siscovick D" first="David S." last="Siscovick">David S. Siscovick</name><affiliation><nlm:aff id="aff43"><addr-line>Department of Epidemiology, University of Washington, Seattle, Washington, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kolcic, Ivana" sort="Kolcic, Ivana" uniqKey="Kolcic I" first="Ivana" last="Kolcic">Ivana Kolcic</name><affiliation><nlm:aff id="aff44"><addr-line>Department of Public Health, University of Split Medical School, Split, Croatia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wild, Sarah H" sort="Wild, Sarah H" uniqKey="Wild S" first="Sarah H." last="Wild">Sarah H. Wild</name><affiliation><nlm:aff id="aff45"><addr-line>Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, Scotland, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Song, Jaejoon" sort="Song, Jaejoon" uniqKey="Song J" first="Jaejoon" last="Song">Jaejoon Song</name><affiliation><nlm:aff id="aff25"><addr-line>Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mcardle, Wendy L" sort="Mcardle, Wendy L" uniqKey="Mcardle W" first="Wendy L." last="Mcardle">Wendy L. Mcardle</name><affiliation><nlm:aff id="aff46"><addr-line>School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ford, Ian" sort="Ford, Ian" uniqKey="Ford I" first="Ian" last="Ford">Ian Ford</name><affiliation><nlm:aff id="aff47"><addr-line>Robertson Center for Biostatistics, University of Glasgow, Glasgow, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sattar, Naveed" sort="Sattar, Naveed" uniqKey="Sattar N" first="Naveed" last="Sattar">Naveed Sattar</name><affiliation><nlm:aff id="aff48"><addr-line>BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Schlessinger, David" sort="Schlessinger, David" uniqKey="Schlessinger D" first="David" last="Schlessinger">David Schlessinger</name><affiliation><nlm:aff id="aff49"><addr-line>Intramural Research Program, National Institute on Aging, Baltimore, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Grotevendt, Anne" sort="Grotevendt, Anne" uniqKey="Grotevendt A" first="Anne" last="Grotevendt">Anne Grotevendt</name><affiliation><nlm:aff id="aff50"><addr-line>Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Franzosi, Maria Grazia" sort="Franzosi, Maria Grazia" uniqKey="Franzosi M" first="Maria Grazia" last="Franzosi">Maria Grazia Franzosi</name><affiliation><nlm:aff id="aff51"><addr-line>Department of Cardiovascular Research, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Illig, Thomas" sort="Illig, Thomas" uniqKey="Illig T" first="Thomas" last="Illig">Thomas Illig</name><affiliation><nlm:aff id="aff52"><addr-line>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff53"><addr-line>Hannover Unified Biobank, Hannover Medical School, Hannover, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Waldenberger, Melanie" sort="Waldenberger, Melanie" uniqKey="Waldenberger M" first="Melanie" last="Waldenberger">Melanie Waldenberger</name><affiliation><nlm:aff id="aff52"><addr-line>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lumley, Thomas" sort="Lumley, Thomas" uniqKey="Lumley T" first="Thomas" last="Lumley">Thomas Lumley</name><affiliation><nlm:aff id="aff54"><addr-line>Department of Statistics, University of Auckland, Auckland, New Zealand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tofler, Geoffrey H" sort="Tofler, Geoffrey H" uniqKey="Tofler G" first="Geoffrey H." last="Tofler">Geoffrey H. Tofler</name><affiliation><nlm:aff id="aff55"><addr-line>Royal North Shore Hospital, University of Sydney, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Willemsen, Gonneke" sort="Willemsen, Gonneke" uniqKey="Willemsen G" first="Gonneke" last="Willemsen">Gonneke Willemsen</name><affiliation><nlm:aff id="aff17"><addr-line>Department of Biological Psychology, VU University & EMGO+ institute, VU Medical Centre, Amsterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Uitterlinden, Andre G" sort="Uitterlinden, Andre G" uniqKey="Uitterlinden A" first="André G." last="Uitterlinden">André G. Uitterlinden</name><affiliation><nlm:aff id="aff18"><addr-line>Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><addr-line>Netherlands Genomics Initiative (NGI)-Sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff56"><addr-line>Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rivadeneira, Fernando" sort="Rivadeneira, Fernando" uniqKey="Rivadeneira F" first="Fernando" last="Rivadeneira">Fernando Rivadeneira</name><affiliation><nlm:aff id="aff57"><addr-line>Division of Preventive Medicine, Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="R Ikkonen, Katri" sort="R Ikkonen, Katri" uniqKey="R Ikkonen K" first="Katri" last="R Ikkönen">Katri R Ikkönen</name><affiliation><nlm:aff id="aff20"><addr-line>Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chasman, Daniel I" sort="Chasman, Daniel I" uniqKey="Chasman D" first="Daniel I." last="Chasman">Daniel I. Chasman</name><affiliation><nlm:aff id="aff57"><addr-line>Division of Preventive Medicine, Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Folsom, Aaron R" sort="Folsom, Aaron R" uniqKey="Folsom A" first="Aaron R." last="Folsom">Aaron R. Folsom</name><affiliation><nlm:aff id="aff15"><addr-line>Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lowe, Gordon D" sort="Lowe, Gordon D" uniqKey="Lowe G" first="Gordon D." last="Lowe">Gordon D. Lowe</name><affiliation><nlm:aff id="aff58"><addr-line>Institute of Cardiovascular & Medical Sciences, University of Glasgow, Glasgow, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Westendorp, Rudi G J" sort="Westendorp, Rudi G J" uniqKey="Westendorp R" first="Rudi G. J." last="Westendorp">Rudi G. J. Westendorp</name><affiliation><nlm:aff id="aff10"><addr-line>Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Slagboom, P Eline" sort="Slagboom, P Eline" uniqKey="Slagboom P" first="P. Eline" last="Slagboom">P. Eline Slagboom</name><affiliation><nlm:aff id="aff59"><addr-line>Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cucca, Francesco" sort="Cucca, Francesco" uniqKey="Cucca F" first="Francesco" last="Cucca">Francesco Cucca</name><affiliation><nlm:aff id="aff7"><addr-line>Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wallaschofski, Henri" sort="Wallaschofski, Henri" uniqKey="Wallaschofski H" first="Henri" last="Wallaschofski">Henri Wallaschofski</name><affiliation><nlm:aff id="aff49"><addr-line>Intramural Research Program, National Institute on Aging, Baltimore, Maryland, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff60"><addr-line>DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Strawbridge, Rona J" sort="Strawbridge, Rona J" uniqKey="Strawbridge R" first="Rona J." last="Strawbridge">Rona J. Strawbridge</name><affiliation><nlm:aff id="aff6"><addr-line>Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Seedorf, Udo" sort="Seedorf, Udo" uniqKey="Seedorf U" first="Udo" last="Seedorf">Udo Seedorf</name><affiliation><nlm:aff id="aff61"><addr-line>Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Koenig, Wolfgang" sort="Koenig, Wolfgang" uniqKey="Koenig W" first="Wolfgang" last="Koenig">Wolfgang Koenig</name><affiliation><nlm:aff id="aff62"><addr-line>Department of Internal Medicine II - Cardiology, University of Ulm Medical Center, Ulm, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bis, Joshua C" sort="Bis, Joshua C" uniqKey="Bis J" first="Joshua C." last="Bis">Joshua C. Bis</name><affiliation><nlm:aff id="aff63"><addr-line>Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mukamal, Kenneth J" sort="Mukamal, Kenneth J" uniqKey="Mukamal K" first="Kenneth J." last="Mukamal">Kenneth J. Mukamal</name><affiliation><nlm:aff id="aff64"><addr-line>Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff65"><addr-line>Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Van Dongen, Jenny" sort="Van Dongen, Jenny" uniqKey="Van Dongen J" first="Jenny" last="Van Dongen">Jenny Van Dongen</name><affiliation><nlm:aff id="aff17"><addr-line>Department of Biological Psychology, VU University & EMGO+ institute, VU Medical Centre, Amsterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Widen, Elisabeth" sort="Widen, Elisabeth" uniqKey="Widen E" first="Elisabeth" last="Widen">Elisabeth Widen</name><affiliation><nlm:aff id="aff40"><addr-line>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Franco, Oscar H" sort="Franco, Oscar H" uniqKey="Franco O" first="Oscar H." last="Franco">Oscar H. Franco</name><affiliation><nlm:aff id="aff18"><addr-line>Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><addr-line>Netherlands Genomics Initiative (NGI)-Sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Starr, John M" sort="Starr, John M" uniqKey="Starr J" first="John M." last="Starr">John M. Starr</name><affiliation><nlm:aff id="aff12"><addr-line>Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff66"><addr-line>Alzheimer Scotland Dementia Research Centre, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Liu, Kiang" sort="Liu, Kiang" uniqKey="Liu K" first="Kiang" last="Liu">Kiang Liu</name><affiliation><nlm:aff id="aff67"><addr-line>Department of Preventive Medicine, Northwestern University Medical School, Chicago, Illinois, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ferrucci, Luigi" sort="Ferrucci, Luigi" uniqKey="Ferrucci L" first="Luigi" last="Ferrucci">Luigi Ferrucci</name><affiliation><nlm:aff id="aff22"><addr-line>Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Polasek, Ozren" sort="Polasek, Ozren" uniqKey="Polasek O" first="Ozren" last="Polasek">Ozren Polasek</name><affiliation><nlm:aff id="aff43"><addr-line>Department of Epidemiology, University of Washington, Seattle, Washington, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wilson, James F" sort="Wilson, James F" uniqKey="Wilson J" first="James F." last="Wilson">James F. Wilson</name><affiliation><nlm:aff id="aff44"><addr-line>Department of Public Health, University of Split Medical School, Split, Croatia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Oudot Mellakh, Tiphaine" sort="Oudot Mellakh, Tiphaine" uniqKey="Oudot Mellakh T" first="Tiphaine" last="Oudot-Mellakh">Tiphaine Oudot-Mellakh</name><affiliation><nlm:aff id="aff68"><addr-line>INSERM, UMR_S 1166, Paris, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff69"><addr-line>Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff70"><addr-line>ICAN Institute for Cardiometabolism and Nutrition, Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Campbell, Harry" sort="Campbell, Harry" uniqKey="Campbell H" first="Harry" last="Campbell">Harry Campbell</name><affiliation><nlm:aff id="aff44"><addr-line>Department of Public Health, University of Split Medical School, Split, Croatia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Navarro, Pau" sort="Navarro, Pau" uniqKey="Navarro P" first="Pau" last="Navarro">Pau Navarro</name><affiliation><nlm:aff id="aff23"><addr-line>MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bandinelli, Stefania" sort="Bandinelli, Stefania" uniqKey="Bandinelli S" first="Stefania" last="Bandinelli">Stefania Bandinelli</name><affiliation><nlm:aff id="aff71"><addr-line>Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Eriksson, Johan" sort="Eriksson, Johan" uniqKey="Eriksson J" first="Johan" last="Eriksson">Johan Eriksson</name><affiliation><nlm:aff id="aff21"><addr-line>Folkhalsan Research Centre, Helsinki, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff72"><addr-line>National Institute for Health and Welfare, Helsinki, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff73"><addr-line>Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff74"><addr-line>Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Boomsma, Dorret I" sort="Boomsma, Dorret I" uniqKey="Boomsma D" first="Dorret I." last="Boomsma">Dorret I. Boomsma</name><affiliation><nlm:aff id="aff17"><addr-line>Department of Biological Psychology, VU University & EMGO+ institute, VU Medical Centre, Amsterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dehghan, Abbas" sort="Dehghan, Abbas" uniqKey="Dehghan A" first="Abbas" last="Dehghan">Abbas Dehghan</name><affiliation><nlm:aff id="aff18"><addr-line>Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><addr-line>Netherlands Genomics Initiative (NGI)-Sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Clarke, Robert" sort="Clarke, Robert" uniqKey="Clarke R" first="Robert" last="Clarke">Robert Clarke</name><affiliation><nlm:aff id="aff75"><addr-line>Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hamsten, Anders" sort="Hamsten, Anders" uniqKey="Hamsten A" first="Anders" last="Hamsten">Anders Hamsten</name><affiliation><nlm:aff id="aff6"><addr-line>Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Boerwinkle, Eric" sort="Boerwinkle, Eric" uniqKey="Boerwinkle E" first="Eric" last="Boerwinkle">Eric Boerwinkle</name><affiliation><nlm:aff id="aff76"><addr-line>Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jukema, J Wouter" sort="Jukema, J Wouter" uniqKey="Jukema J" first="J. Wouter" last="Jukema">J. Wouter Jukema</name><affiliation><nlm:aff id="aff9"><addr-line>Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff77"><addr-line>Durrer Center for Cardiogenetic Research, Amsterdam, the Netherlands</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff78"><addr-line>Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Naitza, Silvia" sort="Naitza, Silvia" uniqKey="Naitza S" first="Silvia" last="Naitza">Silvia Naitza</name><affiliation><nlm:aff id="aff7"><addr-line>Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy</addr-line></nlm:aff></affiliation></author><author><name sortKey="Ridker, Paul M" sort="Ridker, Paul M" uniqKey="Ridker P" first="Paul M." last="Ridker">Paul M. Ridker</name><affiliation><nlm:aff id="aff79"><addr-line>Division of Preventive Medicine, Division of Cardiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Volzke, Henry" sort="Volzke, Henry" uniqKey="Volzke H" first="Henry" last="Völzke">Henry Völzke</name><affiliation><nlm:aff id="aff80"><addr-line>Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Deary, Ian J" sort="Deary, Ian J" uniqKey="Deary I" first="Ian J." last="Deary">Ian J. Deary</name><affiliation><nlm:aff id="aff11"><addr-line>Department of Psychology, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff12"><addr-line>Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Reiner, Alexander P" sort="Reiner, Alexander P" uniqKey="Reiner A" first="Alexander P." last="Reiner">Alexander P. Reiner</name><affiliation><nlm:aff id="aff42"><addr-line>Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tregouet, David Alexandre" sort="Tregouet, David Alexandre" uniqKey="Tregouet D" first="David-Alexandre" last="Trégouët">David-Alexandre Trégouët</name><affiliation><nlm:aff id="aff68"><addr-line>INSERM, UMR_S 1166, Paris, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff69"><addr-line>Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff70"><addr-line>ICAN Institute for Cardiometabolism and Nutrition, Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="O Donnell, Christopher J" sort="O Donnell, Christopher J" uniqKey="O Donnell C" first="Christopher J." last="O'Donnell">Christopher J. O'Donnell</name><affiliation><nlm:aff id="aff2"><addr-line>National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff3"><addr-line>National Heart, Lung and Blood Institute Division of Intramural Research, Bethesda, Maryland, United States of America</addr-line></nlm:aff></affiliation></author><author><name sortKey="Strachan, David P" sort="Strachan, David P" uniqKey="Strachan D" first="David P." last="Strachan">David P. Strachan</name><affiliation><nlm:aff id="aff16"><addr-line>Division of Population Health Sciences & Education, St George's, University of London, Cranmer Terrace, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Peters, Annette" sort="Peters, Annette" uniqKey="Peters A" first="Annette" last="Peters">Annette Peters</name><affiliation><nlm:aff id="aff1"><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff81"><addr-line>DZHK (German Centre for Cardiovascular Research), partner site Munich, Munich, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Smith, Nicholas L" sort="Smith, Nicholas L" uniqKey="Smith N" first="Nicholas L." last="Smith">Nicholas L. Smith</name><affiliation><nlm:aff id="aff42"><addr-line>Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff82"><addr-line>Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff83"><addr-line>Seattle Epidemiologic Research & Information Center, Veterans Affairs Office of Research & Development, Seattle, Washington, United States of America</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2×10<sup>−8</sup>. This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</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">25551457</article-id><article-id pub-id-type="pmc">4281156</article-id><article-id pub-id-type="publisher-id">PONE-D-14-08020</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0111156</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 and Health Sciences</subject><subj-group><subject>Cardiology</subject></subj-group><subj-group><subject>Clinical Genetics</subject></subj-group><subj-group><subject>Epidemiology</subject></subj-group><subj-group><subject>Hematology</subject></subj-group></subj-group></article-categories><title-group><article-title>No Evidence for Genome-Wide Interactions on Plasma Fibrinogen by Smoking, Alcohol Consumption and Body Mass Index: Results from Meta-Analyses of 80,607 Subjects</article-title><alt-title alt-title-type="running-head">Genome-Wide Interactions on Fibrinogen</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Baumert</surname><given-names>Jens</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Huang</surname><given-names>Jie</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>McKnight</surname><given-names>Barbara</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Sabater-Lleal</surname><given-names>Maria</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Steri</surname><given-names>Maristella</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chu</surname><given-names>Audrey Y.</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Trompet</surname><given-names>Stella</given-names></name><xref ref-type="aff" rid="aff9"><sup>9</sup></xref><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lopez</surname><given-names>Lorna M.</given-names></name><xref ref-type="aff" rid="aff11"><sup>11</sup></xref><xref ref-type="aff" rid="aff12"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fornage</surname><given-names>Myriam</given-names></name><xref ref-type="aff" rid="aff13"><sup>13</sup></xref></contrib><contrib contrib-type="author"><name><surname>Teumer</surname><given-names>Alexander</given-names></name><xref ref-type="aff" rid="aff14"><sup>14</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tang</surname><given-names>Weihong</given-names></name><xref ref-type="aff" rid="aff15"><sup>15</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rudnicka</surname><given-names>Alicja R.</given-names></name><xref ref-type="aff" rid="aff16"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mälarstig</surname><given-names>Anders</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hottenga</surname><given-names>Jouke-Jan</given-names></name><xref ref-type="aff" rid="aff17"><sup>17</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kavousi</surname><given-names>Maryam</given-names></name><xref ref-type="aff" rid="aff18"><sup>18</sup></xref><xref ref-type="aff" rid="aff19"><sup>19</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lahti</surname><given-names>Jari</given-names></name><xref ref-type="aff" rid="aff20"><sup>20</sup></xref><xref ref-type="aff" rid="aff21"><sup>21</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tanaka</surname><given-names>Toshiko</given-names></name><xref ref-type="aff" rid="aff22"><sup>22</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hayward</surname><given-names>Caroline</given-names></name><xref ref-type="aff" rid="aff23"><sup>23</sup></xref></contrib><contrib contrib-type="author"><name><surname>Huffman</surname><given-names>Jennifer E.</given-names></name><xref ref-type="aff" rid="aff23"><sup>23</sup></xref></contrib><contrib contrib-type="author"><name><surname>Morange</surname><given-names>Pierre-Emmanuel</given-names></name><xref ref-type="aff" rid="aff24"><sup>24</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rose</surname><given-names>Lynda M.</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Basu</surname><given-names>Saonli</given-names></name><xref ref-type="aff" rid="aff25"><sup>25</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rumley</surname><given-names>Ann</given-names></name><xref ref-type="aff" rid="aff26"><sup>26</sup></xref></contrib><contrib contrib-type="author"><name><surname>Stott</surname><given-names>David J.</given-names></name><xref ref-type="aff" rid="aff27"><sup>27</sup></xref></contrib><contrib contrib-type="author"><name><surname>Buckley</surname><given-names>Brendan M.</given-names></name><xref ref-type="aff" rid="aff28"><sup>28</sup></xref></contrib><contrib contrib-type="author"><name><surname>de Craen</surname><given-names>Anton J. M.</given-names></name><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sanna</surname><given-names>Serena</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Masala</surname><given-names>Marco</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Biffar</surname><given-names>Reiner</given-names></name><xref ref-type="aff" rid="aff29"><sup>29</sup></xref></contrib><contrib contrib-type="author"><name><surname>Homuth</surname><given-names>Georg</given-names></name><xref ref-type="aff" rid="aff14"><sup>14</sup></xref></contrib><contrib contrib-type="author"><name><surname>Silveira</surname><given-names>Angela</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sennblad</surname><given-names>Bengt</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref><xref ref-type="aff" rid="aff30"><sup>30</sup></xref></contrib><contrib contrib-type="author"><name><surname>Goel</surname><given-names>Anuj</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>Watkins</surname><given-names>Hugh</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>Müller-Nurasyid</surname><given-names>Martina</given-names></name><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>Rückerl</surname><given-names>Regina</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff36"><sup>36</sup></xref></contrib><contrib contrib-type="author"><name><surname>Taylor</surname><given-names>Kent</given-names></name><xref ref-type="aff" rid="aff37"><sup>37</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Ming-Huei</given-names></name><xref ref-type="aff" rid="aff38"><sup>38</sup></xref></contrib><contrib contrib-type="author"><name><surname>de Geus</surname><given-names>Eco J. C.</given-names></name><xref ref-type="aff" rid="aff39"><sup>39</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hofman</surname><given-names>Albert</given-names></name><xref ref-type="aff" rid="aff18"><sup>18</sup></xref><xref ref-type="aff" rid="aff19"><sup>19</sup></xref></contrib><contrib contrib-type="author"><name><surname>Witteman</surname><given-names>Jacqueline C. M.</given-names></name><xref ref-type="aff" rid="aff18"><sup>18</sup></xref><xref ref-type="aff" rid="aff19"><sup>19</sup></xref></contrib><contrib contrib-type="author"><name><surname>de Maat</surname><given-names>Moniek P. 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J.</given-names></name><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Slagboom</surname><given-names>P. Eline</given-names></name><xref ref-type="aff" rid="aff59"><sup>59</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cucca</surname><given-names>Francesco</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wallaschofski</surname><given-names>Henri</given-names></name><xref ref-type="aff" rid="aff49"><sup>49</sup></xref><xref ref-type="aff" rid="aff60"><sup>60</sup></xref></contrib><contrib contrib-type="author"><name><surname>Strawbridge</surname><given-names>Rona J.</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Seedorf</surname><given-names>Udo</given-names></name><xref ref-type="aff" rid="aff61"><sup>61</sup></xref></contrib><contrib contrib-type="author"><name><surname>Koenig</surname><given-names>Wolfgang</given-names></name><xref ref-type="aff" rid="aff62"><sup>62</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bis</surname><given-names>Joshua C.</given-names></name><xref ref-type="aff" rid="aff63"><sup>63</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mukamal</surname><given-names>Kenneth J.</given-names></name><xref ref-type="aff" rid="aff64"><sup>64</sup></xref><xref ref-type="aff" rid="aff65"><sup>65</sup></xref></contrib><contrib contrib-type="author"><name><surname>van Dongen</surname><given-names>Jenny</given-names></name><xref ref-type="aff" rid="aff17"><sup>17</sup></xref></contrib><contrib contrib-type="author"><name><surname>Widen</surname><given-names>Elisabeth</given-names></name><xref ref-type="aff" rid="aff40"><sup>40</sup></xref></contrib><contrib contrib-type="author"><name><surname>Franco</surname><given-names>Oscar H.</given-names></name><xref ref-type="aff" rid="aff18"><sup>18</sup></xref><xref ref-type="aff" rid="aff19"><sup>19</sup></xref></contrib><contrib contrib-type="author"><name><surname>Starr</surname><given-names>John M.</given-names></name><xref ref-type="aff" rid="aff12"><sup>12</sup></xref><xref ref-type="aff" rid="aff66"><sup>66</sup></xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Kiang</given-names></name><xref ref-type="aff" rid="aff67"><sup>67</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ferrucci</surname><given-names>Luigi</given-names></name><xref ref-type="aff" rid="aff22"><sup>22</sup></xref></contrib><contrib contrib-type="author"><name><surname>Polasek</surname><given-names>Ozren</given-names></name><xref ref-type="aff" rid="aff43"><sup>43</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wilson</surname><given-names>James F.</given-names></name><xref ref-type="aff" rid="aff44"><sup>44</sup></xref></contrib><contrib contrib-type="author"><name><surname>Oudot-Mellakh</surname><given-names>Tiphaine</given-names></name><xref ref-type="aff" rid="aff68"><sup>68</sup></xref><xref ref-type="aff" rid="aff69"><sup>69</sup></xref><xref ref-type="aff" rid="aff70"><sup>70</sup></xref></contrib><contrib contrib-type="author"><name><surname>Campbell</surname><given-names>Harry</given-names></name><xref ref-type="aff" rid="aff44"><sup>44</sup></xref></contrib><contrib contrib-type="author"><name><surname>Navarro</surname><given-names>Pau</given-names></name><xref ref-type="aff" rid="aff23"><sup>23</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bandinelli</surname><given-names>Stefania</given-names></name><xref ref-type="aff" rid="aff71"><sup>71</sup></xref></contrib><contrib contrib-type="author"><name><surname>Eriksson</surname><given-names>Johan</given-names></name><xref ref-type="aff" rid="aff21"><sup>21</sup></xref><xref ref-type="aff" rid="aff72"><sup>72</sup></xref><xref ref-type="aff" rid="aff73"><sup>73</sup></xref><xref ref-type="aff" rid="aff74"><sup>74</sup></xref></contrib><contrib contrib-type="author"><name><surname>Boomsma</surname><given-names>Dorret I.</given-names></name><xref ref-type="aff" rid="aff17"><sup>17</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dehghan</surname><given-names>Abbas</given-names></name><xref ref-type="aff" rid="aff18"><sup>18</sup></xref><xref ref-type="aff" rid="aff19"><sup>19</sup></xref></contrib><contrib contrib-type="author"><name><surname>Clarke</surname><given-names>Robert</given-names></name><xref ref-type="aff" rid="aff75"><sup>75</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hamsten</surname><given-names>Anders</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Boerwinkle</surname><given-names>Eric</given-names></name><xref ref-type="aff" rid="aff76"><sup>76</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jukema</surname><given-names>J. Wouter</given-names></name><xref ref-type="aff" rid="aff9"><sup>9</sup></xref><xref ref-type="aff" rid="aff77"><sup>77</sup></xref><xref ref-type="aff" rid="aff78"><sup>78</sup></xref></contrib><contrib contrib-type="author"><name><surname>Naitza</surname><given-names>Silvia</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ridker</surname><given-names>Paul M.</given-names></name><xref ref-type="aff" rid="aff79"><sup>79</sup></xref></contrib><contrib contrib-type="author"><name><surname>Völzke</surname><given-names>Henry</given-names></name><xref ref-type="aff" rid="aff80"><sup>80</sup></xref></contrib><contrib contrib-type="author"><name><surname>Deary</surname><given-names>Ian J.</given-names></name><xref ref-type="aff" rid="aff11"><sup>11</sup></xref><xref ref-type="aff" rid="aff12"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Reiner</surname><given-names>Alexander P.</given-names></name><xref ref-type="aff" rid="aff42"><sup>42</sup></xref></contrib><contrib contrib-type="author"><name><surname>Trégouët</surname><given-names>David-Alexandre</given-names></name><xref ref-type="aff" rid="aff68"><sup>68</sup></xref><xref ref-type="aff" rid="aff69"><sup>69</sup></xref><xref ref-type="aff" rid="aff70"><sup>70</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>¶</sup></xref></contrib><contrib contrib-type="author"><name><surname>O'Donnell</surname><given-names>Christopher J.</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>¶</sup></xref></contrib><contrib contrib-type="author"><name><surname>Strachan</surname><given-names>David P.</given-names></name><xref ref-type="aff" rid="aff16"><sup>16</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>¶</sup></xref></contrib><contrib contrib-type="author"><name><surname>Peters</surname><given-names>Annette</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff81"><sup>81</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>¶</sup></xref></contrib><contrib contrib-type="author"><name><surname>Smith</surname><given-names>Nicholas L.</given-names></name><xref ref-type="aff" rid="aff42"><sup>42</sup></xref><xref ref-type="aff" rid="aff82"><sup>82</sup></xref><xref ref-type="aff" rid="aff83"><sup>83</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>¶</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</addr-line></aff><aff id="aff2"><label>2</label><addr-line>National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America</addr-line></aff><aff id="aff3"><label>3</label><addr-line>National Heart, Lung and Blood Institute Division of Intramural Research, Bethesda, Maryland, United States of America</addr-line></aff><aff id="aff4"><label>4</label><addr-line>Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom</addr-line></aff><aff id="aff5"><label>5</label><addr-line>Department of Biostatistics, University of Washington, Seattle, Washington, United States of America</addr-line></aff><aff id="aff6"><label>6</label><addr-line>Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden</addr-line></aff><aff id="aff7"><label>7</label><addr-line>Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Cagliari, Italy</addr-line></aff><aff id="aff8"><label>8</label><addr-line>Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America</addr-line></aff><aff id="aff9"><label>9</label><addr-line>Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands</addr-line></aff><aff id="aff10"><label>10</label><addr-line>Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands</addr-line></aff><aff id="aff11"><label>11</label><addr-line>Department of Psychology, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></aff><aff id="aff12"><label>12</label><addr-line>Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></aff><aff id="aff13"><label>13</label><addr-line>Brown Foundation Institute of Molecular Medicine, Division of Epidemiology, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, United States of America</addr-line></aff><aff id="aff14"><label>14</label><addr-line>Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany</addr-line></aff><aff id="aff15"><label>15</label><addr-line>Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America</addr-line></aff><aff id="aff16"><label>16</label><addr-line>Division of Population Health Sciences & Education, St George's, University of London, Cranmer Terrace, London, United Kingdom</addr-line></aff><aff id="aff17"><label>17</label><addr-line>Department of Biological Psychology, VU University & EMGO+ institute, VU Medical Centre, Amsterdam, the Netherlands</addr-line></aff><aff id="aff18"><label>18</label><addr-line>Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></aff><aff id="aff19"><label>19</label><addr-line>Netherlands Genomics Initiative (NGI)-Sponsored Netherlands Consortium for Healthy Aging (NCHA), Rotterdam, the Netherlands</addr-line></aff><aff id="aff20"><label>20</label><addr-line>Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland</addr-line></aff><aff id="aff21"><label>21</label><addr-line>Folkhalsan Research Centre, Helsinki, Finland</addr-line></aff><aff id="aff22"><label>22</label><addr-line>Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland, United States of America</addr-line></aff><aff id="aff23"><label>23</label><addr-line>MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland, United Kingdom</addr-line></aff><aff id="aff24"><label>24</label><addr-line>INSERM UMR_S 1062, Aix-Marseille Université, Marseille, France</addr-line></aff><aff id="aff25"><label>25</label><addr-line>Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota, United States of America</addr-line></aff><aff id="aff26"><label>26</label><addr-line>Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom</addr-line></aff><aff id="aff27"><label>27</label><addr-line>Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom</addr-line></aff><aff id="aff28"><label>28</label><addr-line>Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland</addr-line></aff><aff id="aff29"><label>29</label><addr-line>Department of Prosthetic Dentistry, Gerostomatology and Dental Materials, University Medicine Greifswald, Greifswald, Germany</addr-line></aff><aff id="aff30"><label>30</label><addr-line>Science for Life Laboratory, Karolinska Insitutet, Stockholm, Sweden</addr-line></aff><aff id="aff31"><label>31</label><addr-line>Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, United Kingdom</addr-line></aff><aff id="aff32"><label>32</label><addr-line>Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom</addr-line></aff><aff id="aff33"><label>33</label><addr-line>Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</addr-line></aff><aff id="aff34"><label>34</label><addr-line>Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany</addr-line></aff><aff id="aff35"><label>35</label><addr-line>Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität München, Munich, Germany</addr-line></aff><aff id="aff36"><label>36</label><addr-line>ESC-Environmental Science Center, University of Augsburg, Augsburg, Germany</addr-line></aff><aff id="aff37"><label>37</label><addr-line>Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America</addr-line></aff><aff id="aff38"><label>38</label><addr-line>Department of Biostatistics, Boston University, Boston, Massachusetts, United States of America</addr-line></aff><aff id="aff39"><label>39</label><addr-line>Department of Haematology, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></aff><aff id="aff40"><label>40</label><addr-line>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom</addr-line></aff><aff id="aff41"><label>41</label><addr-line>Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland</addr-line></aff><aff id="aff42"><label>42</label><addr-line>Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland</addr-line></aff><aff id="aff43"><label>43</label><addr-line>Department of Epidemiology, University of Washington, Seattle, Washington, United States of America</addr-line></aff><aff id="aff44"><label>44</label><addr-line>Department of Public Health, University of Split Medical School, Split, Croatia</addr-line></aff><aff id="aff45"><label>45</label><addr-line>Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, Scotland, United Kingdom</addr-line></aff><aff id="aff46"><label>46</label><addr-line>School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom</addr-line></aff><aff id="aff47"><label>47</label><addr-line>Robertson Center for Biostatistics, University of Glasgow, Glasgow, United Kingdom</addr-line></aff><aff id="aff48"><label>48</label><addr-line>BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow, United Kingdom</addr-line></aff><aff id="aff49"><label>49</label><addr-line>Intramural Research Program, National Institute on Aging, Baltimore, Maryland, United States of America</addr-line></aff><aff id="aff50"><label>50</label><addr-line>Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany</addr-line></aff><aff id="aff51"><label>51</label><addr-line>Department of Cardiovascular Research, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy</addr-line></aff><aff id="aff52"><label>52</label><addr-line>Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</addr-line></aff><aff id="aff53"><label>53</label><addr-line>Hannover Unified Biobank, Hannover Medical School, Hannover, Germany</addr-line></aff><aff id="aff54"><label>54</label><addr-line>Department of Statistics, University of Auckland, Auckland, New Zealand</addr-line></aff><aff id="aff55"><label>55</label><addr-line>Royal North Shore Hospital, University of Sydney, Sydney, Australia</addr-line></aff><aff id="aff56"><label>56</label><addr-line>Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands</addr-line></aff><aff id="aff57"><label>57</label><addr-line>Division of Preventive Medicine, Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></aff><aff id="aff58"><label>58</label><addr-line>Institute of Cardiovascular & Medical Sciences, University of Glasgow, Glasgow, United Kingdom</addr-line></aff><aff id="aff59"><label>59</label><addr-line>Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands</addr-line></aff><aff id="aff60"><label>60</label><addr-line>DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, Germany</addr-line></aff><aff id="aff61"><label>61</label><addr-line>Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany</addr-line></aff><aff id="aff62"><label>62</label><addr-line>Department of Internal Medicine II - Cardiology, University of Ulm Medical Center, Ulm, Germany</addr-line></aff><aff id="aff63"><label>63</label><addr-line>Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America</addr-line></aff><aff id="aff64"><label>64</label><addr-line>Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></aff><aff id="aff65"><label>65</label><addr-line>Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America</addr-line></aff><aff id="aff66"><label>66</label><addr-line>Alzheimer Scotland Dementia Research Centre, The University of Edinburgh, Edinburgh, United Kingdom</addr-line></aff><aff id="aff67"><label>67</label><addr-line>Department of Preventive Medicine, Northwestern University Medical School, Chicago, Illinois, United States of America</addr-line></aff><aff id="aff68"><label>68</label><addr-line>INSERM, UMR_S 1166, Paris, France</addr-line></aff><aff id="aff69"><label>69</label><addr-line>Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France</addr-line></aff><aff id="aff70"><label>70</label><addr-line>ICAN Institute for Cardiometabolism and Nutrition, Paris, France</addr-line></aff><aff id="aff71"><label>71</label><addr-line>Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy</addr-line></aff><aff id="aff72"><label>72</label><addr-line>National Institute for Health and Welfare, Helsinki, Finland</addr-line></aff><aff id="aff73"><label>73</label><addr-line>Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland</addr-line></aff><aff id="aff74"><label>74</label><addr-line>Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland</addr-line></aff><aff id="aff75"><label>75</label><addr-line>Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom</addr-line></aff><aff id="aff76"><label>76</label><addr-line>Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, United States of America</addr-line></aff><aff id="aff77"><label>77</label><addr-line>Durrer Center for Cardiogenetic Research, Amsterdam, the Netherlands</addr-line></aff><aff id="aff78"><label>78</label><addr-line>Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands</addr-line></aff><aff id="aff79"><label>79</label><addr-line>Division of Preventive Medicine, Division of Cardiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America</addr-line></aff><aff id="aff80"><label>80</label><addr-line>Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany</addr-line></aff><aff id="aff81"><label>81</label><addr-line>DZHK (German Centre for Cardiovascular Research), partner site Munich, Munich, Germany</addr-line></aff><aff id="aff82"><label>82</label><addr-line>Group Health Research Institute, Group Health Cooperative, Seattle, Washington, United States of America</addr-line></aff><aff id="aff83"><label>83</label><addr-line>Seattle Epidemiologic Research & Information Center, Veterans Affairs Office of Research & Development, Seattle, Washington, United States of America</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Meyre</surname><given-names>David</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>McMaster University, Canada</addr-line></aff><author-notes><corresp id="cor1">* E-mail: <email>peters@helmholtz-muenchen.de</email> (A. Peters); <email>nlsmith@u.washington.edu</email> (NLS)</corresp><fn fn-type="conflict"><p><bold>Competing Interests: </bold>The authors have the following interests: The Framingham Heart Study (FHS) was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). The PROSPER/PHASE study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Dr. Kavousi is supported by AXA Research Fund. Oscar H. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestle Nutrition (Nestec Ltd), Metagenics Inc, and AXA. Part of the SHIP study was funded by a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg West Pomerania. The University of Greifswald is a member of the ‘Center of Knowledge Interchange’ program of the Siemens AG and the Caché Campus program of the InterSystems GmbH. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors at the time of submission.</p></fn><fn fn-type="con"><p>Conceived and designed the experiments: ARF EB (ARIC) DPS (B58C) APR (CARDIA) NLS (CHS) CH IK OP (CROATIA-Vis) CJO (FHS) JE (HBCS) LF S. Bandinelli (InCHIANTI) A. Peters TI WK (KORA) IJD JMS (LBC) DAT (MARTHA) GW EJCDG DIB (NTR) SHW JFW HC (ORCADES) H. Watkins US A. Hamsten (PROCARDIS) IF RGJW JWJ DJS BMB AJMdC PES (PROSPER) AGU AD (RS) DS FC SN (SardiNIA) HV (SHIP) DIC PMR (WGHS). Wrote the paper: WT S. Basu ARF EB (ARIC) DPS (B58C) APR MF (CARDIA) BM KT TL KJM JCB NLS (CHS) CH IK OP PN (CROATIA-Vis) JH CJO (FHS) JL KR EW A. Palotie JE (HBCS) TT (InCHIANTI) JB RR WK A. Peters (KORA) LML GD JMS IJD (LBC) PEM DAT (MARTHA) JJH EJCDG DIB (NTR) JEH SHW JFW HC (ORCADES) MS-L H. Watkins US A. Hamsten (PROCARDIS) ST RGJW JWJ DJS NS AJMdC PES (PROSPER) MK AD (RS) MS SS SN (SardiNIA) AT RB A. Grotevendt H. Wallaschofski HV (SHIP) AYC DIC PMR (WGHS). Performed or contributed data measurements: ARF EB (ARIC) AR WLM GDL DPS (B58C) MF KL DSS (CARDIA) KT KJM (CHS) CH IK OP PN (CROATIA-Vis) MHC GHT (FHS) JL EW A Palotie KR JE (HBCS) LF S. Bandinelli (InCHIANTI) MMN TI MW WK (KORA) GD IJD JMS (LBC) PEM (MARTHA) JJH GW EJCDG DIB (NTR) SHW JFW HC (ORCADES) AM RS AS BS A. Goel MGF RC (PROCARDIS) IF RGJW JWJ DJS BMB (PROSPER) A. Hofman JCMW AGU MPMM FR OHF (RS) MM DS FC (SardiNIA) A. Grotevendt H. Wallaschofski HV (SHIP) LMR DIC PMR (WGHS). Performed data analyses: JS WT S. Basu (ARIC) ARR DPS (B58C) MF (CARDIA) BM JCB (CHS) CH (CROATIA-Vis) JH (FHS) JL (HBCS) TT (InCHIANTI) JB (KORA) LML (LBC) TOM DAT (MARTHA) JJH JVD (NTR) JEH (ORCADES) MS-L (PROCARDIS) ST (PROSPER) MK (RS) MS SS (SardiNIA) AT GH (SHIP) AYC LMR (WGHS). Drafted the manuscript: JB (KORA).</p></fn><fn id="fn1" fn-type="other"><p>¶ These authors also contributed equally to this work as last authors.</p></fn></author-notes><pub-date pub-type="collection"><year>2014</year></pub-date><pub-date pub-type="epub"><day>31</day><month>12</month><year>2014</year></pub-date><volume>9</volume><issue>12</issue><elocation-id>e111156</elocation-id><history><date date-type="received"><day>28</day><month>2</month><year>2014</year></date><date date-type="accepted"><day>23</day><month>9</month><year>2014</year></date></history><permissions><copyright-year>2014</copyright-year><copyright-holder>Baumert et al</copyright-holder><license><license-p>This is an open-access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><abstract><p>Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade having strong associations with smoking, alcohol consumption and body mass index (BMI). Genome-wide association studies (GWAS) have identified a variety of gene regions associated with elevated plasma fibrinogen concentrations. However, little is yet known about how associations between environmental factors and fibrinogen might be modified by genetic variation. Therefore, we conducted large-scale meta-analyses of genome-wide interaction studies to identify possible interactions of genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentration. The present study included 80,607 subjects of European ancestry from 22 studies. Genome-wide interaction analyses were performed separately in each study for about 2.6 million single nucleotide polymorphisms (SNPs) across the 22 autosomal chromosomes. For each SNP and risk factor, we performed a linear regression under an additive genetic model including an interaction term between SNP and risk factor. Interaction estimates were meta-analysed using a fixed-effects model. No genome-wide significant interaction with smoking status, alcohol consumption or BMI was observed in the meta-analyses. The most suggestive interaction was found for smoking and rs10519203, located in the LOC123688 region on chromosome 15, with a p value of 6.2×10<sup>−8</sup>. This large genome-wide interaction study including 80,607 participants found no strong evidence of interaction between genetic variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. Further studies are needed to yield deeper insight in the interplay between environmental factors and gene variants on the regulation of fibrinogen concentrations.</p></abstract><funding-group><funding-statement>See the supporting information file S1 Funding for the complete funding statement.</funding-statement></funding-group><counts><page-count count="18"></page-count></counts></article-meta></front><body><sec id="s1"><title>Introduction</title><p>Plasma fibrinogen is an acute phase protein playing an important role in the blood coagulation cascade and is strongly associated with a variety of environmental factors such as smoking status, alcohol consumption or obesity <xref rid="pone.0111156-Krobot1" ref-type="bibr">[1]</xref>–<xref rid="pone.0111156-Kaptoge1" ref-type="bibr">[7]</xref>. Moreover, elevated fibrinogen concentrations indicate increased risks for developing cardiovascular diseases <xref rid="pone.0111156-Danesh1" ref-type="bibr">[8]</xref>–<xref rid="pone.0111156-Koenig1" ref-type="bibr">[10]</xref>. Genetic studies reported substantial relationships between specific genetic variants and fibrinogen concentrations <xref rid="pone.0111156-deLange1" ref-type="bibr">[11]</xref>–<xref rid="pone.0111156-SabaterLleal1" ref-type="bibr">[17]</xref>; the heritability of plasma fibrinogen concentrations has been estimated to range from 34% to 51% <xref rid="pone.0111156-deLange1" ref-type="bibr">[11]</xref>, <xref rid="pone.0111156-Yang1" ref-type="bibr">[12]</xref>, <xref rid="pone.0111156-Hamsten1" ref-type="bibr">[18]</xref>, <xref rid="pone.0111156-Souto1" ref-type="bibr">[19]</xref>. Therefore, the regulation of fibrinogen concentrations might be seen as a complex interplay between environmental and genetic factors <xref rid="pone.0111156-deMaat1" ref-type="bibr">[20]</xref>. However, knowledge about potential interactions between environmental factors such as cardiovascular risk factors and gene variants on fibrinogen is still limited.</p><p>Smoking status, alcohol consumption and body mass index (BMI) are strong determinants of fibrinogen concentrations <xref rid="pone.0111156-Krobot1" ref-type="bibr">[1]</xref>–<xref rid="pone.0111156-Kaptoge1" ref-type="bibr">[7]</xref>. A large meta-analysis showed elevated fibrinogen concentrations in current smokers compared with non-smokers; moreover, fibrinogen concentrations increased with the number of cigarettes smoked per day showing a dose-related trend <xref rid="pone.0111156-Kaptoge1" ref-type="bibr">[7]</xref>. Similarly, elevated fibrinogen concentrations have been reported in subjects with higher BMI values <xref rid="pone.0111156-Kaptoge1" ref-type="bibr">[7]</xref>. For alcohol consumption, a lower mean fibrinogen concentration was observed in subjects reporting current alcohol intake compared with subjects reporting no alcohol intake <xref rid="pone.0111156-Kaptoge1" ref-type="bibr">[7]</xref>. All three factors represent behavioral risk factors which are easy to assess and for which we hypothesized that gene-environment interactions may modify individual risks enabling potentially targeted and individualized preventive approaches.</p><p>Several family-based and genome-wide studies have reported associations of specific gene regions with fibrinogen concentrations <xref rid="pone.0111156-deLange1" ref-type="bibr">[11]</xref>–<xref rid="pone.0111156-SabaterLleal1" ref-type="bibr">[17]</xref>. Recently, three large genome-wide association studies (GWAS) including as many as 90,000 participants of European origin identified up to 24 strong association signals with plasma fibrinogen concentration, among them one located in the fibrinogen <italic>β</italic> chain (<italic>FGB</italic>) gene <xref rid="pone.0111156-Danik1" ref-type="bibr">[15]</xref>–<xref rid="pone.0111156-SabaterLleal1" ref-type="bibr">[17]</xref>. One of these analyses <xref rid="pone.0111156-SabaterLleal1" ref-type="bibr">[17]</xref> was essentially based on the same study population as in the present analyses.</p><p>However, little is known about whether the impact of smoking, alcohol consumption, and BMI on fibrinogen concentrations is modified by specific gene variants. Knowledge of such interactions might improve the understanding of the underlying mechanism of fibrinogen synthesis and its regulation. Two candidate-gene studies showed modifications in the association of smoking status and fibrinogen concentration by the G/A-455 polymorphism (rs1800790) located at the <italic>FGB</italic> gene <xref rid="pone.0111156-Green1" ref-type="bibr">[21]</xref>, <xref rid="pone.0111156-Thomas1" ref-type="bibr">[22]</xref>.</p><p>No genome-wide studies of effect modifications have been reported thus far for fibrinogen concentrations. Therefore, the aim of the present study was to assess potential gene-environment interactions (GxE) by smoking status, alcohol consumption, and BMI on fibrinogen concentrations, using genome-wide data from 22 studies with 80,607 subjects of European origin.</p></sec><sec sec-type="methods" id="s2"><title>Methods</title><sec id="s2a"><title>Study population</title><p>The present study was carried out within the framework of the <italic>Cohorts for Heart and Aging Research in Genomic Epidemiology</italic> (CHARGE) consortium which combines data from several studies of participants of European origin conducted in the United States and Europe <xref rid="pone.0111156-Psaty1" ref-type="bibr">[23]</xref>. Twenty-two studies comprising 80,607 participants provided results from their genome-wide interaction analyses for the present investigation; an overview of these studies with basic information and respective references is given in the online supporting information (<xref ref-type="supplementary-material" rid="pone.0111156.s010">S1 Methods</xref> and <xref ref-type="supplementary-material" rid="pone.0111156.s003">S1 Table</xref>) All participants provided informed consent to use their DNA for these analyses and all studies.</p></sec><sec id="s2b"><title>Fibrinogen measurements</title><p>Plasma fibrinogen concentrations were measured in 17 studies by a functional method based on the Clauss assay and in five studies by an immunonephelometric method and given in g/L <xref rid="pone.0111156-CLAUSS1" ref-type="bibr">[24]</xref>, <xref rid="pone.0111156-Cremer1" ref-type="bibr">[25]</xref>. Fibrinogen concentrations were approximately normally distributed in all studies and therefore analysed untransformed. More details are given in the online supporting information (<xref ref-type="supplementary-material" rid="pone.0111156.s010">S1 Methods</xref> and <xref ref-type="supplementary-material" rid="pone.0111156.s003">S1 Table</xref>).</p></sec><sec id="s2c"><title>Assessment of smoking status, alcohol consumption and BMI</title><p>In all studies, smoking status and alcohol consumption were assessed by self-reports from study participants; assessment of BMI was based on clinical examination or self-report and described in kg/m<sup>2</sup>. For smoking status, current smokers (“smokers”) were compared with a combined group of former smokers and never-smokers (“non-smokers”). Former smokers were defined as not smoking at time of examination in 19 studies; the remaining 3 studies set a minimum cessation time before the examination which ranged between 30 days and 3 years. For alcohol consumption, coding was “0” for no alcohol consumption, “1” for alcohol consumption with less than 1 drink daily equivalent to less than 10 g alcohol per day and “2” for alcohol consumption with 1 or more drinks daily equivalent to 10 g alcohol or more per day. Information on smoking status and BMI was available in all 22 studies and on alcohol consumption in 20 studies. The assessments of smoking status, alcohol consumption and BMI were made at the same time as the fibrinogen measurements for all participants in all studies.</p></sec><sec id="s2d"><title>Genotyping and imputation</title><p>Genotyping was conducted separately in each study using Affymetrix or Illumina platforms and included from ∼300,000 to ∼1,000,000 genotyped single nucleotide polymorphisms (SNPs). Genotype quality control and data cleaning based on individual call rate, SNP call rate, and/or Hardy-Weinberg equilibrium thresholds, and performed independently by each study.</p><p>Genotyped data were imputed in each study separately to the ∼2.6 million SNPs identified in the HapMap II Caucasian (CEU) sample from the Centre d'Etude du Polymorphisme Humain <xref rid="pone.0111156-Marchini1" ref-type="bibr">[26]</xref>, <xref rid="pone.0111156-Li1" ref-type="bibr">[27]</xref>.</p><p>More details about genotyping and imputation are given in the online supporting information (<xref ref-type="supplementary-material" rid="pone.0111156.s010">S1 Methods</xref> and <xref ref-type="supplementary-material" rid="pone.0111156.s004">S2 Table</xref>).</p></sec><sec id="s2e"><title>Statistical analysis</title><sec id="s2e1"><title>Association of smoking status, alcohol consumption and BMI with fibrinogen concentration</title><p>Associations of smoking status, alcohol consumption and BMI with fibrinogen concentrations were assessed independently and separately in each study using linear regression. Analyses were adjusted for age (linear) and sex as well as study-specific covariates if required (see <xref ref-type="supplementary-material" rid="pone.0111156.s010">S1 Methods</xref>). Study-specific associations of smoking status, alcohol consumption and BMI with fibrinogen concentration were then meta-analysed using an inverse-variance weighted fixed-effect model.</p></sec><sec id="s2e2"><title>Interaction between gene variants and smoking status, alcohol consumption and BMI on fibrinogen concentration</title><p>Genome-wide analyses of the interaction between gene variants and smoking status, alcohol consumption or BMI on fibrinogen concentration were performed independently and separately in each study assuming an additive-genetic model with an additive interaction. In all studies of unrelated individuals, linear regression models with fibrinogen concentration as the outcome variable and the SNP, the risk factor under consideration, and the interaction term ‘SNP x risk factor’ were fit with adjustments for age (linear) and sex as well as study-specific covariates if required (see <xref ref-type="supplementary-material" rid="pone.0111156.s010">S1 Methods</xref>). In family-based studies, linear mixed effects models were applied to account for family correlations. Estimates of study-specific genome-wide interactions were then meta-analysed applying inverse-variance weighted fixed-effect models. To account for population stratification, study-specific test statistics were corrected using the method of genomic control <xref rid="pone.0111156-Devlin1" ref-type="bibr">[28]</xref>. SNPs with a low minor allele frequency (MAF) (<0.05) and a low imputation quality (observed to expected variance ratio <0.3) were omitted from the meta-analyses.</p><p>The meta-analyses were performed using the software METAL developed for genome-wide data <xref rid="pone.0111156-Willer1" ref-type="bibr">[29]</xref>. To assess heterogeneity, the I<sup>2</sup> index was computed for each interaction estimate assuming that an I<sup>2</sup> index around 25% or below indicates no or low and around 50% moderate heterogeneity as suggested by Higgins et al <xref rid="pone.0111156-Higgins1" ref-type="bibr">[30]</xref>. Genome-wide significance of interaction was defined as a p value <5.0×10<sup>−8</sup> for each of the three GxE analyses. Power analyses were conducted using the R (version 3.0.2) <italic>pwr</italic> package.</p></sec></sec></sec><sec id="s3"><title>Results</title><sec id="s3a"><title>Description of studies</title><p>The study population comprised a total of 80,607 participants of European ancestry from 22 studies. Distributions of basic characteristics are provided for each study in <xref ref-type="table" rid="pone-0111156-t001">Table 1</xref>. Across the 22 studies, the average age ranged from 43.3 to 79.1 years and the percent of male participants ranged from 0 to 75.5%. Current smoking behaviour was reported for 6.9 to 50.3% of the participants. No alcohol consumption was reported for 5.8 to 54.9% of the participants and the mean BMI ranged from 24.3 to 28.4 kg/m<sup>2</sup>. Mean fibrinogen concentration varied from 2.67 to 3.88 g/L.</p><table-wrap id="pone-0111156-t001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0111156.t001</object-id><label>Table 1</label><caption><title>Characteristics at the time of fibrinogen measurement by study.</title></caption><alternatives><graphic id="pone-0111156-t001-1" xlink:href="pone.0111156.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><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1">Study</td><td align="left" rowspan="1" colspan="1">Sample (N)</td><td align="left" rowspan="1" colspan="1">Age<xref ref-type="table-fn" rid="nt102">*</xref> (years)</td><td align="left" rowspan="1" colspan="1">Male sex (%)</td><td align="left" rowspan="1" colspan="1">Current smokers (%)</td><td align="left" rowspan="1" colspan="1">No alcohol consumption (%)</td><td align="left" rowspan="1" colspan="1">Alcohol consumption <10 g/day (%)</td><td align="left" rowspan="1" colspan="1">Alcohol consumption ≥10 g/day (%)</td><td align="left" rowspan="1" colspan="1">BMI (kg/m<sup>2</sup>)</td><td align="left" rowspan="1" colspan="1">Fibrinogen<xref ref-type="table-fn" rid="nt102">*</xref> (g/L)</td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">ARIC</td><td align="left" rowspan="1" colspan="1">9,256</td><td align="left" rowspan="1" colspan="1">54.3 (5.7)</td><td align="left" rowspan="1" colspan="1">47.1</td><td align="left" rowspan="1" colspan="1">24.6</td><td align="left" rowspan="1" colspan="1">55.9</td><td align="left" rowspan="1" colspan="1">23.0</td><td align="left" rowspan="1" colspan="1">21.1</td><td align="left" rowspan="1" colspan="1">27.0 (4.8)</td><td align="left" rowspan="1" colspan="1">2.97 (0.61)</td></tr><tr><td align="left" rowspan="1" colspan="1">B58C</td><td align="left" rowspan="1" colspan="1">6,085</td><td align="left" rowspan="1" colspan="1">45.2 (0.4)</td><td align="left" rowspan="1" colspan="1">49.7</td><td align="left" rowspan="1" colspan="1">23.5</td><td align="left" rowspan="1" colspan="1">20.3</td><td align="left" rowspan="1" colspan="1">39.1</td><td align="left" rowspan="1" colspan="1">40.6</td><td align="left" rowspan="1" colspan="1">27.4 (4.9)</td><td align="left" rowspan="1" colspan="1">2.95 (0.60)</td></tr><tr><td align="left" rowspan="1" colspan="1">CARDIA</td><td align="left" rowspan="1" colspan="1">1,435</td><td align="left" rowspan="1" colspan="1">45.8 (3.3)</td><td align="left" rowspan="1" colspan="1">47.0</td><td align="left" rowspan="1" colspan="1">20.3</td><td align="left" rowspan="1" colspan="1">NA</td><td align="left" rowspan="1" colspan="1">NA</td><td align="left" rowspan="1" colspan="1">NA</td><td align="left" rowspan="1" colspan="1">25.4 (5.1)</td><td align="left" rowspan="1" colspan="1">3.18 (0.66)</td></tr><tr><td align="left" rowspan="1" colspan="1">CHS</td><td align="left" rowspan="1" colspan="1">3,242</td><td align="left" rowspan="1" colspan="1">72.3 (5.4)</td><td align="left" rowspan="1" colspan="1">39.0</td><td align="left" rowspan="1" colspan="1">11.3</td><td align="left" rowspan="1" colspan="1">46.0</td><td align="left" rowspan="1" colspan="1">38.5</td><td align="left" rowspan="1" colspan="1">15.5</td><td align="left" rowspan="1" colspan="1">26.3 (4.4)</td><td align="left" rowspan="1" colspan="1">3.15 (0.62)</td></tr><tr><td align="left" rowspan="1" colspan="1">CROATIA-Vis</td><td align="left" rowspan="1" colspan="1">761</td><td align="left" rowspan="1" colspan="1">56.6 (15.5)</td><td align="left" rowspan="1" colspan="1">41.7</td><td align="left" rowspan="1" colspan="1">27.9</td><td align="left" rowspan="1" colspan="1">43.0</td><td align="left" rowspan="1" colspan="1">19.2</td><td align="left" rowspan="1" colspan="1">37.8</td><td align="left" rowspan="1" colspan="1">27.1 (4.9)</td><td align="left" rowspan="1" colspan="1">3.58 (0.82)</td></tr><tr><td align="left" rowspan="1" colspan="1">FHS</td><td align="left" rowspan="1" colspan="1">2,797</td><td align="left" rowspan="1" colspan="1">54.1 (9.7)</td><td align="left" rowspan="1" colspan="1">45.5</td><td align="left" rowspan="1" colspan="1">18.5</td><td align="left" rowspan="1" colspan="1">29.8</td><td align="left" rowspan="1" colspan="1">57.9</td><td align="left" rowspan="1" colspan="1">12.3</td><td align="left" rowspan="1" colspan="1">27.4 (5.0)</td><td align="left" rowspan="1" colspan="1">3.05 (0.57)</td></tr><tr><td align="left" rowspan="1" colspan="1">HBCS</td><td align="left" rowspan="1" colspan="1">1,728</td><td align="left" rowspan="1" colspan="1">61.4 (2.9)</td><td align="left" rowspan="1" colspan="1">40.2</td><td align="left" rowspan="1" colspan="1">23.9</td><td align="left" rowspan="1" colspan="1">16.5</td><td align="left" rowspan="1" colspan="1">54.6</td><td align="left" rowspan="1" colspan="1">28.9</td><td align="left" rowspan="1" colspan="1">27.4 (4.5)</td><td align="left" rowspan="1" colspan="1">3.23 (1.04)</td></tr><tr><td align="left" rowspan="1" colspan="1">InCHIANTI</td><td align="left" rowspan="1" colspan="1">1,128</td><td align="left" rowspan="1" colspan="1">67.7 (15.1)</td><td align="left" rowspan="1" colspan="1">44.9</td><td align="left" rowspan="1" colspan="1">19.0</td><td align="left" rowspan="1" colspan="1">24.5</td><td align="left" rowspan="1" colspan="1">30.0</td><td align="left" rowspan="1" colspan="1">45.5</td><td align="left" rowspan="1" colspan="1">27.2 (4.1)</td><td align="left" rowspan="1" colspan="1">3.48 (0.75)</td></tr><tr><td align="left" rowspan="1" colspan="1">KORA F3</td><td align="left" rowspan="1" colspan="1">1,520</td><td align="left" rowspan="1" colspan="1">52.1 (10.2)</td><td align="left" rowspan="1" colspan="1">49.3</td><td align="left" rowspan="1" colspan="1">18.0</td><td align="left" rowspan="1" colspan="1">29.9</td><td align="left" rowspan="1" colspan="1">23.6</td><td align="left" rowspan="1" colspan="1">46.1</td><td align="left" rowspan="1" colspan="1">27.2 (4.1)</td><td align="left" rowspan="1" colspan="1">2.89 (0.66)</td></tr><tr><td align="left" rowspan="1" colspan="1">KORA F4</td><td align="left" rowspan="1" colspan="1">1,777</td><td align="left" rowspan="1" colspan="1">53.9 (8.9)</td><td align="left" rowspan="1" colspan="1">48.9</td><td align="left" rowspan="1" colspan="1">20.0</td><td align="left" rowspan="1" colspan="1">24.5</td><td align="left" rowspan="1" colspan="1">29.9</td><td align="left" rowspan="1" colspan="1">45.6</td><td align="left" rowspan="1" colspan="1">27.7 (4.6)</td><td align="left" rowspan="1" colspan="1">2.67 (0.60)</td></tr><tr><td align="left" rowspan="1" colspan="1">LBC1921</td><td align="left" rowspan="1" colspan="1">466</td><td align="left" rowspan="1" colspan="1">79.1 (0.6)</td><td align="left" rowspan="1" colspan="1">42.1</td><td align="left" rowspan="1" colspan="1">6.9</td><td align="left" rowspan="1" colspan="1">23.2</td><td align="left" rowspan="1" colspan="1">56.9</td><td align="left" rowspan="1" colspan="1">20.0</td><td align="left" rowspan="1" colspan="1">26.2 (4.1)</td><td align="left" rowspan="1" colspan="1">3.56 (0.85)</td></tr><tr><td align="left" rowspan="1" colspan="1">LBC1936</td><td align="left" rowspan="1" colspan="1">989</td><td align="left" rowspan="1" colspan="1">69.6 (0.8)</td><td align="left" rowspan="1" colspan="1">50.8</td><td align="left" rowspan="1" colspan="1">12.6</td><td align="left" rowspan="1" colspan="1">19.2</td><td align="left" rowspan="1" colspan="1">40.7</td><td align="left" rowspan="1" colspan="1">40.0</td><td align="left" rowspan="1" colspan="1">27.8 (4.4)</td><td align="left" rowspan="1" colspan="1">3.27 (0.63)</td></tr><tr><td align="left" rowspan="1" colspan="1">MARTHA</td><td align="left" rowspan="1" colspan="1">613</td><td align="left" rowspan="1" colspan="1">44.1 (14.2)</td><td align="left" rowspan="1" colspan="1">23.8</td><td align="left" rowspan="1" colspan="1">25.9</td><td align="left" rowspan="1" colspan="1">NA</td><td align="left" rowspan="1" colspan="1">NA</td><td align="left" rowspan="1" colspan="1">NA</td><td align="left" rowspan="1" colspan="1">24.3 (4.4)</td><td align="left" rowspan="1" colspan="1">3.36 (0.68)</td></tr><tr><td align="left" rowspan="1" colspan="1">NTR</td><td align="left" rowspan="1" colspan="1">2,343</td><td align="left" rowspan="1" colspan="1">47.1 (13.9)</td><td align="left" rowspan="1" colspan="1">35.8</td><td align="left" rowspan="1" colspan="1">16.8</td><td align="left" rowspan="1" colspan="1">5.8</td><td align="left" rowspan="1" colspan="1">74.2</td><td align="left" rowspan="1" colspan="1">20.0</td><td align="left" rowspan="1" colspan="1">25.4 (4.0)</td><td align="left" rowspan="1" colspan="1">2.78 (0.66)</td></tr><tr><td align="left" rowspan="1" colspan="1">ORCADES</td><td align="left" rowspan="1" colspan="1">686</td><td align="left" rowspan="1" colspan="1">53.7 (15.3)</td><td align="left" rowspan="1" colspan="1">46.6</td><td align="left" rowspan="1" colspan="1">8.7</td><td align="left" rowspan="1" colspan="1">10.8</td><td align="left" rowspan="1" colspan="1">59.2</td><td align="left" rowspan="1" colspan="1">30.0</td><td align="left" rowspan="1" colspan="1">27.7 (4.9)</td><td align="left" rowspan="1" colspan="1">3.45 (0.81)</td></tr><tr><td align="left" rowspan="1" colspan="1">PROCARDIS-CL</td><td align="left" rowspan="1" colspan="1">3,490</td><td align="left" rowspan="1" colspan="1">61.9 (7.0)</td><td align="left" rowspan="1" colspan="1">75.5</td><td align="left" rowspan="1" colspan="1">50.3</td><td align="left" rowspan="1" colspan="1">37.3</td><td align="left" rowspan="1" colspan="1">33.7</td><td align="left" rowspan="1" colspan="1">29.0</td><td align="left" rowspan="1" colspan="1">28.4 (4.4)</td><td align="left" rowspan="1" colspan="1">3.88 (0.86)</td></tr><tr><td align="left" rowspan="1" colspan="1">PROCARDIS-Im</td><td align="left" rowspan="1" colspan="1">3,405</td><td align="left" rowspan="1" colspan="1">58.1 (8.9)</td><td align="left" rowspan="1" colspan="1">73.5</td><td align="left" rowspan="1" colspan="1">33.0</td><td align="left" rowspan="1" colspan="1">23.9</td><td align="left" rowspan="1" colspan="1">36.7</td><td align="left" rowspan="1" colspan="1">39.4</td><td align="left" rowspan="1" colspan="1">27.1 (4.2)</td><td align="left" rowspan="1" colspan="1">3.86 (1.00)</td></tr><tr><td align="left" rowspan="1" colspan="1">PROSPER</td><td align="left" rowspan="1" colspan="1">5,244</td><td align="left" rowspan="1" colspan="1">75.3 (3.3)</td><td align="left" rowspan="1" colspan="1">48.1</td><td align="left" rowspan="1" colspan="1">26.5</td><td align="left" rowspan="1" colspan="1">44.5</td><td align="left" rowspan="1" colspan="1">28.6</td><td align="left" rowspan="1" colspan="1">27.0</td><td align="left" rowspan="1" colspan="1">26.8 (4.2)</td><td align="left" rowspan="1" colspan="1">3.60 (0.74)</td></tr><tr><td align="left" rowspan="1" colspan="1">RS</td><td align="left" rowspan="1" colspan="1">2,068</td><td align="left" rowspan="1" colspan="1">70.4 (9.0)</td><td align="left" rowspan="1" colspan="1">35.0</td><td align="left" rowspan="1" colspan="1">23.5</td><td align="left" rowspan="1" colspan="1">18.1</td><td align="left" rowspan="1" colspan="1">51.6</td><td align="left" rowspan="1" colspan="1">30.3</td><td align="left" rowspan="1" colspan="1">26.4 (3.8)</td><td align="left" rowspan="1" colspan="1">2.81 (0.68)</td></tr><tr><td align="left" rowspan="1" colspan="1">SardiNIA</td><td align="left" rowspan="1" colspan="1">4,691</td><td align="left" rowspan="1" colspan="1">43.3 (17.6)</td><td align="left" rowspan="1" colspan="1">43.7</td><td align="left" rowspan="1" colspan="1">19.8</td><td align="left" rowspan="1" colspan="1">54.9</td><td align="left" rowspan="1" colspan="1">10.2</td><td align="left" rowspan="1" colspan="1">34.9</td><td align="left" rowspan="1" colspan="1">25.3 (4.7)</td><td align="left" rowspan="1" colspan="1">3.28 (0.66)</td></tr><tr><td align="left" rowspan="1" colspan="1">SHIP</td><td align="left" rowspan="1" colspan="1">3,807</td><td align="left" rowspan="1" colspan="1">48.7 (16.0)</td><td align="left" rowspan="1" colspan="1">48.4</td><td align="left" rowspan="1" colspan="1">31.5</td><td align="left" rowspan="1" colspan="1">34.3</td><td align="left" rowspan="1" colspan="1">19.1</td><td align="left" rowspan="1" colspan="1">46.6</td><td align="left" rowspan="1" colspan="1">27.2 (4.8)</td><td align="left" rowspan="1" colspan="1">2.98 (0.69)</td></tr><tr><td align="left" rowspan="1" colspan="1">WGHS</td><td align="left" rowspan="1" colspan="1">23,076</td><td align="left" rowspan="1" colspan="1">54.7 (7.1)</td><td align="left" rowspan="1" colspan="1">0</td><td align="left" rowspan="1" colspan="1">13.2</td><td align="left" rowspan="1" colspan="1">43.3</td><td align="left" rowspan="1" colspan="1">42.7</td><td align="left" rowspan="1" colspan="1">14.0</td><td align="left" rowspan="1" colspan="1">25.9 (5.0)</td><td align="left" rowspan="1" colspan="1">3.59 (0.78)</td></tr><tr><td align="left" rowspan="1" colspan="1">total</td><td align="left" rowspan="1" colspan="1">80,607</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"></td><td align="left" rowspan="1" colspan="1"></td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt101"><label></label><p>BMI: body mass index.</p></fn><fn id="nt102"><label></label><p>* Mean (standard deviation).</p></fn></table-wrap-foot></table-wrap></sec><sec id="s3b"><title>Association of smoking status, alcohol consumption and BMI with fibrinogen concentration</title><p>Strong significant associations of smoking status, alcohol consumption and BMI with mean fibrinogen concentrations were observed in the vast majority of the 22 studies as can be seen in <xref ref-type="fig" rid="pone-0111156-g001">Fig. 1</xref>. Meta-analysis revealed mean differences in fibrinogen concentrations of 0.163 g/L (95% CI 0.154 to 0.172, 8.5×10<sup>−280</sup>) for current smokers compared with non-smokers, of -0.108 g/L (95% CI −0.113 to −0.102, 1.2×10<sup>−334</sup>) for one category increase of alcohol consumption (no, <10 g/day, ≥10 g/day), and of 0.021 g/L (95% CI 0.020 to 0.022, p value 7.1×10<sup>−691</sup>) for one kg/m<sup>2</sup> of BMI increase.</p><fig id="pone-0111156-g001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0111156.g001</object-id><label>Figure 1</label><caption><title>Association of environmental factors with fibrinogen concentration (in g/L), adjusted for age and sex.</title><p><bold>A</bold>) Forest plot for smoking status. The beta estimate with 95% confidence intervals indicates the change in mean fibrinogen concentration (in g/L) by smoking status for each study and across all studies (“overall”, estimated by meta-analysis). <bold>B</bold>) Forest plot for alcohol consumption. The beta estimate with 95% confidence intervals indicates the change in mean fibrinogen concentration (in g/L) by alcohol consumption for each study and across all studies (“overall”, estimated by meta-analysis). Alcohol consumption was assessed only in 20 studies. <bold>C</bold>) Forest plot for BMI. The beta estimate with 95% confidence intervals indicates the change in mean fibrinogen concentration (in g/L) by BMI for each study and across all studies (“overall”, estimated by meta-analysis).</p></caption><graphic xlink:href="pone.0111156.g001"></graphic></fig></sec><sec id="s3c"><title>Interaction between gene variants and smoking status, alcohol consumption and BMI on fibrinogen concentration – genome-wide analyses</title><sec id="s3c1"><title>Overall</title><p>No genome-wide significant interactions with smoking status, alcohol consumption and BMI were observed on fibrinogen concentration (<xref ref-type="fig" rid="pone-0111156-g002">Fig. 2</xref>). The overall genomic inflation factors from the meta-analyses were 1.0174 for interaction with smoking status, 0.9838 for interaction with alcohol consumption and 1.0075 for interaction with BMI (see QQ plots in <xref ref-type="supplementary-material" rid="pone.0111156.s001">S1 Fig</xref>.). Exclusion of studies with a genomic inflation factor >1.15 or <1/1.15 (see <xref ref-type="supplementary-material" rid="pone.0111156.s005">S3 Table</xref>) did not substantially alter these findings and revealed no genome-wide significant interactions either. The heterogeneity of interaction estimates across studies was rather weak. More than 85% of SNPs had an I<sup>2</sup> index of 25% or less in all three interaction analyses. The upper quartile of the I<sup>2</sup> index value distribution was 15.5% for smoking, 16.1% for alcohol consumption and 15.5% for BMI analyses.</p><fig id="pone-0111156-g002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0111156.g002</object-id><label>Figure 2</label><caption><title>Interaction of gene variants and environmental factors on fibrinogen concentration (in g/L), adjusted for age and sex.</title><p><bold>A</bold>) Manhattan plot for smoking status. The horizontal axis denotes chromosome and position of each gene variant and the vertical axis gives the negative log10 of the p value for interaction of each gene variant and smoking status on fibrinogen concentration (in g/L), estimated by meta-analyses. The dotted line denotes genome-wide significance (5.0×10<sup>−8</sup>). <bold>B</bold>) Manhattan plot for alcohol consumption. The horizontal axis denotes chromosome and position of each gene variant and the vertical axis gives the negative log10 of the p value for interaction of each gene variant and alcohol consumption on fibrinogen concentration (in g/L), estimated by meta-analyses. The dotted line denotes genome-wide significance (5.0×10<sup>−8</sup>). Alcohol consumption was assessed only in 20 studies. <bold>C</bold>) Manhattan plot for BMI. The horizontal axis denotes chromosome and position of each gene variant and the vertical axis gives the negative log10 of the p value for interaction of each gene variant and BMI on fibrinogen concentration (in g/L), estimated by meta-analyses. The dotted line denotes genome-wide significance (5.0×10<sup>−8</sup>).</p></caption><graphic xlink:href="pone.0111156.g002"></graphic></fig></sec><sec id="s3c2"><title>High-signal interactions</title><p>The Manhattan plot in <xref ref-type="fig" rid="pone-0111156-g002">Fig. 2</xref> for smoking status (A) shows a peak on chromosome 15 revealing suggestive evidence of an interaction with smoking status for rs10519203, located in the <italic>LOC123688</italic> region on chromosome 15, with a p value of 6.2×10<sup>−8</sup> (<xref ref-type="table" rid="pone-0111156-t002">Table 2</xref>). The difference in mean fibrinogen concentration between smokers and non-smokers was 0.048 g/L lower per copy of the A allele of rs10519203. A forest plot providing the interaction estimates with smoking status for each study and for the meta-analysis is given in <xref ref-type="supplementary-material" rid="pone.0111156.s002">S2 Fig</xref>. Heterogeneity was estimated as I<sup>2</sup> index = 45.4% indicating a moderate level of variation of the interaction estimates across studies. The SNP rs10519203 alone was not significantly associated with fibrinogen concentration in a “G” alone analysis (p value 0.0005) performed by Sabater-Lleal et al. <xref rid="pone.0111156-SabaterLleal1" ref-type="bibr">[17]</xref>.</p><table-wrap id="pone-0111156-t002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0111156.t002</object-id><label>Table 2</label><caption><title>Interaction between gene variants and smoking status, alcohol consumption and BMI on fibrinogen concentration (in g/L) with lowest p value for interaction.</title></caption><alternatives><graphic id="pone-0111156-t002-2" xlink:href="pone.0111156.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">Environmental factor x SNP</td><td align="left" rowspan="1" colspan="1">Chr</td><td align="left" rowspan="1" colspan="1">Position</td><td align="left" rowspan="1" colspan="1">A1<xref ref-type="table-fn" rid="nt104">*</xref></td><td align="left" rowspan="1" colspan="1">A2</td><td align="left" rowspan="1" colspan="1">% A1</td><td align="left" rowspan="1" colspan="1">Beta (SE)</td><td align="left" rowspan="1" colspan="1">P value</td><td align="left" rowspan="1" colspan="1">N studies</td><td align="left" rowspan="1" colspan="1">Direction**</td><td align="left" rowspan="1" colspan="1">I<sup>2</sup> index</td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Smoking status x rs10519203</td><td align="left" rowspan="1" colspan="1">15</td><td align="left" rowspan="1" colspan="1">76601101</td><td align="left" rowspan="1" colspan="1">A</td><td align="left" rowspan="1" colspan="1">G</td><td align="left" rowspan="1" colspan="1">64.8</td><td align="left" rowspan="1" colspan="1">−0.048 (0.009)</td><td align="left" rowspan="1" colspan="1">6.2×10<sup>−08</sup></td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">---+—+-+-------+-+---</td><td align="left" rowspan="1" colspan="1">45.4%</td></tr><tr><td align="left" rowspan="1" colspan="1">Alcohol consumption x rs11102001</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">110011733</td><td align="left" rowspan="1" colspan="1">A</td><td align="left" rowspan="1" colspan="1">G</td><td align="left" rowspan="1" colspan="1">59.0</td><td align="left" rowspan="1" colspan="1">0.057 (0.012)</td><td align="left" rowspan="1" colspan="1">7.0×10<sup>−07</sup></td><td align="left" rowspan="1" colspan="1">18</td><td align="left" rowspan="1" colspan="1">++++-++?+++-+++++?++</td><td align="left" rowspan="1" colspan="1">0.0%</td></tr><tr><td align="left" rowspan="1" colspan="1">BMI x rs7120820</td><td align="left" rowspan="1" colspan="1">11</td><td align="left" rowspan="1" colspan="1">21350435</td><td align="left" rowspan="1" colspan="1">T</td><td align="left" rowspan="1" colspan="1">C</td><td align="left" rowspan="1" colspan="1">37.6</td><td align="left" rowspan="1" colspan="1">0.004 (0.009)</td><td align="left" rowspan="1" colspan="1">1.8×10<sup>−06</sup></td><td align="left" rowspan="1" colspan="1">21</td><td align="left" rowspan="1" colspan="1">++++-++—+-+-+---++?++</td><td align="left" rowspan="1" colspan="1">20.2%</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt103"><label></label><p>BMI: body mass index, SNP: single nucleotide polymorphism, Chr: chromosome, SE: standard error.</p></fn><fn id="nt104"><label></label><p><italic>* Allele 1 is effect allele, ** The order of studies under “direction” refers to the order of studies in </italic><xref ref-type="table" rid="pone-0111156-t001"><italic>Table 1</italic></xref><italic>.</italic></p></fn></table-wrap-foot></table-wrap><p>For alcohol consumption and BMI, the lowest p values were found for rs11102001 in <italic>EPS8L3</italic> on chromosome 1 (p value = 7.0×10<sup>−7</sup>) and rs7120820 in <italic>NELL1</italic> on chromosome 11 (p value = 1.8×10<sup>−6</sup>), see <xref ref-type="table" rid="pone-0111156-t002">Table 2</xref>. In both cases, weak heterogeneity was observed (I<sup>2</sup> index≤25%).</p></sec></sec><sec id="s3d"><title>Interaction between gene variants and smoking status, alcohol consumption and BMI on fibrinogen concentration - selected candidate SNPs</title><p>The interaction of rs1800790 at the <italic>FGB</italic> locus and smoking status on fibrinogen concentration (as it was shown in two candidate-gene approach studies previously) was estimated with beta = 0.029 in the present meta-analysis (p value for interaction 0.006) indicating a 0.029 g/L higher level in mean fibrinogen concentration per A allele copy in smokers compared with non-smokers (<xref ref-type="table" rid="pone-0111156-t003">Table 3</xref>). The I<sup>2</sup> index of almost 60% indicated moderate heterogeneity.</p><table-wrap id="pone-0111156-t003" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.pone.0111156.t003</object-id><label>Table 3</label><caption><title>Interaction with smoking status for association with fibrinogen concentration (in g/L) in SNPs with previously reported interactions (Green et al. 1993; Thomas et al. 1996) or among SNPs associated with circulating fibrinogen (Sabater-Leal et al. 2013).</title></caption><alternatives><graphic id="pone-0111156-t003-3" xlink:href="pone.0111156.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></colgroup><thead><tr><td align="left" rowspan="1" colspan="1">SNP</td><td align="left" rowspan="1" colspan="1">Chr</td><td align="left" rowspan="1" colspan="1">Position</td><td align="left" rowspan="1" colspan="1">A1<xref ref-type="table-fn" rid="nt106">*</xref></td><td align="left" rowspan="1" colspan="1">A2</td><td align="left" rowspan="1" colspan="1">% A1</td><td align="left" rowspan="1" colspan="1">Beta (SE)</td><td align="left" rowspan="1" colspan="1">P value</td><td align="left" rowspan="1" colspan="1">N studies</td><td align="left" rowspan="1" colspan="1">Direction**</td><td align="left" rowspan="1" colspan="1">I<sup>2</sup> index</td></tr></thead><tbody><tr><td colspan="10" align="left" rowspan="1"><underline>Significant interaction according to Green et al. (1993) and Thomas et al. (1996):</underline></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">rs1800790</td><td align="left" rowspan="1" colspan="1">4</td><td align="left" rowspan="1" colspan="1">155703158</td><td align="left" rowspan="1" colspan="1">A</td><td align="left" rowspan="1" colspan="1">G</td><td align="left" rowspan="1" colspan="1">23.2</td><td align="left" rowspan="1" colspan="1">0.029 (0.011)</td><td align="left" rowspan="1" colspan="1">0.0062</td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">+++++---++-+++-++—+—</td><td align="left" rowspan="1" colspan="1">59.2%</td></tr><tr><td colspan="10" align="left" rowspan="1"><underline>Significant SNPs according to Sabater-Leal et al. (2013):</underline></td><td align="left" rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1">rs1938492</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">65890417</td><td align="left" rowspan="1" colspan="1">A</td><td align="left" rowspan="1" colspan="1">C</td><td align="left" rowspan="1" colspan="1">62.1</td><td align="left" rowspan="1" colspan="1">0.017 (0.009)</td><td align="left" rowspan="1" colspan="1">0.058</td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">++-+---+-+++-+-+++—++</td><td align="left" rowspan="1" colspan="1">0.0%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs4129267</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">152692888</td><td align="left" rowspan="1" colspan="1">T</td><td align="left" rowspan="1" colspan="1">C</td><td align="left" rowspan="1" colspan="1">39.1</td><td align="left" rowspan="1" colspan="1">−0.004 (0.009)</td><td align="left" rowspan="1" colspan="1">0.614</td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">+-+-+-++—+++++---++-+</td><td align="left" rowspan="1" colspan="1">43.9%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs10157379</td><td align="left" rowspan="1" colspan="1">1</td><td align="left" rowspan="1" colspan="1">245672222</td><td align="left" rowspan="1" colspan="1">T</td><td align="left" rowspan="1" colspan="1">C</td><td align="left" rowspan="1" colspan="1">62.3</td><td align="left" rowspan="1" colspan="1">0.008 (0.009)</td><td align="left" rowspan="1" colspan="1">0.386</td><td align="left" rowspan="1" colspan="1">21</td><td align="left" rowspan="1" colspan="1">------+++++-++++++-?++</td><td align="left" rowspan="1" colspan="1">0.0%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs12712127</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">102093093</td><td align="left" rowspan="1" colspan="1">A</td><td align="left" rowspan="1" colspan="1">G</td><td align="left" rowspan="1" colspan="1">40.6</td><td align="left" rowspan="1" colspan="1">0.009 (0.009)</td><td align="left" rowspan="1" colspan="1">0.286</td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">++-++-++—+-++-+++++—</td><td align="left" rowspan="1" colspan="1">0.0%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs6734238</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">113557501</td><td align="left" rowspan="1" colspan="1">A</td><td align="left" rowspan="1" colspan="1">G</td><td align="left" rowspan="1" colspan="1">58.6</td><td align="left" rowspan="1" colspan="1">−0.005 (0.009)</td><td align="left" rowspan="1" colspan="1">0.561</td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">+---+++-+-+-+—+-+-+-+</td><td align="left" rowspan="1" colspan="1">0.8%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs715</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">211251300</td><td align="left" rowspan="1" colspan="1">T</td><td align="left" rowspan="1" colspan="1">C</td><td align="left" rowspan="1" colspan="1">68.0</td><td align="left" rowspan="1" colspan="1">−0.007 (0.011)</td><td align="left" rowspan="1" colspan="1">0.501</td><td align="left" rowspan="1" colspan="1">17</td><td align="left" rowspan="1" colspan="1">-?+?-+—?+—?+-+—+?+-</td><td align="left" rowspan="1" colspan="1">0.7%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs1476698</td><td align="left" rowspan="1" colspan="1">2</td><td align="left" rowspan="1" colspan="1">241945122</td><td align="left" rowspan="1" colspan="1">A</td><td align="left" rowspan="1" colspan="1">G</td><td align="left" rowspan="1" colspan="1">64.5</td><td align="left" rowspan="1" colspan="1">0.008 (0.009)</td><td align="left" rowspan="1" colspan="1">0.357</td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">++------+---+—++++-++</td><td align="left" rowspan="1" colspan="1">34.9%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs1154988</td><td align="left" rowspan="1" colspan="1">3</td><td align="left" rowspan="1" colspan="1">137407881</td><td align="left" rowspan="1" colspan="1">A</td><td align="left" rowspan="1" colspan="1">T</td><td align="left" rowspan="1" colspan="1">78.1</td><td align="left" rowspan="1" colspan="1">−0.013 (0.010)</td><td align="left" rowspan="1" colspan="1">0.194</td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">-----+-++++---+—+-+-+</td><td align="left" rowspan="1" colspan="1">0.0%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs16844401</td><td align="left" rowspan="1" colspan="1">4</td><td align="left" rowspan="1" colspan="1">3419450</td><td align="left" rowspan="1" colspan="1">A</td><td align="left" rowspan="1" colspan="1">G</td><td align="left" rowspan="1" colspan="1">7.5</td><td align="left" rowspan="1" colspan="1">0.017 (0.020)</td><td align="left" rowspan="1" colspan="1">0.392</td><td align="left" rowspan="1" colspan="1">18</td><td align="left" rowspan="1" colspan="1">—??+?-+++++—+++-+?-+</td><td align="left" rowspan="1" colspan="1">1.0%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs1800789</td><td align="left" rowspan="1" colspan="1">4</td><td align="left" rowspan="1" colspan="1">155702193</td><td align="left" rowspan="1" colspan="1">A</td><td align="left" rowspan="1" colspan="1">G</td><td align="left" rowspan="1" colspan="1">21.1</td><td align="left" rowspan="1" colspan="1">0.031 (0.011)</td><td align="left" rowspan="1" colspan="1">0.0028</td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">+++++---++-++—++-----</td><td align="left" rowspan="1" colspan="1">61.1%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs11242111</td><td align="left" rowspan="1" colspan="1">5</td><td align="left" rowspan="1" colspan="1">131783957</td><td align="left" rowspan="1" colspan="1">A</td><td align="left" rowspan="1" colspan="1">G</td><td align="left" rowspan="1" colspan="1">5.7</td><td align="left" rowspan="1" colspan="1">0.051 (0.033)</td><td align="left" rowspan="1" colspan="1">0.124</td><td align="left" rowspan="1" colspan="1">9</td><td align="left" rowspan="1" colspan="1">+??+?+?+?-?++?-????+??</td><td align="left" rowspan="1" colspan="1">30.0%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs2106854</td><td align="left" rowspan="1" colspan="1">5</td><td align="left" rowspan="1" colspan="1">131797073</td><td align="left" rowspan="1" colspan="1">T</td><td align="left" rowspan="1" colspan="1">C</td><td align="left" rowspan="1" colspan="1">20.8</td><td align="left" rowspan="1" colspan="1">−0.004 (0.011)</td><td align="left" rowspan="1" colspan="1">0.737</td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">---------+-+++++-+++++</td><td align="left" rowspan="1" colspan="1">0.0%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs10226084</td><td align="left" rowspan="1" colspan="1">7</td><td align="left" rowspan="1" colspan="1">17964137</td><td align="left" rowspan="1" colspan="1">T</td><td align="left" rowspan="1" colspan="1">C</td><td align="left" rowspan="1" colspan="1">51.9</td><td align="left" rowspan="1" colspan="1">−0.008 (0.009)</td><td align="left" rowspan="1" colspan="1">0.374</td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">-++++---+---+-++---+—</td><td align="left" rowspan="1" colspan="1">0.0%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs2286503</td><td align="left" rowspan="1" colspan="1">7</td><td align="left" rowspan="1" colspan="1">22823131</td><td align="left" rowspan="1" colspan="1">T</td><td align="left" rowspan="1" colspan="1">C</td><td align="left" rowspan="1" colspan="1">36.1</td><td align="left" rowspan="1" colspan="1">−0.013 (0.009)</td><td align="left" rowspan="1" colspan="1">0.131</td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">+-+-++++++—+-+----+—</td><td align="left" rowspan="1" colspan="1">0.0%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs7464572</td><td align="left" rowspan="1" colspan="1">8</td><td align="left" rowspan="1" colspan="1">145093155</td><td align="left" rowspan="1" colspan="1">C</td><td align="left" rowspan="1" colspan="1">G</td><td align="left" rowspan="1" colspan="1">59.7</td><td align="left" rowspan="1" colspan="1">−0.004 (0.009)</td><td align="left" rowspan="1" colspan="1">0.672</td><td align="left" rowspan="1" colspan="1">19</td><td align="left" rowspan="1" colspan="1">+?++----?-++?-+----+-+</td><td align="left" rowspan="1" colspan="1">0.0%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs7896783</td><td align="left" rowspan="1" colspan="1">10</td><td align="left" rowspan="1" colspan="1">64832159</td><td align="left" rowspan="1" colspan="1">A</td><td align="left" rowspan="1" colspan="1">G</td><td align="left" rowspan="1" colspan="1">48.4</td><td align="left" rowspan="1" colspan="1">−0.014 (0.008)</td><td align="left" rowspan="1" colspan="1">0.094</td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">-+-++—++-----+----+—</td><td align="left" rowspan="1" colspan="1">0.0%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs1019670</td><td align="left" rowspan="1" colspan="1">11</td><td align="left" rowspan="1" colspan="1">59697175</td><td align="left" rowspan="1" colspan="1">A</td><td align="left" rowspan="1" colspan="1">T</td><td align="left" rowspan="1" colspan="1">35.8</td><td align="left" rowspan="1" colspan="1">−0.009 (0.009)</td><td align="left" rowspan="1" colspan="1">0.345</td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">+---++++++---+----+---</td><td align="left" rowspan="1" colspan="1">0.0%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs7968440</td><td align="left" rowspan="1" colspan="1">12</td><td align="left" rowspan="1" colspan="1">49421008</td><td align="left" rowspan="1" colspan="1">A</td><td align="left" rowspan="1" colspan="1">G</td><td align="left" rowspan="1" colspan="1">64.0</td><td align="left" rowspan="1" colspan="1">0.003 (0.009)</td><td align="left" rowspan="1" colspan="1">0.855</td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">+-+-+----+----++++—++</td><td align="left" rowspan="1" colspan="1">52.0%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs434943</td><td align="left" rowspan="1" colspan="1">14</td><td align="left" rowspan="1" colspan="1">68383812</td><td align="left" rowspan="1" colspan="1">A</td><td align="left" rowspan="1" colspan="1">G</td><td align="left" rowspan="1" colspan="1">31.7</td><td align="left" rowspan="1" colspan="1">−0.002 (0.010)</td><td align="left" rowspan="1" colspan="1">0.884</td><td align="left" rowspan="1" colspan="1">21</td><td align="left" rowspan="1" colspan="1">-----+-++++----++++?++</td><td align="left" rowspan="1" colspan="1">0.0%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs12915708</td><td align="left" rowspan="1" colspan="1">15</td><td align="left" rowspan="1" colspan="1">48835894</td><td align="left" rowspan="1" colspan="1">C</td><td align="left" rowspan="1" colspan="1">G</td><td align="left" rowspan="1" colspan="1">30.6</td><td align="left" rowspan="1" colspan="1">−0.003 (0.009)</td><td align="left" rowspan="1" colspan="1">0.776</td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">-+—++---+-++----+-+—</td><td align="left" rowspan="1" colspan="1">20.7%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs7204230</td><td align="left" rowspan="1" colspan="1">16</td><td align="left" rowspan="1" colspan="1">51749832</td><td align="left" rowspan="1" colspan="1">T</td><td align="left" rowspan="1" colspan="1">C</td><td align="left" rowspan="1" colspan="1">69.7</td><td align="left" rowspan="1" colspan="1">0.008 (0.010)</td><td align="left" rowspan="1" colspan="1">0.447</td><td align="left" rowspan="1" colspan="1">19</td><td align="left" rowspan="1" colspan="1">+?-++—+?+—?-+++++-++</td><td align="left" rowspan="1" colspan="1">0.0%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs10512597</td><td align="left" rowspan="1" colspan="1">17</td><td align="left" rowspan="1" colspan="1">70211428</td><td align="left" rowspan="1" colspan="1">T</td><td align="left" rowspan="1" colspan="1">C</td><td align="left" rowspan="1" colspan="1">17.9</td><td align="left" rowspan="1" colspan="1">−0.008 (0.012)</td><td align="left" rowspan="1" colspan="1">0.490</td><td align="left" rowspan="1" colspan="1">21</td><td align="left" rowspan="1" colspan="1">----+-+—+-+—+-+++?++</td><td align="left" rowspan="1" colspan="1">0.0%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs4817986</td><td align="left" rowspan="1" colspan="1">21</td><td align="left" rowspan="1" colspan="1">39387382</td><td align="left" rowspan="1" colspan="1">T</td><td align="left" rowspan="1" colspan="1">G</td><td align="left" rowspan="1" colspan="1">27.9</td><td align="left" rowspan="1" colspan="1">−0.025 (0.010)</td><td align="left" rowspan="1" colspan="1">0.011</td><td align="left" rowspan="1" colspan="1">20</td><td align="left" rowspan="1" colspan="1">—?+---+-----++---+?—</td><td align="left" rowspan="1" colspan="1">12.8%</td></tr><tr><td align="left" rowspan="1" colspan="1">rs6010044</td><td align="left" rowspan="1" colspan="1">22</td><td align="left" rowspan="1" colspan="1">49448804</td><td align="left" rowspan="1" colspan="1">A</td><td align="left" rowspan="1" colspan="1">C</td><td align="left" rowspan="1" colspan="1">79.5</td><td align="left" rowspan="1" colspan="1">0.005 (0.012)</td><td align="left" rowspan="1" colspan="1">0.669</td><td align="left" rowspan="1" colspan="1">21</td><td align="left" rowspan="1" colspan="1">+—++++---++++—?-++++</td><td align="left" rowspan="1" colspan="1">0.0%</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt105"><label></label><p>SNP: single nucleotide polymorphism, Chr: chromosome, SE: standard error.</p></fn><fn id="nt106"><label></label><p><italic>* Allele 1 is effect allele, ** The order of studies under “direction” refers to the order of studies in </italic><xref ref-type="table" rid="pone-0111156-t001"><italic>Table 1</italic></xref><italic>.</italic></p></fn></table-wrap-foot></table-wrap><p>Finally, we examined 24 signals previously shown to be associated with circulating fibrinogen in genome-wide analysis in almost the same study population <xref rid="pone.0111156-SabaterLleal1" ref-type="bibr">[17]</xref> assuming a significance threshold of 0.0021 (Bonferroni correction for 24 tests: 0.05/24). None of these candidates was significant at this threshold in the present GxE meta-analyses. For smoking status, a suggestive interaction was found for rs1800789 in the <italic>FGB</italic> gene on chromosome 4 (p value for interaction 0.0028) revealing a 0.031 g/L higher difference in mean fibrinogen concentration per A allele copy in smokers compared with non-smokers (<xref ref-type="table" rid="pone-0111156-t003">Table 3</xref>). This SNP represents almost the same signal as rs1800790 (r<sup>2</sup> = 0.911, D′ = 1.00) for which interactions with smoking was found previously and a similar I<sup>2</sup> index was estimated (see above).</p><p>For alcohol consumption and BMI, the lowest p values among the 24 signals were observed for rs715 in <italic>CPS1</italic> on chromosome 2 (p value = 0.0195) and for rs10512597 in <italic>CD300LF</italic> on chromosome 17 (p value = 0.0049), see <xref ref-type="supplementary-material" rid="pone.0111156.s006">S4</xref> and <xref ref-type="supplementary-material" rid="pone.0111156.s002">S5 Tables</xref>.</p></sec></sec><sec id="s4"><title>Discussion</title><sec id="s4a"><title>Overall</title><p>The present study is the first to investigate interactions between smoking status, alcohol consumption, and BMI and gene variants on fibrinogen concentrations based on data from genome-wide interaction studies. Meta-analysing a population of 80,607 participants of European ancestry drawn from 22 studies did not identify any variant that modified the association of smoking status, alcohol consumption and BMI with plasma fibrinogen concentrations with genome-wide significance.</p></sec><sec id="s4b"><title>Association of smoking status, alcohol consumption and BMI with fibrinogen concentration</title><p>Several studies have identified strong and significant associations of smoking status, alcohol consumption and BMI with fibrinogen concentrations <xref rid="pone.0111156-Krobot1" ref-type="bibr">[1]</xref>–<xref rid="pone.0111156-Kaptoge1" ref-type="bibr">[7]</xref>. The present study confirmed these associations and is in line with findings from a large meta-analysis of 154,211 participants in 31 prospective studies conducted by the Fibrinogen Studies Collaboration (FSC) which showed comparable estimates of fibrinogen concentration differences in smokers compared to non-smokers and for differences in BMI and alcohol consumption amounts <xref rid="pone.0111156-Kaptoge1" ref-type="bibr">[7]</xref>. These strong associations of smoking status, alcohol consumption and BMI with fibrinogen might be explained mainly by their relation with the acute phase reaction which contributes to the regulation of the fibrinogen synthesis <xref rid="pone.0111156-Krobot1" ref-type="bibr">[1]</xref>.</p></sec><sec id="s4c"><title>Interaction between gene variants and smoking status, alcohol consumption and BMI on fibrinogen concentration – genome-wide analyses</title><p>The present study found no evidence that the strong associations of smoking status, alcohol consumption and BMI with fibrinogen concentrations were significantly modified by any of the approximately 2.6 million polymorphisms identified in the HapMap II Caucasian (CEU) sample. However, a peak on chromosome 15 with suggestive evidence of an interaction with smoking status was found for rs10519203 (p value for interaction 6.2×10<sup>−8</sup>) which is located in the <italic>LOC123688</italic> region. The effect on fibrinogen level by smoking status was lower per copy of the A allele (major allele) indicating that fibrinogen regulation by tobacco exposure might be attenuated depending on the genotype of rs10519203. A strong association of genetic variants in the <italic>LOC123688</italic> region with lung cancer has been reported recently <xref rid="pone.0111156-Hung1" ref-type="bibr">[31]</xref>–<xref rid="pone.0111156-Truong1" ref-type="bibr">[33]</xref>. One of these variants, rs8034191, was in complete linkage disequilibrium with rs10519203 (r<sup>2</sup> = 1, D′ = 1). Interestingly, Truong et al. found that these variants were associated with significantly increased lung cancer risk per copy of their minor allele in former or current but not in never smokers <xref rid="pone.0111156-Truong1" ref-type="bibr">[33]</xref>.</p></sec><sec id="s4d"><title>Interaction between gene variants and smoking status, alcohol consumption and BMI on fibrinogen concentration - selected candidate SNPs</title><p>Two previous studies with a candidate-gene approach reported interactions between the G/A-455 polymorphism at the <italic>FGB</italic> gene (rs1800790) and smoking status on fibrinogen concentration in samples of healthy men; however, these studies reported contradictory findings <xref rid="pone.0111156-Green1" ref-type="bibr">[21]</xref>, <xref rid="pone.0111156-Thomas1" ref-type="bibr">[22]</xref>: whereas, in 86 healthy men, fibrinogen concentrations were significantly higher per copy of the A allele in smokers only <xref rid="pone.0111156-Green1" ref-type="bibr">[21]</xref>, the opposite was true in 482 healthy middle-aged men with significant associations only in non-smokers <xref rid="pone.0111156-Thomas1" ref-type="bibr">[22]</xref>. The present meta-analyses could confirm the findings of an association only in smokers <xref rid="pone.0111156-Green1" ref-type="bibr">[21]</xref> albeit with a sample size more than 200 times larger.</p><p>Several studies have identified strong associations of specific variants with fibrinogen levels; one of these was in the fibrinogen <italic>β</italic> chain <italic>(FBG)</italic> gene <xref rid="pone.0111156-Danik1" ref-type="bibr">[15]</xref>–<xref rid="pone.0111156-SabaterLleal1" ref-type="bibr">[17]</xref>. A very recently performed meta-analysis conducted also within the framework of the CHARGE consortium and comprising almost the same study population as the present investigation revealed 24 independent signals in 23 loci being significantly associated with fibrinogen concentration <xref rid="pone.0111156-SabaterLleal1" ref-type="bibr">[17]</xref>. The present GxE meta-analyses indicated no significant modifications of the associations of smoking status, alcohol consumption and BMI with fibrinogen concentration.</p></sec><sec id="s4e"><title>Strengths and limitations</title><p>The present study was restricted to genetic variants with a minor allele frequency of at least 5%. Analyses for variants with a lower MAF produced an excess of small p values which were likely due to a poor approximation of true null distribution of the test statistics by the normal distribution. It is possible, however, that there may be significant interactions for rare variants which could be detected in studies with improved approximations or with even larger sample sizes. Moreover, the three determinants of fibrinogen were employed in commonly used categorizations across all studies; however, other definitions (e.g. never smokers versus ever smokers, other cut-off values than 10 g/day for alcohol consumption or categorized BMI) might yield significant interactions. Finally, we observed heterogeneity in covariate distribution and effect estimates which may affect our findings.</p><p>The present study is the first genome-wide interaction study aimed to detect interactions between environmental factors and gene variants on fibrinogen concentration. Its strength relies on the large numbers of studies and participants which was confirmed by a power analysis: If we assume a study population with a prevalence of exposed of ≥20% (e.g. smokers), a SNP with a MAF of ≥0.05, and an interaction of ≥0.1 meaning that the difference in mean fibrinogen concentration between exposed and non-exposed participants is at least 0.1 g/L higher per one copy of the minor allele, the power to detect an interaction would be greater than 90% based on 80,000 participants and a significance level of 5.0×10<sup>−8</sup>.These estimations indicate that the power of our study is large enough to detect genome-wide relevant interactions between SNPs and smoking, alcohol consumption and BMI on fibrinogen concentration.</p></sec><sec id="s4f"><title>Conclusions</title><p>The present large genome-wide interaction analyses including 22 studies comprising 80,607 subjects of European ancestry did not identify significant interaction of gene variants and smoking status, alcohol consumption or BMI on fibrinogen concentrations. The strong associations of these three variables with fibrinogen are not modified substantially by any of the 2.6 million common genetic variants analysed in this study. Suggestive evidence of an interaction could be found for smoking status with a fibrinogen-SNP association in smokers and but not in non-smokers. Further studies are needed to yield deeper insight in the interplay between environmental factors and functional genomics on the regulation of fibrinogen concentrations.</p></sec></sec><sec sec-type="supplementary-material" id="s5"><title>Supporting Information</title><supplementary-material content-type="local-data" id="pone.0111156.s001"><label>S1 Fig</label><caption><p>QQ plots for interaction of gene variants and environmental factors on fibrinogen concentration (in g/L), adjusted for age and sex.</p><p>(TIF)</p></caption><media xlink:href="pone.0111156.s001.tif"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0111156.s002"><label>S2 Fig</label><caption><p>Forest plot for interaction of rs10519203 and smoking status on fibrinogen concentration (in g/L) with 95% confidence interval, adjusted for age and sex.</p><p>(TIF)</p></caption><media xlink:href="pone.0111156.s002.tif"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0111156.s003"><label>S1 Table</label><caption><p><bold>Basic information about studies.</bold></p><p>(DOC)</p></caption><media xlink:href="pone.0111156.s003.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0111156.s004"><label>S2 Table</label><caption><p><bold>Genotype information about studies.</bold></p><p>(DOC)</p></caption><media xlink:href="pone.0111156.s004.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0111156.s005"><label>S3 Table</label><caption><p><bold>Genomic inflation factor per study.</bold></p><p>(DOC)</p></caption><media xlink:href="pone.0111156.s005.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0111156.s006"><label>S4 Table</label><caption><p><bold>Interaction with alcohol consumption for association with fibrinogen concentration (in g/L) among SNPs associated with circulating fibrinogen (Sabater-Leal et al. 2013).</bold></p><p>(DOC)</p></caption><media xlink:href="pone.0111156.s006.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0111156.s007"><label>S5 Table</label><caption><p><bold>Interaction with BMI for association with fibrinogen concentration (in g/L) among SNPs associated with circulating fibrinogen (Sabater-Leal et al. 2013).</bold></p><p>(DOC)</p></caption><media xlink:href="pone.0111156.s007.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0111156.s008"><label>S1 Funding</label><caption><p><bold>Funding statement.</bold></p><p>(DOC)</p></caption><media xlink:href="pone.0111156.s008.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0111156.s009"><label>S1 Checklist</label><caption><p><bold>PRISMA checklist.</bold></p><p>(DOC)</p></caption><media xlink:href="pone.0111156.s009.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pone.0111156.s010"><label>S1 Methods</label><caption><p><bold>This file gives additional information about the study samples, fibrinogen measurements, genotyping/imputation and statistical analyses.</bold></p><p>(DOC)</p></caption><media xlink:href="pone.0111156.s010.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></sec></body><back><ref-list><title>References</title><ref id="pone.0111156-Krobot1"><label>1</label><mixed-citation publication-type="journal"><name><surname>Krobot</surname><given-names>K</given-names></name>, <name><surname>Hense</surname><given-names>HW</given-names></name>, <name><surname>Cremer</surname><given-names>P</given-names></name>, <name><surname>Eberle</surname><given-names>E</given-names></name>, <name><surname>Keil</surname><given-names>U</given-names></name> (<year>1992</year>) <article-title>Determinants of plasma fibrinogen: relation to body weight, waist-to-hip ratio, smoking, alcohol, age, and sex. 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