Gene–environment interactions involving functional variants: Results from the Breast Cancer Association Consortium
Identifieur interne : 002444 ( Pmc/Curation ); précédent : 002443; suivant : 002445Gene–environment interactions involving functional variants: Results from the Breast Cancer Association Consortium
Auteurs : Myrto Barrdahl ; Anja Rudolph ; John L. Hopper ; Melissa C. Southey ; Annegien Broeks ; Peter A. Fasching ; Matthias W. Beckmann ; Manuela Gago-Dominguez ; J. Esteban Castelao ; Pascal Guénel ; Thérèse Truong ; Stig E. Bojesen ; Susan M. Gapstur ; Mia M. Gaudet ; Hermann Brenner ; Volker Arndt ; Hiltrud Brauch ; Ute Hamann ; Arto Mannermaa ; Diether Lambrechts ; Lynn Jongen ; Dieter Flesch-Janys ; Kathrin Thoene ; Fergus J. Couch ; Graham G. Giles ; Jacques Simard ; Mark S. Goldberg ; Jonine Figueroa ; Kyriaki Michailidou ; Manjeet K. Bolla ; Joe Dennis ; Qin Wang ; Ursula Eilber ; Sabine Behrens ; Kamila Czene ; Per Hall ; Angela Cox ; Simon Cross ; Anthony Swerdlow ; Minouk J. Schoemaker ; Alison M. Dunning ; Rudolf Kaaks ; Paul D. P. Pharoah ; Marjanka Schmidt ; Montserrat Garcia-Closas ; Douglas F. Easton ; Roger L. Milne ; Jenny Chang-ClaudeSource :
- International Journal of Cancer [ 0020-7136 ] ; 2017.
Abstract
Investigating the most likely causal variants identified by fine‐mapping analyses may improve the power to detect gene–environment interactions. We assessed the interplay between 70 single nucleotide polymorphisms identified by genetic fine‐scale mapping of susceptibility loci and 11 epidemiological breast cancer risk factors in relation to breast cancer. Analyses were conducted on up to 58,573 subjects (26,968 cases and 31,605 controls) from the Breast Cancer Association Consortium, in one of the largest studies of its kind. Analyses were carried out separately for estrogen receptor (ER) positive (ER+) and ER negative (ER–) disease. The Bayesian False Discovery Probability (BFDP) was computed to assess the noteworthiness of the results. Four potential gene–environment interactions were identified as noteworthy (BFDP < 0.80) when assuming a true prior interaction probability of 0.01. The strongest interaction result in relation to overall breast cancer risk was found between
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DOI: 10.1002/ijc.30859
PubMed: 28670784
PubMed Central: 5601244
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Schoemaker</name><affiliation><nlm:aff id="ijc30859-aff-0042"></nlm:aff></affiliation></author><author><name sortKey="Dunning, Alison M" sort="Dunning, Alison M" uniqKey="Dunning A" first="Alison M." last="Dunning">Alison M. Dunning</name><affiliation><nlm:aff id="ijc30859-aff-0043"></nlm:aff></affiliation></author><author><name sortKey="Kaaks, Rudolf" sort="Kaaks, Rudolf" uniqKey="Kaaks R" first="Rudolf" last="Kaaks">Rudolf Kaaks</name><affiliation><nlm:aff id="ijc30859-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Pharoah, Paul D P" sort="Pharoah, Paul D P" uniqKey="Pharoah P" first="Paul D. P." last="Pharoah">Paul D. P. Pharoah</name><affiliation><nlm:aff id="ijc30859-aff-0036"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0043"></nlm:aff></affiliation></author><author><name sortKey="Schmidt, Marjanka" sort="Schmidt, Marjanka" uniqKey="Schmidt M" first="Marjanka" last="Schmidt">Marjanka Schmidt</name><affiliation><nlm:aff id="ijc30859-aff-0004"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0044"></nlm:aff></affiliation></author><author><name sortKey="Garcia Losas, Montserrat" sort="Garcia Losas, Montserrat" uniqKey="Garcia Losas M" first="Montserrat" last="Garcia-Closas">Montserrat Garcia-Closas</name><affiliation><nlm:aff id="ijc30859-aff-0035"></nlm:aff></affiliation></author><author><name sortKey="Easton, Douglas F" sort="Easton, Douglas F" uniqKey="Easton D" first="Douglas F." last="Easton">Douglas F. Easton</name><affiliation><nlm:aff id="ijc30859-aff-0036"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0043"></nlm:aff></affiliation></author><author><name sortKey="Milne, Roger L" sort="Milne, Roger L" uniqKey="Milne R" first="Roger L." last="Milne">Roger L. Milne</name><affiliation><nlm:aff id="ijc30859-aff-0002"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0030"></nlm:aff></affiliation></author><author><name sortKey="Chang Laude, Jenny" sort="Chang Laude, Jenny" uniqKey="Chang Laude J" first="Jenny" last="Chang-Claude">Jenny Chang-Claude</name><affiliation><nlm:aff id="ijc30859-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0045"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28670784</idno><idno type="pmc">5601244</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601244</idno><idno type="RBID">PMC:5601244</idno><idno type="doi">10.1002/ijc.30859</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">002594</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002594</idno><idno type="wicri:Area/Pmc/Curation">002444</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">002444</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Gene–environment interactions involving functional variants: Results from the Breast Cancer Association Consortium</title><author><name sortKey="Barrdahl, Myrto" sort="Barrdahl, Myrto" uniqKey="Barrdahl M" first="Myrto" last="Barrdahl">Myrto Barrdahl</name><affiliation><nlm:aff id="ijc30859-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Rudolph, Anja" sort="Rudolph, Anja" uniqKey="Rudolph A" first="Anja" last="Rudolph">Anja Rudolph</name><affiliation><nlm:aff id="ijc30859-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L." last="Hopper">John L. Hopper</name><affiliation><nlm:aff id="ijc30859-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Southey, Melissa C" sort="Southey, Melissa C" uniqKey="Southey M" first="Melissa C." last="Southey">Melissa C. Southey</name><affiliation><nlm:aff id="ijc30859-aff-0003"></nlm:aff></affiliation></author><author><name sortKey="Broeks, Annegien" sort="Broeks, Annegien" uniqKey="Broeks A" first="Annegien" last="Broeks">Annegien Broeks</name><affiliation><nlm:aff id="ijc30859-aff-0004"></nlm:aff></affiliation></author><author><name sortKey="Fasching, Peter A" sort="Fasching, Peter A" uniqKey="Fasching P" first="Peter A." last="Fasching">Peter A. Fasching</name><affiliation><nlm:aff id="ijc30859-aff-0005"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0006"></nlm:aff></affiliation></author><author><name sortKey="Beckmann, Matthias W" sort="Beckmann, Matthias W" uniqKey="Beckmann M" first="Matthias W." last="Beckmann">Matthias W. Beckmann</name><affiliation><nlm:aff id="ijc30859-aff-0005"></nlm:aff></affiliation></author><author><name sortKey="Gago Ominguez, Manuela" sort="Gago Ominguez, Manuela" uniqKey="Gago Ominguez M" first="Manuela" last="Gago-Dominguez">Manuela Gago-Dominguez</name><affiliation><nlm:aff id="ijc30859-aff-0007"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0008"></nlm:aff></affiliation></author><author><name sortKey="Castelao, J Esteban" sort="Castelao, J Esteban" uniqKey="Castelao J" first="J. Esteban" last="Castelao">J. Esteban Castelao</name><affiliation><nlm:aff id="ijc30859-aff-0009"></nlm:aff></affiliation></author><author><name sortKey="Guenel, Pascal" sort="Guenel, Pascal" uniqKey="Guenel P" first="Pascal" last="Guénel">Pascal Guénel</name><affiliation><nlm:aff id="ijc30859-aff-0010"></nlm:aff></affiliation></author><author><name sortKey="Truong, Therese" sort="Truong, Therese" uniqKey="Truong T" first="Thérèse" last="Truong">Thérèse Truong</name><affiliation><nlm:aff id="ijc30859-aff-0010"></nlm:aff></affiliation></author><author><name sortKey="Bojesen, Stig E" sort="Bojesen, Stig E" uniqKey="Bojesen S" first="Stig E." last="Bojesen">Stig E. Bojesen</name><affiliation><nlm:aff id="ijc30859-aff-0011"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0012"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0013"></nlm:aff></affiliation></author><author><name sortKey="Gapstur, Susan M" sort="Gapstur, Susan M" uniqKey="Gapstur S" first="Susan M." last="Gapstur">Susan M. Gapstur</name><affiliation><nlm:aff id="ijc30859-aff-0014"></nlm:aff></affiliation></author><author><name sortKey="Gaudet, Mia M" sort="Gaudet, Mia M" uniqKey="Gaudet M" first="Mia M." last="Gaudet">Mia M. Gaudet</name><affiliation><nlm:aff id="ijc30859-aff-0014"></nlm:aff></affiliation></author><author><name sortKey="Brenner, Hermann" sort="Brenner, Hermann" uniqKey="Brenner H" first="Hermann" last="Brenner">Hermann Brenner</name><affiliation><nlm:aff id="ijc30859-aff-0015"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0016"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0017"></nlm:aff></affiliation></author><author><name sortKey="Arndt, Volker" sort="Arndt, Volker" uniqKey="Arndt V" first="Volker" last="Arndt">Volker Arndt</name><affiliation><nlm:aff id="ijc30859-aff-0015"></nlm:aff></affiliation></author><author><name sortKey="Brauch, Hiltrud" sort="Brauch, Hiltrud" uniqKey="Brauch H" first="Hiltrud" last="Brauch">Hiltrud Brauch</name><affiliation><nlm:aff id="ijc30859-aff-0017"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0018"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0019"></nlm:aff></affiliation></author><author><name sortKey="Hamann, Ute" sort="Hamann, Ute" uniqKey="Hamann U" first="Ute" last="Hamann">Ute Hamann</name><affiliation><nlm:aff id="ijc30859-aff-0020"></nlm:aff></affiliation></author><author><name sortKey="Mannermaa, Arto" sort="Mannermaa, Arto" uniqKey="Mannermaa A" first="Arto" last="Mannermaa">Arto Mannermaa</name><affiliation><nlm:aff id="ijc30859-aff-0021"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0022"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0023"></nlm:aff></affiliation></author><author><name sortKey="Lambrechts, Diether" sort="Lambrechts, Diether" uniqKey="Lambrechts D" first="Diether" last="Lambrechts">Diether Lambrechts</name><affiliation><nlm:aff id="ijc30859-aff-0024"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0025"></nlm:aff></affiliation></author><author><name sortKey="Jongen, Lynn" sort="Jongen, Lynn" uniqKey="Jongen L" first="Lynn" last="Jongen">Lynn Jongen</name><affiliation><nlm:aff id="ijc30859-aff-0026"></nlm:aff></affiliation></author><author><name sortKey="Flesch Anys, Dieter" sort="Flesch Anys, Dieter" uniqKey="Flesch Anys D" first="Dieter" last="Flesch-Janys">Dieter Flesch-Janys</name><affiliation><nlm:aff id="ijc30859-aff-0027"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0028"></nlm:aff></affiliation></author><author><name sortKey="Thoene, Kathrin" sort="Thoene, Kathrin" uniqKey="Thoene K" first="Kathrin" last="Thoene">Kathrin Thoene</name><affiliation><nlm:aff id="ijc30859-aff-0028"></nlm:aff></affiliation></author><author><name sortKey="Couch, Fergus J" sort="Couch, Fergus J" uniqKey="Couch F" first="Fergus J." last="Couch">Fergus J. Couch</name><affiliation><nlm:aff id="ijc30859-aff-0029"></nlm:aff></affiliation></author><author><name sortKey="Giles, Graham G" sort="Giles, Graham G" uniqKey="Giles G" first="Graham G." last="Giles">Graham G. Giles</name><affiliation><nlm:aff id="ijc30859-aff-0002"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0030"></nlm:aff></affiliation></author><author><name sortKey="Simard, Jacques" sort="Simard, Jacques" uniqKey="Simard J" first="Jacques" last="Simard">Jacques Simard</name><affiliation><nlm:aff id="ijc30859-aff-0031"></nlm:aff></affiliation></author><author><name sortKey="Goldberg, Mark S" sort="Goldberg, Mark S" uniqKey="Goldberg M" first="Mark S." last="Goldberg">Mark S. Goldberg</name><affiliation><nlm:aff id="ijc30859-aff-0032"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0033"></nlm:aff></affiliation></author><author><name sortKey="Figueroa, Jonine" sort="Figueroa, Jonine" uniqKey="Figueroa J" first="Jonine" last="Figueroa">Jonine Figueroa</name><affiliation><nlm:aff id="ijc30859-aff-0034"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0035"></nlm:aff></affiliation></author><author><name sortKey="Michailidou, Kyriaki" sort="Michailidou, Kyriaki" uniqKey="Michailidou K" first="Kyriaki" last="Michailidou">Kyriaki Michailidou</name><affiliation><nlm:aff id="ijc30859-aff-0036"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0037"></nlm:aff></affiliation></author><author><name sortKey="Bolla, Manjeet K" sort="Bolla, Manjeet K" uniqKey="Bolla M" first="Manjeet K." last="Bolla">Manjeet K. Bolla</name><affiliation><nlm:aff id="ijc30859-aff-0036"></nlm:aff></affiliation></author><author><name sortKey="Dennis, Joe" sort="Dennis, Joe" uniqKey="Dennis J" first="Joe" last="Dennis">Joe Dennis</name><affiliation><nlm:aff id="ijc30859-aff-0036"></nlm:aff></affiliation></author><author><name sortKey="Wang, Qin" sort="Wang, Qin" uniqKey="Wang Q" first="Qin" last="Wang">Qin Wang</name><affiliation><nlm:aff id="ijc30859-aff-0036"></nlm:aff></affiliation></author><author><name sortKey="Eilber, Ursula" sort="Eilber, Ursula" uniqKey="Eilber U" first="Ursula" last="Eilber">Ursula Eilber</name><affiliation><nlm:aff id="ijc30859-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Behrens, Sabine" sort="Behrens, Sabine" uniqKey="Behrens S" first="Sabine" last="Behrens">Sabine Behrens</name><affiliation><nlm:aff id="ijc30859-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Czene, Kamila" sort="Czene, Kamila" uniqKey="Czene K" first="Kamila" last="Czene">Kamila Czene</name><affiliation><nlm:aff id="ijc30859-aff-0038"></nlm:aff></affiliation></author><author><name sortKey="Hall, Per" sort="Hall, Per" uniqKey="Hall P" first="Per" last="Hall">Per Hall</name><affiliation><nlm:aff id="ijc30859-aff-0038"></nlm:aff></affiliation></author><author><name sortKey="Cox, Angela" sort="Cox, Angela" uniqKey="Cox A" first="Angela" last="Cox">Angela Cox</name><affiliation><nlm:aff id="ijc30859-aff-0039"></nlm:aff></affiliation></author><author><name sortKey="Cross, Simon" sort="Cross, Simon" uniqKey="Cross S" first="Simon" last="Cross">Simon Cross</name><affiliation><nlm:aff id="ijc30859-aff-0040"></nlm:aff></affiliation></author><author><name sortKey="Swerdlow, Anthony" sort="Swerdlow, Anthony" uniqKey="Swerdlow A" first="Anthony" last="Swerdlow">Anthony Swerdlow</name><affiliation><nlm:aff id="ijc30859-aff-0041"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0042"></nlm:aff></affiliation></author><author><name sortKey="Schoemaker, Minouk J" sort="Schoemaker, Minouk J" uniqKey="Schoemaker M" first="Minouk J." last="Schoemaker">Minouk J. Schoemaker</name><affiliation><nlm:aff id="ijc30859-aff-0042"></nlm:aff></affiliation></author><author><name sortKey="Dunning, Alison M" sort="Dunning, Alison M" uniqKey="Dunning A" first="Alison M." last="Dunning">Alison M. Dunning</name><affiliation><nlm:aff id="ijc30859-aff-0043"></nlm:aff></affiliation></author><author><name sortKey="Kaaks, Rudolf" sort="Kaaks, Rudolf" uniqKey="Kaaks R" first="Rudolf" last="Kaaks">Rudolf Kaaks</name><affiliation><nlm:aff id="ijc30859-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Pharoah, Paul D P" sort="Pharoah, Paul D P" uniqKey="Pharoah P" first="Paul D. P." last="Pharoah">Paul D. P. Pharoah</name><affiliation><nlm:aff id="ijc30859-aff-0036"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0043"></nlm:aff></affiliation></author><author><name sortKey="Schmidt, Marjanka" sort="Schmidt, Marjanka" uniqKey="Schmidt M" first="Marjanka" last="Schmidt">Marjanka Schmidt</name><affiliation><nlm:aff id="ijc30859-aff-0004"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0044"></nlm:aff></affiliation></author><author><name sortKey="Garcia Losas, Montserrat" sort="Garcia Losas, Montserrat" uniqKey="Garcia Losas M" first="Montserrat" last="Garcia-Closas">Montserrat Garcia-Closas</name><affiliation><nlm:aff id="ijc30859-aff-0035"></nlm:aff></affiliation></author><author><name sortKey="Easton, Douglas F" sort="Easton, Douglas F" uniqKey="Easton D" first="Douglas F." last="Easton">Douglas F. Easton</name><affiliation><nlm:aff id="ijc30859-aff-0036"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0043"></nlm:aff></affiliation></author><author><name sortKey="Milne, Roger L" sort="Milne, Roger L" uniqKey="Milne R" first="Roger L." last="Milne">Roger L. Milne</name><affiliation><nlm:aff id="ijc30859-aff-0002"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0030"></nlm:aff></affiliation></author><author><name sortKey="Chang Laude, Jenny" sort="Chang Laude, Jenny" uniqKey="Chang Laude J" first="Jenny" last="Chang-Claude">Jenny Chang-Claude</name><affiliation><nlm:aff id="ijc30859-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="ijc30859-aff-0045"></nlm:aff></affiliation></author></analytic><series><title level="j">International Journal of Cancer</title><idno type="ISSN">0020-7136</idno><idno type="eISSN">1097-0215</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Investigating the most likely causal variants identified by fine‐mapping analyses may improve the power to detect gene–environment interactions. We assessed the interplay between 70 single nucleotide polymorphisms identified by genetic fine‐scale mapping of susceptibility loci and 11 epidemiological breast cancer risk factors in relation to breast cancer. Analyses were conducted on up to 58,573 subjects (26,968 cases and 31,605 controls) from the Breast Cancer Association Consortium, in one of the largest studies of its kind. Analyses were carried out separately for estrogen receptor (ER) positive (ER+) and ER negative (ER–) disease. The Bayesian False Discovery Probability (BFDP) was computed to assess the noteworthiness of the results. Four potential gene–environment interactions were identified as noteworthy (BFDP < 0.80) when assuming a true prior interaction probability of 0.01. The strongest interaction result in relation to overall breast cancer risk was found between <italic>CFLAR</italic>‐rs7558475 and current smoking (OR<sub>int</sub> = 0.77, 95% CI: 0.67–0.88, <italic>p</italic><sub>int</sub> = 1.8 × 10<sup>−4</sup>). The interaction with the strongest statistical evidence was found between 5q14‐rs7707921 and alcohol consumption (OR<sub>int</sub> =1.36, 95% CI: 1.16–1.59, <italic>p</italic><sub>int</sub> = 1.9 × 10<sup>−5</sup>) in relation to ER– disease risk. The remaining two gene–environment interactions were also identified in relation to ER– breast cancer risk and were found between 3p21‐rs6796502 and age at menarche (OR<sub>int</sub> = 1.26, 95% CI: 1.12–1.43, <italic>p</italic><sub>int</sub> =1.8 × 10<sup>−4</sup>) and between 8q23‐rs13267382 and age at first full‐term pregnancy (OR<sub>int</sub> = 0.89, 95% CI: 0.83–0.95, <italic>p</italic><sub>int</sub> = 5.2 × 10<sup>−4</sup>). While these results do not suggest any strong gene–environment interactions, our results may still be useful to inform experimental studies. These may in turn, shed light on the potential interactions observed.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Int J Cancer</journal-id><journal-id journal-id-type="iso-abbrev">Int. J. Cancer</journal-id><journal-id journal-id-type="doi">10.1002/(ISSN)1097-0215</journal-id><journal-id journal-id-type="publisher-id">IJC</journal-id><journal-title-group><journal-title>International Journal of Cancer</journal-title></journal-title-group><issn pub-type="ppub">0020-7136</issn><issn pub-type="epub">1097-0215</issn><publisher><publisher-name>John Wiley and Sons Inc.</publisher-name><publisher-loc>Hoboken</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28670784</article-id><article-id pub-id-type="pmc">5601244</article-id><article-id pub-id-type="doi">10.1002/ijc.30859</article-id><article-id pub-id-type="publisher-id">IJC30859</article-id><article-categories><subj-group subj-group-type="overline"><subject>Cancer Genetics and Epigenetics</subject></subj-group><subj-group subj-group-type="heading"><subject>Cancer Genetics and Epigenetics</subject></subj-group></article-categories><title-group><article-title>Gene–environment interactions involving functional variants: Results from the Breast Cancer Association Consortium</article-title><alt-title alt-title-type="right-running-head">Gene–environment interactions involving functional variants</alt-title><alt-title alt-title-type="left-running-head">Barrdahl <italic>et al</italic>.</alt-title></title-group><contrib-group><contrib id="ijc30859-cr-0001" contrib-type="author"><name><surname>Barrdahl</surname><given-names>Myrto</given-names></name><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-4661-0763</contrib-id><xref ref-type="aff" rid="ijc30859-aff-0001"><sup>1</sup></xref></contrib><contrib id="ijc30859-cr-0002" contrib-type="author"><name><surname>Rudolph</surname><given-names>Anja</given-names></name><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-7520-2035</contrib-id><xref ref-type="aff" rid="ijc30859-aff-0001"><sup>1</sup></xref></contrib><contrib id="ijc30859-cr-0003" contrib-type="author"><name><surname>Hopper</surname><given-names>John L.</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0002"><sup>2</sup></xref></contrib><contrib id="ijc30859-cr-0004" contrib-type="author"><name><surname>Southey</surname><given-names>Melissa C.</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0003"><sup>3</sup></xref></contrib><contrib id="ijc30859-cr-0005" contrib-type="author"><name><surname>Broeks</surname><given-names>Annegien</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0004"><sup>4</sup></xref></contrib><contrib id="ijc30859-cr-0006" contrib-type="author"><name><surname>Fasching</surname><given-names>Peter A.</given-names></name><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-4885-8471</contrib-id><xref ref-type="aff" rid="ijc30859-aff-0005"><sup>5</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0006"><sup>6</sup></xref></contrib><contrib id="ijc30859-cr-0007" contrib-type="author"><name><surname>Beckmann</surname><given-names>Matthias W.</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0005"><sup>5</sup></xref></contrib><contrib id="ijc30859-cr-0008" contrib-type="author"><name><surname>Gago‐Dominguez</surname><given-names>Manuela</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0007"><sup>7</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0008"><sup>8</sup></xref></contrib><contrib id="ijc30859-cr-0009" contrib-type="author"><name><surname>Castelao</surname><given-names>J. Esteban</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0009"><sup>9</sup></xref></contrib><contrib id="ijc30859-cr-00010" contrib-type="author"><name><surname>Guénel</surname><given-names>Pascal</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0010"><sup>10</sup></xref></contrib><contrib id="ijc30859-cr-00011" contrib-type="author"><name><surname>Truong</surname><given-names>Thérèse</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0010"><sup>10</sup></xref></contrib><contrib id="ijc30859-cr-00012" contrib-type="author"><name><surname>Bojesen</surname><given-names>Stig E.</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0011"><sup>11</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0012"><sup>12</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0013"><sup>13</sup></xref></contrib><contrib id="ijc30859-cr-00013" contrib-type="author"><name><surname>Gapstur</surname><given-names>Susan M.</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0014"><sup>14</sup></xref></contrib><contrib id="ijc30859-cr-00014" contrib-type="author"><name><surname>Gaudet</surname><given-names>Mia M.</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0014"><sup>14</sup></xref></contrib><contrib id="ijc30859-cr-00015" contrib-type="author"><name><surname>Brenner</surname><given-names>Hermann</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0015"><sup>15</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0016"><sup>16</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0017"><sup>17</sup></xref></contrib><contrib id="ijc30859-cr-00016" contrib-type="author"><name><surname>Arndt</surname><given-names>Volker</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0015"><sup>15</sup></xref></contrib><contrib id="ijc30859-cr-00017" contrib-type="author"><name><surname>Brauch</surname><given-names>Hiltrud</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0017"><sup>17</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0018"><sup>18</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0019"><sup>19</sup></xref></contrib><contrib id="ijc30859-cr-00018" contrib-type="author"><name><surname>Hamann</surname><given-names>Ute</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0020"><sup>20</sup></xref></contrib><contrib id="ijc30859-cr-00019" contrib-type="author"><name><surname>Mannermaa</surname><given-names>Arto</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0021"><sup>21</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0022"><sup>22</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0023"><sup>23</sup></xref></contrib><contrib id="ijc30859-cr-00020" contrib-type="author"><name><surname>Lambrechts</surname><given-names>Diether</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0024"><sup>24</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0025"><sup>25</sup></xref></contrib><contrib id="ijc30859-cr-00021" contrib-type="author"><name><surname>Jongen</surname><given-names>Lynn</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0026"><sup>26</sup></xref></contrib><contrib id="ijc30859-cr-00022" contrib-type="author"><name><surname>Flesch‐Janys</surname><given-names>Dieter</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0027"><sup>27</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0028"><sup>28</sup></xref></contrib><contrib id="ijc30859-cr-00023" contrib-type="author"><name><surname>Thoene</surname><given-names>Kathrin</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0028"><sup>28</sup></xref></contrib><contrib id="ijc30859-cr-00024" contrib-type="author"><name><surname>Couch</surname><given-names>Fergus J.</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0029"><sup>29</sup></xref></contrib><contrib id="ijc30859-cr-00025" contrib-type="author"><name><surname>Giles</surname><given-names>Graham G.</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0002"><sup>2</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0030"><sup>30</sup></xref></contrib><contrib id="ijc30859-cr-00026" contrib-type="author"><name><surname>Simard</surname><given-names>Jacques</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0031"><sup>31</sup></xref></contrib><contrib id="ijc30859-cr-00027" contrib-type="author"><name><surname>Goldberg</surname><given-names>Mark S.</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0032"><sup>32</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0033"><sup>33</sup></xref></contrib><contrib id="ijc30859-cr-00028" contrib-type="author"><name><surname>Figueroa</surname><given-names>Jonine</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0034"><sup>34</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0035"><sup>35</sup></xref></contrib><contrib id="ijc30859-cr-00029" contrib-type="author"><name><surname>Michailidou</surname><given-names>Kyriaki</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0036"><sup>36</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0037"><sup>37</sup></xref></contrib><contrib id="ijc30859-cr-00030" contrib-type="author"><name><surname>Bolla</surname><given-names>Manjeet K.</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0036"><sup>36</sup></xref></contrib><contrib id="ijc30859-cr-00031" contrib-type="author"><name><surname>Dennis</surname><given-names>Joe</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0036"><sup>36</sup></xref></contrib><contrib id="ijc30859-cr-00032" contrib-type="author"><name><surname>Wang</surname><given-names>Qin</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0036"><sup>36</sup></xref></contrib><contrib id="ijc30859-cr-00033" contrib-type="author"><name><surname>Eilber</surname><given-names>Ursula</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0001"><sup>1</sup></xref></contrib><contrib id="ijc30859-cr-00034" contrib-type="author"><name><surname>Behrens</surname><given-names>Sabine</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0001"><sup>1</sup></xref></contrib><contrib id="ijc30859-cr-00035" contrib-type="author"><name><surname>Czene</surname><given-names>Kamila</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0038"><sup>38</sup></xref></contrib><contrib id="ijc30859-cr-00036" contrib-type="author"><name><surname>Hall</surname><given-names>Per</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0038"><sup>38</sup></xref></contrib><contrib id="ijc30859-cr-00037" contrib-type="author"><name><surname>Cox</surname><given-names>Angela</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0039"><sup>39</sup></xref></contrib><contrib id="ijc30859-cr-00038" contrib-type="author"><name><surname>Cross</surname><given-names>Simon</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0040"><sup>40</sup></xref></contrib><contrib id="ijc30859-cr-00039" contrib-type="author"><name><surname>Swerdlow</surname><given-names>Anthony</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0041"><sup>41</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0042"><sup>42</sup></xref></contrib><contrib id="ijc30859-cr-00040" contrib-type="author"><name><surname>Schoemaker</surname><given-names>Minouk J.</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0042"><sup>42</sup></xref></contrib><contrib id="ijc30859-cr-00041" contrib-type="author"><name><surname>Dunning</surname><given-names>Alison M.</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0043"><sup>43</sup></xref></contrib><contrib id="ijc30859-cr-00042" contrib-type="author"><name><surname>Kaaks</surname><given-names>Rudolf</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0001"><sup>1</sup></xref></contrib><contrib id="ijc30859-cr-00043" contrib-type="author"><name><surname>Pharoah</surname><given-names>Paul D.P.</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0036"><sup>36</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0043"><sup>43</sup></xref></contrib><contrib id="ijc30859-cr-00044" contrib-type="author"><name><surname>Schmidt</surname><given-names>Marjanka</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0004"><sup>4</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0044"><sup>44</sup></xref></contrib><contrib id="ijc30859-cr-00045" contrib-type="author"><name><surname>Garcia‐Closas</surname><given-names>Montserrat</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0035"><sup>35</sup></xref></contrib><contrib id="ijc30859-cr-00046" contrib-type="author"><name><surname>Easton</surname><given-names>Douglas F.</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0036"><sup>36</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0043"><sup>43</sup></xref></contrib><contrib id="ijc30859-cr-00047" contrib-type="author"><name><surname>Milne</surname><given-names>Roger L.</given-names></name><xref ref-type="aff" rid="ijc30859-aff-0002"><sup>2</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0030"><sup>30</sup></xref></contrib><contrib id="ijc30859-cr-00048" contrib-type="author" corresp="yes"><name><surname>Chang‐Claude</surname><given-names>Jenny</given-names></name><address><email>j.chang-claude@dkfz.de</email></address><xref ref-type="aff" rid="ijc30859-aff-0001"><sup>1</sup></xref><xref ref-type="aff" rid="ijc30859-aff-0045"><sup>45</sup></xref></contrib></contrib-group><aff id="ijc30859-aff-0001"><label><sup>1</sup></label><named-content content-type="organisation-division">Division of Cancer Epidemiology</named-content><institution>German Cancer Research Center (DKFZ)</institution><named-content content-type="city">Heidelberg</named-content><country country="DE">Germany</country></aff><aff id="ijc30859-aff-0002"><label><sup>2</sup></label><named-content content-type="organisation-division">Centre for Epidemiology and Biostatistics</named-content><institution>Melbourne School of Population and Global Health, The University of Melbourne</institution><named-content content-type="city">Melbourne</named-content><named-content content-type="country-part">VIC</named-content><country country="AU">Australia</country></aff><aff id="ijc30859-aff-0003"><label><sup>3</sup></label><named-content content-type="organisation-division">Department of Pathology</named-content><institution>The University of Melbourne</institution><named-content content-type="city">Melbourne</named-content><named-content content-type="country-part">VIC</named-content><country country="AU">Australia</country></aff><aff id="ijc30859-aff-0004"><label><sup>4</sup></label><named-content content-type="organisation-division">Division of Molecular Pathology</named-content><institution>Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital</institution><named-content content-type="city">Amsterdam</named-content><country country="NL">The Netherlands</country></aff><aff id="ijc30859-aff-0005"><label><sup>5</sup></label><named-content content-type="organisation-division">Department of Gynaecology and Obstetrics</named-content><institution>University Hospital Erlangen, Friedrich‐Alexander University Erlangen‐Nuremberg, Comprehensive Cancer Center Erlangen‐EMN</institution><named-content content-type="city">Erlangen</named-content><country country="DE">Germany</country></aff><aff id="ijc30859-aff-0006"><label><sup>6</sup></label><named-content content-type="organisation-division">David Geffen School of Medicine</named-content><institution>Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles</institution><named-content content-type="city">Los Angeles</named-content><named-content content-type="country-part">CA</named-content></aff><aff id="ijc30859-aff-0007"><label><sup>7</sup></label><named-content content-type="organisation-division">Genomic Medicine Group</named-content><institution>Galician Foundation of Genomic Medicine, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, Servicio Galego de Saúde, SERGAS</institution><named-content content-type="city">Santiago De Compostela</named-content><country country="ES">Spain</country></aff><aff id="ijc30859-aff-0008"><label><sup>8</sup></label><named-content content-type="organisation-division">Moores Cancer Center</named-content><institution>University of California San Diego</institution><named-content content-type="city">La Jolla</named-content><named-content content-type="country-part">CA</named-content></aff><aff id="ijc30859-aff-0009"><label><sup>9</sup></label><named-content content-type="organisation-division">Oncology and Genetics Unit</named-content><institution>Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo‐SERGAS</institution><named-content content-type="city">Vigo</named-content><country country="ES">Spain</country></aff><aff id="ijc30859-aff-0010"><label><sup>10</sup></label><institution>CESP–Cancer and Environment team, INSERM U1018, Université Paris‐Sud, Université Paris‐Saclay</institution><named-content content-type="city">Villejuif</named-content><country country="FR">France</country></aff><aff id="ijc30859-aff-0011"><label><sup>11</sup></label><institution>Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital</institution><named-content content-type="city">Herlev</named-content><country country="DK">Denmark</country></aff><aff id="ijc30859-aff-0012"><label><sup>12</sup></label><named-content content-type="organisation-division">Department of Clinical Biochemistry</named-content><institution>Herlev and Gentofte Hospital, Copenhagen University Hospital</institution><named-content content-type="city">Herlev</named-content><country country="DK">Denmark</country></aff><aff id="ijc30859-aff-0013"><label><sup>13</sup></label><named-content content-type="organisation-division">Faculty of Health and Medical Sciences</named-content><institution>University of Copenhagen</institution><named-content content-type="city">Copenhagen</named-content><country country="DK">Denmark</country></aff><aff id="ijc30859-aff-0014"><label><sup>14</sup></label><institution>Epidemiology Research Program, American Cancer Society</institution><named-content content-type="city">Atlanta</named-content><named-content content-type="country-part">GA</named-content></aff><aff id="ijc30859-aff-0015"><label><sup>15</sup></label><named-content content-type="organisation-division">Division of Clinical Epidemiology and Aging Research</named-content><institution>German Cancer Research Center (DKFZ)</institution><named-content content-type="city">Heidelberg</named-content><country country="DE">Germany</country></aff><aff id="ijc30859-aff-0016"><label><sup>16</sup></label><named-content content-type="organisation-division">Division of Preventive Oncology</named-content><institution>German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT)</institution><named-content content-type="city">Heidelberg</named-content><country country="DE">Germany</country></aff><aff id="ijc30859-aff-0017"><label><sup>17</sup></label><institution>German Cancer Consortium (DKTK)</institution><named-content content-type="city">Heidelberg</named-content><country country="DE">Germany</country></aff><aff id="ijc30859-aff-0018"><label><sup>18</sup></label><institution>Dr. Margarete Fischer‐Bosch‐Institute of Clinical Pharmacology</institution><named-content content-type="city">Stuttgart</named-content><country country="DE">Germany</country></aff><aff id="ijc30859-aff-0019"><label><sup>19</sup></label><institution>University of Tübingen</institution><named-content content-type="city">Tübingen</named-content><country country="DE">Germany</country></aff><aff id="ijc30859-aff-0020"><label><sup>20</sup></label><institution>Molecular Epidemiology Group, German Cancer Research Center (DKFZ)</institution><named-content content-type="city">Heidelberg</named-content><country country="DE">Germany</country></aff><aff id="ijc30859-aff-0021"><label><sup>21</sup></label><institution>Translational Cancer Research Area, University of Eastern Finland</institution><named-content content-type="city">Kuopio</named-content><country country="FI">Finland</country></aff><aff id="ijc30859-aff-0022"><label><sup>22</sup></label><named-content content-type="organisation-division">Pathology and Forensic Medicine</named-content><institution>Institute of Clinical Medicine, University of Eastern Finland</institution><named-content content-type="city">Kuopio</named-content><country country="FI">Finland</country></aff><aff id="ijc30859-aff-0023"><label><sup>23</sup></label><institution>Imaging Center, Department of Clinical Pathology, Kuopio University Hospital</institution><named-content content-type="city">Kuopio</named-content><country country="FI">Finland</country></aff><aff id="ijc30859-aff-0024"><label><sup>24</sup></label><institution>Vesalius Research Center, VIB</institution><named-content content-type="city">Leuven</named-content><country country="BE">Belgium</country></aff><aff id="ijc30859-aff-0025"><label><sup>25</sup></label><named-content content-type="organisation-division">Laboratory for Translational Genetics</named-content><institution>Department of Human Genetics, University of Leuven</institution><named-content content-type="city">Leuven</named-content><country country="BE">Belgium</country></aff><aff id="ijc30859-aff-0026"><label><sup>26</sup></label><institution>Leuven Multidisciplinary Breast Center, Department of Oncology, KU Leuven and Leuven Cancer Institute, University Hospitals Leuven</institution><named-content content-type="city">Leuven</named-content><country country="BE">Belgium</country></aff><aff id="ijc30859-aff-0027"><label><sup>27</sup></label><institution>Institute for Medical Biometrics and Epidemiology, University Medical Center Hamburg‐Eppendorf</institution><named-content content-type="city">Hamburg</named-content><country country="DE">Germany</country></aff><aff id="ijc30859-aff-0028"><label><sup>28</sup></label><named-content content-type="organisation-division">Department of Cancer Epidemiology</named-content><institution>University Cancer Center Hamburg (UCCH), University Medical Center Hamburg‐Eppendorf</institution><named-content content-type="city">Hamburg</named-content><country country="DE">Germany</country></aff><aff id="ijc30859-aff-0029"><label><sup>29</sup></label><named-content content-type="organisation-division">Department of Laboratory Medicine and Pathology</named-content><institution>Mayo Clinic</institution><named-content content-type="city">Rochester</named-content><named-content content-type="country-part">MN</named-content></aff><aff id="ijc30859-aff-0030"><label><sup>30</sup></label><named-content content-type="organisation-division">Cancer Epidemiology and Intelligence Division</named-content><institution>Cancer Council Victoria</institution><named-content content-type="city">Melbourne</named-content><named-content content-type="country-part">VIC</named-content><country country="AU">Australia</country></aff><aff id="ijc30859-aff-0031"><label><sup>31</sup></label><institution>Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University</institution><named-content content-type="city">Québec City</named-content><named-content content-type="country-part">QC</named-content><country country="CA">Canada</country></aff><aff id="ijc30859-aff-0032"><label><sup>32</sup></label><named-content content-type="organisation-division">Department of Medicine</named-content><institution>McGill University</institution><named-content content-type="city">Montréal</named-content><named-content content-type="country-part">QC</named-content><country country="CA">Canada</country></aff><aff id="ijc30859-aff-0033"><label><sup>33</sup></label><named-content content-type="organisation-division">Division of Clinical Epidemiology</named-content><institution>Royal Victoria Hospital, McGill University</institution><named-content content-type="city">Montréal</named-content><named-content content-type="country-part">QC</named-content><country country="CA">Canada</country></aff><aff id="ijc30859-aff-0034"><label><sup>34</sup></label><institution>Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Teviot Place Edinburgh</institution><named-content content-type="city">Edinburgh</named-content><country country="GB">United Kingdom</country></aff><aff id="ijc30859-aff-0035"><label><sup>35</sup></label><named-content content-type="organisation-division">Division of Cancer Epidemiology and Genetics</named-content><institution>National Cancer Institute</institution><named-content content-type="city">Bethesda</named-content><named-content content-type="country-part">MD</named-content></aff><aff id="ijc30859-aff-0036"><label><sup>36</sup></label><named-content content-type="organisation-division">Centre for Cancer Genetic Epidemiology</named-content><institution>Department of Public Health and Primary Care, University of Cambridge, Worts Causeway</institution><named-content content-type="city">Cambridge</named-content><country country="GB">United Kingdom</country></aff><aff id="ijc30859-aff-0037"><label><sup>37</sup></label><named-content content-type="organisation-division">Department of Electron Microscopy/Molecular Pathology</named-content><institution>The Cyprus Institute of Neurology and Genetics, Nicosia</institution><country country="CY">Cyprus</country><named-content content-type="city">Nicosia</named-content></aff><aff id="ijc30859-aff-0038"><label><sup>38</sup></label><named-content content-type="organisation-division">Department of Medical Epidemiology and Biostatistics</named-content><institution>Karolinska Institutet</institution><named-content content-type="city">Stockholm</named-content><country country="SE">Sweden</country></aff><aff id="ijc30859-aff-0039"><label><sup>39</sup></label><institution>Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield</institution><named-content content-type="city">Sheffield</named-content><country country="GB">United Kingdom</country></aff><aff id="ijc30859-aff-0040"><label><sup>40</sup></label><named-content content-type="organisation-division">Academic Unit of Pathology</named-content><institution>Department of Neuroscience, University of Sheffield</institution><named-content content-type="city">Sheffield</named-content><country country="GB">United Kingdom</country></aff><aff id="ijc30859-aff-0041"><label><sup>41</sup></label><named-content content-type="organisation-division">Division of Genetics and Epidemiology</named-content><institution>The Institute of Cancer Research</institution><named-content content-type="city">Sutton, London</named-content><country country="GB">United Kingdom</country></aff><aff id="ijc30859-aff-0042"><label><sup>42</sup></label><named-content content-type="organisation-division">Division of Breast Cancer Research</named-content><institution>The Institute of Cancer Research</institution><named-content content-type="city">Sutton, London</named-content><country country="GB">United Kingdom</country></aff><aff id="ijc30859-aff-0043"><label><sup>43</sup></label><named-content content-type="organisation-division">Department of Oncology</named-content><institution>University of Cambridge, Worts Causeway, Centre for Cancer Genetic Epidemiology</institution><named-content content-type="city">Cambridge</named-content><country country="GB">United Kingdom</country></aff><aff id="ijc30859-aff-0044"><label><sup>44</sup></label><named-content content-type="organisation-division">Division of Psychosocial Research and Epidemiology</named-content><institution>The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital</institution><named-content content-type="city">Amsterdam</named-content><country country="NL">The Netherlands</country></aff><aff id="ijc30859-aff-0045"><label><sup>45</sup></label><institution>Research Group Genetic Cancer Epidemiology, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg‐Eppendorf</institution><named-content content-type="city">Hamburg</named-content><country country="DE">Germany</country></aff><author-notes><corresp id="correspondenceTo"><label>*</label><bold>Correspondence to</bold>: Jenny Chang‐Claude, Im Neuenheimer Feld 581, 69120 Heidelberg, Germany, Tel.: +49‐6221‐42‐2373, Fax: +49‐6221‐42‐2203, E‐mail: <email>j.chang-claude@dkfz.de</email></corresp></author-notes><pub-date pub-type="epub"><day>11</day><month>8</month><year>2017</year></pub-date><pub-date pub-type="ppub"><day>01</day><month>11</month><year>2017</year></pub-date><volume>141</volume><issue>9</issue><issue-id pub-id-type="doi">10.1002/ijc.v141.9</issue-id><fpage>1830</fpage><lpage>1840</lpage><history><date date-type="received"><day>07</day><month>11</month><year>2016</year></date><date date-type="rev-recd"><day>09</day><month>3</month><year>2017</year></date><date date-type="accepted"><day>11</day><month>4</month><year>2017</year></date></history><permissions><pmc-comment> © 2017 UICC </pmc-comment>
<copyright-statement content-type="article-copyright">© 2017 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC</copyright-statement><license license-type="creativeCommonsBy"><license-p>This is an open access article under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution</ext-link> License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><self-uri content-type="pdf" xlink:type="simple" xlink:href="file:IJC-141-1830.pdf"></self-uri><abstract><p>Investigating the most likely causal variants identified by fine‐mapping analyses may improve the power to detect gene–environment interactions. We assessed the interplay between 70 single nucleotide polymorphisms identified by genetic fine‐scale mapping of susceptibility loci and 11 epidemiological breast cancer risk factors in relation to breast cancer. Analyses were conducted on up to 58,573 subjects (26,968 cases and 31,605 controls) from the Breast Cancer Association Consortium, in one of the largest studies of its kind. Analyses were carried out separately for estrogen receptor (ER) positive (ER+) and ER negative (ER–) disease. The Bayesian False Discovery Probability (BFDP) was computed to assess the noteworthiness of the results. Four potential gene–environment interactions were identified as noteworthy (BFDP < 0.80) when assuming a true prior interaction probability of 0.01. The strongest interaction result in relation to overall breast cancer risk was found between <italic>CFLAR</italic>‐rs7558475 and current smoking (OR<sub>int</sub> = 0.77, 95% CI: 0.67–0.88, <italic>p</italic><sub>int</sub> = 1.8 × 10<sup>−4</sup>). The interaction with the strongest statistical evidence was found between 5q14‐rs7707921 and alcohol consumption (OR<sub>int</sub> =1.36, 95% CI: 1.16–1.59, <italic>p</italic><sub>int</sub> = 1.9 × 10<sup>−5</sup>) in relation to ER– disease risk. The remaining two gene–environment interactions were also identified in relation to ER– breast cancer risk and were found between 3p21‐rs6796502 and age at menarche (OR<sub>int</sub> = 1.26, 95% CI: 1.12–1.43, <italic>p</italic><sub>int</sub> =1.8 × 10<sup>−4</sup>) and between 8q23‐rs13267382 and age at first full‐term pregnancy (OR<sub>int</sub> = 0.89, 95% CI: 0.83–0.95, <italic>p</italic><sub>int</sub> = 5.2 × 10<sup>−4</sup>). While these results do not suggest any strong gene–environment interactions, our results may still be useful to inform experimental studies. These may in turn, shed light on the potential interactions observed.</p></abstract><abstract abstract-type="short"><p><bold>What's new?</bold></p><p>Although it is widely acknowledged that genes and environment may interact to cooperatively modify breast cancer risk, no such interaction is known at the single nucleotide polymorphism (SNP) level. Here, the authors assessed the interplay of 70 SNPs with 11 known breast cancer risk factors in estrogen receptor‐positive and ‐negative disease. Weak interactions were found with individual SNPs and current smoking or alcohol consumption but no strong gene–environment interaction was identified. These data do not support the model of strong modification of genetic cancer risk by environmental factors.</p></abstract><kwd-group kwd-group-type="author-generated"><kwd id="ijc30859-kwd-0001">breast cancer</kwd><kwd id="ijc30859-kwd-0002">single nucleotide polymorphism</kwd><kwd id="ijc30859-kwd-0003">Breast Cancer Association Consortium</kwd><kwd id="ijc30859-kwd-0004">gene–environment</kwd><kwd id="ijc30859-kwd-0005">interaction</kwd></kwd-group><funding-group><award-group><funding-source>Cancer Research UK</funding-source><award-id>C1287/A16563</award-id><award-id>C1287/A10118</award-id><award-id>C1287/A10710</award-id><award-id>C12292/A11174</award-id><award-id>C1281/A12014</award-id><award-id>C5047/A8384</award-id><award-id>C5047/A15007</award-id><award-id>C5047/A10692</award-id><award-id>C8197/A16565</award-id></award-group><award-group><funding-source>European Union's Horizon 2020 Research and Innovation Programme</funding-source><award-id>634935</award-id><award-id>633784</award-id></award-group><award-group><funding-source>European Community's Seventh Framework Programme</funding-source><award-id>223175 (HEALTHF2‐2009‐223175)</award-id></award-group><award-group><funding-source>National Institutes of Health</funding-source><award-id>CA128978</award-id></award-group><award-group><funding-source>Post‐Cancer GWAS initiative</funding-source><award-id>1U19 CA148537</award-id><award-id>1U19 CA148065</award-id><award-id>1U19 CA148112</award-id></award-group><award-group><funding-source>Department of Defence</funding-source><award-id>W81XWH‐10‐1‐0341</award-id></award-group><award-group><funding-source>Canadian Institutes of Health Research (CIHR)</funding-source><award-id>CRN‐87521</award-id></award-group><award-group><funding-source>Komen Foundation for the Cure</funding-source></award-group><award-group><funding-source>Breast Cancer Research Foundation</funding-source></award-group><award-group><funding-source>Ovarian Cancer Research Fund</funding-source></award-group><award-group><funding-source>United States National Cancer Institute</funding-source><award-id>RFA‐CA‐06‐503</award-id></award-group><award-group><funding-source>Breast Cancer Family Registry (BCFR)</funding-source><award-id>U01 CA69467</award-id></award-group><award-group><funding-source>Cancer Prevention Institute of California</funding-source><award-id>U01 CA69417</award-id></award-group><award-group><funding-source>University of Melbourne</funding-source><award-id>U01 CA69638</award-id></award-group><award-group><funding-source>National Cancer Institute</funding-source><award-id>UM1 CA164920</award-id></award-group><award-group><funding-source>New South Wales Cancer Council</funding-source></award-group><award-group><funding-source>Victorian Breast Cancer Research Consortium</funding-source></award-group><award-group><funding-source>Dutch Cancer Society</funding-source><award-id>NKI 2007‐3839; 2009‐4363</award-id></award-group><award-group><funding-source>Dutch Government</funding-source><award-id>NWO 184.021.007</award-id></award-group><award-group><funding-source>Dutch National Genomics Initiative</funding-source></award-group><award-group><funding-source>ELAN‐Fond</funding-source></award-group><award-group><funding-source>KAU</funding-source><award-id>1‐117‐1434‐HiCi</award-id></award-group><award-group><funding-source>Botin Foundation's Fund</funding-source></award-group><award-group><funding-source>Programa Grupos Emergentes, Cancer Genetics Unit, CHUVI Vigo Hospital, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Instituto de Salud Carlos III, Spain</funding-source></award-group><award-group><funding-source>Consellería de Industria Programa Sectorial de Investigación Aplicada, PEME I + D e I + D Suma del Plan Gallego de Investigación, Desarrollo e Innovación Tecnológica de la Consellería de Industria de la Xunta de Galicia, Spain</funding-source><award-id>10CSA012E</award-id></award-group><award-group><funding-source>Fomento de la Investigación Clínica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain</funding-source><award-id>EC11‐192</award-id></award-group><award-group><funding-source>Grant FEDER‐Innterconecta, Ministerio de Economia y Competitividad, Xunta de Galicia, Spain</funding-source></award-group><award-group><funding-source>Fondation de France</funding-source></award-group><award-group><funding-source>Institut National du Cancer (INCa)</funding-source></award-group><award-group><funding-source>Ligue Nationale contre le Cancer</funding-source></award-group><award-group><funding-source>Ligue contre le Cancer Grand Ouest</funding-source></award-group><award-group><funding-source>Agence Nationale de Sécurité Sanitaire (ANSES)</funding-source></award-group><award-group><funding-source>Agence Nationale de la Recherche (ANR)</funding-source></award-group><award-group><funding-source>Chief Physician Johan Boserup and Lise Boserup Fund</funding-source></award-group><award-group><funding-source>Danish Medical Research Council</funding-source></award-group><award-group><funding-source>Herlev Hospital</funding-source></award-group><award-group><funding-source>American Cancer Society</funding-source></award-group><award-group><funding-source>Baden Württemberg Ministry of Science, Research and Arts</funding-source></award-group><award-group><funding-source>German Cancer Aid (Deutsche Krebshilfe)</funding-source></award-group><award-group><funding-source>Federal Ministry of Education and Research (BMBF), Germany</funding-source><award-id>01KW9975/5</award-id><award-id>01KW9976/8</award-id><award-id>01KW9977/0</award-id><award-id>01KW0114</award-id></award-group><award-group><funding-source>Robert Bosch Foundation, Stuttgart</funding-source></award-group><award-group><funding-source>Deutsches Krebsforschungszentrum (DKFZ), Heidelberg</funding-source></award-group><award-group><funding-source>Institute for Prevention and Occupational Medicine of the German Social Accident Insurance</funding-source></award-group><award-group><funding-source>Institute of the Ruhr University Bochum (IPA), Bochum</funding-source></award-group><award-group><funding-source>Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany</funding-source></award-group><award-group><funding-source>Government Funding (EVO) of Kuopio University Hospital</funding-source></award-group><award-group><funding-source>Cancer Fund of North Savo</funding-source></award-group><award-group><funding-source>Finnish Cancer Organizations</funding-source></award-group><award-group><funding-source>University of Eastern Finland</funding-source></award-group><award-group><funding-source>Stichting tegen 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Centre</funding-source></award-group><award-group><funding-source>Swedish Research Council</funding-source><award-id>70867902</award-id></award-group><award-group><funding-source>Agency for Science, Technology and Research of Singapore (A*STAR)</funding-source></award-group><award-group><funding-source>US National Institute of Health (NIH)</funding-source></award-group><award-group><funding-source>Susan G. Komen Breast Cancer Foundation</funding-source></award-group><award-group><funding-source>Yorkshire Cancer Research</funding-source><award-id>S295</award-id><award-id>S299</award-id><award-id>S305PA</award-id></award-group><award-group><funding-source>Sheffield Experimental Cancer Medicine Centre</funding-source></award-group><award-group><funding-source>UK National Institute for Health Research Biomedical Research Centre, University of Cambridge</funding-source></award-group><award-group><funding-source>Breast Cancer Now</funding-source></award-group><award-group><funding-source>Institute of Cancer Research (ICR), London</funding-source></award-group><award-group><funding-source>Cancer Care Ontario</funding-source><award-id>U01 CA69467</award-id></award-group><award-group><funding-source>Acción Estratégica de Salud del Instituto de Salud Carlos III</funding-source><award-id>FIS PI12/02125</award-id><award-id>PI13/01136</award-id></award-group></funding-group><counts><fig-count count="0"></fig-count><table-count count="3"></table-count><page-count count="11"></page-count><word-count count="9436"></word-count></counts><custom-meta-group><custom-meta><meta-name>source-schema-version-number</meta-name><meta-value>2.0</meta-value></custom-meta><custom-meta><meta-name>component-id</meta-name><meta-value>ijc30859</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>1 November 2017</meta-value></custom-meta><custom-meta><meta-name>details-of-publishers-convertor</meta-name><meta-value>Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.9 mode:remove_FC converted:18.09.2017</meta-value></custom-meta></custom-meta-group></article-meta><notes><fn-group><fn id="ijc30859-note-0001"><p><bold>Conflicts of Interest</bold> J.S. is Chairholder of the Canada Research Chair in Oncogenetics. J.L.H. is a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellow. M.C.S. is a NHMRC Senior Research Fellow. Fergus J. Couch received research support from GRAIL Inc.</p></fn></fn-group></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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