Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors

Stefan Nickels, Thérèse Truong, Rebecca Hein, Kristen Stevens, Katharina Buck, Sabine Behrens, Ursula Eilber, Martina Schmidt, Lothar Häberle, Alina Vrieling, Mia Gaudet, Jonine Figueroa, Nils Schoof, Amanda B. Spurdle, Anja Rudolph, Peter A. Fasching, John L. Hopper, Enes Makalic, Daniel F. Schmidt, Melissa C. SoutheyMatthias W. Beckmann, Arif B. Ekici, Olivia Fletcher, Lorna Gibson, Isabel dos Santos Silva, Julian Peto, Manjeet K. Humphreys, Jean Wang, Emilie Cordina-Duverger, Florence Menegaux, Børge G. Nordestgaard, Stig E. Bojesen, Charlotte Lanng, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina A. Clarke, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Hiltrud Brauch, Thomas Brüning, Volker Harth, Arto Mannermaa, Vesa Kataja, Veli Matti Kosma, Jaana M. Hartikainen, Diether Lambrechts, Dominiek Smeets, Patrick Neven, Robert Paridaens, Dieter Flesch-Janys, Nadia Obi, Shan Wang-Gohrke, Fergus J. Couch, Janet E. Olson, Celine M. Vachon, Graham G. Giles, Gianluca Severi, Laura Baglietto, Kenneth Offit, Esther M. John, Alexander Miron, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Anna Marie Mulligan, Stephen J. Chanock, Jolanta Lissowska, Jianjun Liu, Angela Cox, Helen Cramp, Dan Connley, Sabapathy Balasubramanian, Alison M. Dunning, Mitul Shah, Amy Trentham-Dietz, Polly Newcomb, Linda Titus, Kathleen Egan, Elizabeth K. Cahoon, Preetha Rajaraman, Alice J. Sigurdson, Michele M. Doody, Pascal Guénel, Paul D.P. Pharoah, Marjanka K. Schmidt, Per Hall, Doug F. Easton, Montserrat Garcia-Closas, Roger L. Milne, Jenny Chang-Claude, H. B. Christina Justenhoven, Yon Dschun Ko, Christian Baisch, Hans Peter Fischer, Ute Hamann, Beate Pesch, Sylvia Rabstein, Anne Lotz, Eija Myöhänen, Helena Kemiläinen, Heather Thorne, Eveline Niedermayr, D. Bowtell, G. Chenevix-Trench, A. deFazio, D. Gertig, A. Green, P. Webb

Research output: Contribution to journalArticlepeer-review

110 Scopus citations


Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4×10-6) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1×10-4). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01-1.16) in nulliparous women and ranged from 1.03 (0.96-1.10) in parous women with one birth to 1.26 (1.16-1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3×10-5), with a per-allele OR of 1.14 (1.11-1.17) in parous women and 0.98 (0.92-1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.

Original languageEnglish (US)
Article numbere1003284
JournalPLoS genetics
Issue number3
StatePublished - 2013

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research


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