Investigation of gene‐environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors
Authors: Rudolph Anja , Milne Roger L. , Truong Thérèse , Knight Julia A. , Seibold Petra , Flesch‐Janys Dieter , Behrens Sabine , Eilber Ursula , Bolla Manjeet K. , Wang Qin , Dennis Joe , Dunning Alison M. , Shah Mitul , Munday Hannah R. , Darabi Hatef , Eriksson Mikael , Brand Judith S. , Olson Janet , Vachon Celine M. , Hallberg Emily , Castelao J. Esteban , Carracedo Angel , Torres Maria , Li Jingmei , Humphreys Keith , Cordina‐Duverger Emilie , Menegaux Florence , Flyger Henrik , Nordestgaard Børge G. , Nielsen Sune F. , Yesilyurt Betul T. , Floris Giuseppe , Leunen Karin , Engelhardt Ellen G. , Broeks Annegien , Rutgers Emiel J. , Glendon Gord , Mulligan Anna Marie , Cross Simon , Reed Malcolm , Gonzalez‐Neira Anna , Arias Perez José Ignacio , Provenzano Elena , Apicella Carmel , Southey Melissa C. , Spurdle Amanda ,   kConFab Investigators,   AOCS Group, Häberle Lothar , Beckmann Matthias W. , Ekici Arif B. , Dieffenbach Aida Karina , Arndt Volker , Stegmaier Christa , McLean Catriona , Baglietto Laura , Chanock Stephen J. , Lissowska Jolanta , Sherman Mark E. , Brüning Thomas , Hamann Ute , Ko Yon‐Dschun , Orr Nick , Schoemaker Minouk , Ashworth Alan , Kosma Veli‐Matti , Kataja Vesa , Hartikainen Jaana M. , Mannermaa Arto , Swerdlow Anthony ,   GENICA‐Network, Giles Graham G. , Brenner Hermann , Fasching Peter A. , Chenevix‐Trench Georgia , Hopper John , Benítez Javier , Cox Angela , Andrulis Irene L. , Lambrechts Diether , Gago‐Dominguez Manuela , Couch Fergus , Czene Kamila , Bojesen Stig E. , Easton Doug F. , Schmidt Marjanka K. , Guénel Pascal , Hall Per , Pharoah Paul D. P. , Garcia‐Closas Montserrat , Chang‐Claude Jenny 
Published: September 2014

A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes‐type shrinkage estimator. Six SNPs showed interactions with associated p‐values (pint) <1.1 × 10−3. None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER‐negative BC risk in women ≥170 cm (OR = 1.22, p = 0.017), but inversely associated with ER‐negative BC risk in women <160 cm (OR = 0.83, p = 0.039, pint = 1.9 × 10−4). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR = 0.85, p = 2.0 × 10−4), and absent in women who had had just one (OR = 0.96, p = 0.19, pint = 6.1 × 10−4). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR = 0.93, p = 2.8 × 10−5), but no association was observed in current smokers (OR = 1.07, p = 0.14, pint = 3.4 × 10−4). In conclusion, recently identified BC susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies.