Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study
Authors: Milne Roger L , Gaudet Mia M , Spurdle Amanda B , Fasching Peter A , Couch Fergus J , Benítez Javier , Arias Pérez José Ignacio , Zamora M Pilar , Malats Núria , dos Santos Silva Isabel , Gibson Lorna J , Fletcher Olivia , Johnson Nichola , Anton-Culver Hoda , Ziogas Argyrios , Figueroa Jonine , Brinton Louise , Sherman Mark E , Lissowska Jolanta , Hopper John L , Dite Gillian S , Apicella Carmel , Southey Melissa C , Sigurdson Alice J , Linet Martha S , Schonfeld Sara J , Freedman D Michal , Mannermaa Arto , Kosma Veli-Matti , Kataja Vesa , Auvinen Päivi , Andrulis Irene L , Glendon Gord , Knight Julia A , Weerasooriya Nayana , Cox Angela , Reed Malcolm WR , Cross Simon S , Dunning Alison M , Ahmed Shahana , Shah Mitul , Brauch Hiltrud , Ko Yon-Dschun , Brüning Thomas ,   GENICA Network, Lambrechts Diether , Reumers Joke , Smeets Ann , Wang-Gohrke Shan , Hall Per , Czene Kamila , Liu Jianjun , Irwanto Astrid K , Chenevix-Trench Georgia , Holland Helene ,   kConFab,   AOCS, Giles Graham G , Baglietto Laura , Severi Gianluca , Bojensen Stig E , Nordestgaard Børge G , Flyger Henrik , John Esther M , West Dee W , Whittemore Alice S , Vachon Celine , Olson Janet E , Fredericksen Zachary , Kosel Matthew , Hein Rebecca , Vrieling Alina , Flesch-Janys Dieter , Heinz Judith , Beckmann Matthias W , Heusinger Katharina , Ekici Arif B , Haeberle Lothar , Humphreys Manjeet K , Morrison Jonathan , Easton Doug F , Pharoah Paul D , García-Closas Montserrat , Goode Ellen L , Chang-Claude Jenny 
Published: January 2011

Abstract
Introduction
Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium.

Methods
We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects.

Results
These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar.

Conclusions
The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified.