Genome-Wide Interaction Analysis of Menopausal Hormone Therapy Use and Breast Cancer Risk Among 62,370 Women
Authors: Wang Xiaoliang , Kapoor Pooja Middha , Auer Paul L. , Dennis Joe , Dunning Alison M. , Wang Qin , Lush Michael , Michailidou Kyriaki , Bolla Manjeet K. , Aronson Kristan J. , Murphy Rachel A. , Brooks-Wilson Angela , Lee Derrick G. , Cordina-Duverger Emilie , Guénel Pascal , Truong Thérèse , Mulot Claire , Teras Lauren R. , Patel Alpa V. , Dossus Laure , Kaaks Rudolf , Hoppe Reiner , Lo Wing-Yee , Brüning Thomas , Hamann Ute , Czene Kamila , Gabrielson Marike , Hall Per , Eriksson Mikael , Jung Audrey , Becher Heiko , Couch Fergus J. , Larson Nicole L. , Olson Janet E. , Ruddy Kathryn J. , Giles Graham G. , MacInnis Robert J. , Southey Melissa C. , Marchand Loic Le , Wilkens Lynne R. , Haiman Christopher A. , Olsson Håkan , Augustinsson Annelie , Krüger Ute , Wagner Philippe , Scott Christopher , Winham Stacey J. , Vachon Celine M. , Perou Charles M. , Olshan Andrew F. , Troester Melissa A. , Hunter David J. , Eliassen A. Heather , Tamimi Rulla M. , Brantley Kristen , Andrulis Irene L. , Figueroa Jonine , Chanock Stephen J. , Ahearn Thomas U. , García-Closas Montserrat , Evans Gareth D. , Newman William G. , Veen Elke M. van , Howell Anthony , Wolk Alicja , Håkansson Niclas , Anton-Culver Hoda , Ziogas Argyrios , Jones Michael E. , Orr Nick , Schoemaker Minouk J. , Swerdlow Anthony J. , Kitahara Cari M. , Linet Martha , Prentice Ross L , Easton Douglas F. , Milne Roger L. , Kraft Peter , Chang-Claude Jenny , Lindström Sara 
Published: May 2021

Abstract
Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values<5x10-8 as genome-wide significant, and p-values<1x10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants.Results: None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values<1x105. The strongest evidence was found for rs4674019 (p-value=2.27x10-7), which showed genome-wide significant interaction (p-value=3.8x10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. Conclusions: In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association.