Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women

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

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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. 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 < 5 × 10–8 as genome-wide significant, and p-values < 1 × 10–5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants. 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 < 1 × 105. The strongest evidence was found for rs4674019 (p-value = 2.27 × 10–7), which showed genome-wide significant interaction (p-value = 3.8 × 10–8) 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. 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.
Original languageEnglish
Article number6199
JournalScientific Reports
Publication statusPublished - 13 Apr 2022


  • Humans
  • Breast
  • Hormone Replacement Therapy - adverse effects
  • Estrogen Replacement Therapy - adverse effects
  • Male
  • Female
  • Menopause
  • Breast Neoplasms - chemically induced - epidemiology - genetics
  • Risk Factors


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