Abstract
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 language | English (US) |
|---|---|
| Article number | 6199 |
| Journal | Scientific reports |
| Volume | 12 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2022 |
ASJC Scopus subject areas
- General
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Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women. / Wang, Xiaoliang; Kapoor, Pooja Middha; Auer, Paul L. et al.
In: Scientific reports, Vol. 12, No. 1, 6199, 12.2022.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women
AU - Wang, Xiaoliang
AU - Kapoor, Pooja Middha
AU - Auer, Paul L.
AU - Dennis, Joe
AU - Dunning, Alison M.
AU - Wang, Qin
AU - Lush, Michael
AU - Michailidou, Kyriaki
AU - Bolla, Manjeet K.
AU - Aronson, Kristan J.
AU - Murphy, Rachel A.
AU - Brooks-Wilson, Angela
AU - Lee, Derrick G.
AU - Cordina-Duverger, Emilie
AU - Guénel, Pascal
AU - Truong, Thérèse
AU - Mulot, Claire
AU - Teras, Lauren R.
AU - Patel, Alpa V.
AU - Dossus, Laure
AU - Kaaks, Rudolf
AU - Hoppe, Reiner
AU - Lo, Wing Yee
AU - Brüning, Thomas
AU - Hamann, Ute
AU - Czene, Kamila
AU - Gabrielson, Marike
AU - Hall, Per
AU - Eriksson, Mikael
AU - Jung, Audrey
AU - Becher, Heiko
AU - Couch, Fergus J.
AU - Larson, Nicole L.
AU - Olson, Janet E.
AU - Ruddy, Kathryn J.
AU - Giles, Graham G.
AU - MacInnis, Robert J.
AU - Southey, Melissa C.
AU - Le Marchand, Loic
AU - Wilkens, Lynne R.
AU - Haiman, Christopher A.
AU - Olsson, Håkan
AU - Augustinsson, Annelie
AU - Krüger, Ute
AU - Wagner, Philippe
AU - Scott, Christopher
AU - Winham, Stacey J.
AU - Vachon, Celine M.
AU - Perou, Charles M.
AU - Olshan, Andrew F.
AU - Troester, Melissa A.
AU - Hunter, David J.
AU - Eliassen, Heather A.
AU - Tamimi, Rulla M.
AU - Brantley, Kristen
AU - Andrulis, Irene L.
AU - Figueroa, Jonine
AU - Chanock, Stephen J.
AU - Ahearn, Thomas U.
AU - García-Closas, Montserrat
AU - Evans, Gareth D.
AU - Newman, William G.
AU - van Veen, Elke M.
AU - Howell, Anthony
AU - Wolk, Alicja
AU - Håkansson, Niclas
AU - Anton-Culver, Hoda
AU - Ziogas, Argyrios
AU - Jones, Michael E.
AU - Orr, Nick
AU - Schoemaker, Minouk J.
AU - Swerdlow, Anthony J.
AU - Kitahara, Cari M.
AU - Linet, Martha
AU - Prentice, Ross L.
AU - Easton, Douglas F.
AU - Milne, Roger L.
AU - Kraft, Peter
AU - Chang-Claude, Jenny
AU - Lindström, Sara
N1 - Funding Information: We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. The COGS study would not have been possible without the contributions of the following: Andrew Lee, and Ed Dicks, Craig Luccarini and the staff of the Centre for Genetic Epidemiology Laboratory, Javier Benitez, Anna Gonzalez-Neira and the staff of the CNIO genotyping unit, Jacques Simard and Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie LaBoissi?re and Frederic Robidoux and the staff of the McGill University and G?nome Qu?bec Innovation Centre, Stig E. Bojesen, Sune F. Nielsen, Borge G. Nordestgaard, and the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. ABCFS thank Maggie Angelakos, Judi Maskiell, Gillian Dite. CBCS thanks study participants, co-investigators, collaborators and staff of the Canadian Breast Cancer Study, and project coordinators Agnes Lai and Celine Morissette. Investigators from the CPS-II cohort thank the participants and Study Management Group for their invaluable contributions to this research. They also acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, as well as cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. We thank the participants and the investigators of EPIC (European Prospective Investigation into Cancer and Nutrition). The GENICA Network: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of T?bingen, Germany [Hiltrud Brauch, WYL, RH], German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site T?bingen [Hiltrud Brauch], Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy?EXC 2180?390900677 [Hiltrud Brauch], Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany [Yon-Dschun Ko, Christian Baisch], Institute of Pathology, University of Bonn, Germany [Hans-Peter Fischer], Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany [UH], Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany [TB, Beate Pesch, Sylvia Rabstein, Anne Lotz]; and Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Germany [Volker Harth]. KARMA and SASBAC thank the Swedish Medical Research Counsel. MARIE thanks Petra Seibold, Dieter Flesch-Janys, Judith Heinz, Nadia Obi, Alina Vrieling, Sabine Behrens, Ursula Eilber, Muhabbet Celik, Til Olchers and Stefan Nickels. The MCCS was made possible by the contribution of many people, including the original investigators, the teams that recruited the participants and continue working on follow-up, and the many thousands of Melbourne residents who continue to participate in the study. We thank the coordinators, the research staff and especially the MMHS participants for their continued collaboration on research studies in breast cancer. MSKCC thanks Marina Corines, Lauren Jacobs. `For NHS and NHS2 the study protocol was approved by the institutional review boards of the Brigham and Women?s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. We would like to thank the participants and staff of the NHS and NHS2 for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. The OFBCR thanks Teresa Selander, Nayana Weerasooriya and Steve Gallinger. ORIGO thanks E. Krol-Warmerdam, and J. Blom for patient accrual, administering questionnaires, and managing clinical information. The LUMC survival data were retrieved from the Leiden hospital-based cancer registry system (ONCDOC) with the help of Dr. J. Molenaar. PBCS thanks Louise Brinton, Mark Sherman, Neonila Szeszenia-Dabrowska, Beata?Peplonska, Witold?Zatonski, Pei Chao, Michael Stagner. PROCAS thanks NIHR for funding. UCIBCS thanks Irene Masunaka. UKBGS thanks Breast Cancer Now and the Institute of Cancer Research for support and funding of the Generations Study, and the study participants, study staff, and the doctors, nurses and other health care providers and health information sources who have contributed to the study. We acknowledge NHS funding to the Royal Marsden/ICR NIHR Biomedical Research Centre. We acknowledge funding to the Manchester NIHR Biomedical Research Centre (IS-BRC-1215-20007). The authors thank the WHI investigators and staff for their dedication and the study participants for making the program possible. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health. Publisher Copyright: © 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85128281436&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85128281436&partnerID=8YFLogxK
U2 - 10.1038/s41598-022-10121-2
DO - 10.1038/s41598-022-10121-2
M3 - Article
C2 - 35418701
AN - SCOPUS:85128281436
SN - 2045-2322
VL - 12
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 6199
ER -