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

About this Publication
Title
Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women.
Pubmed ID
35418701 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Sci Rep. 2022 Apr 13; Volume 12 (Issue 1): Pages 6199
Authors
Wang X , Kapoor PM , Auer PL , Dennis J , Dunning AM , Wang Q , Lush M , Michailidou K , Bolla MK , Aronson KJ , Murphy RA , Brooks-Wilson A , Lee DG , Cordina-Duverger E , Guénel P , Truong T , Mulot C , Teras LR , Patel AV , Dossus L , ...show more Kaaks R , Hoppe R , Lo WY , Brüning T , Hamann U , Czene K , Gabrielson M , Hall P , Eriksson M , Jung A , Becher H , Couch FJ , Larson NL , Olson JE , Ruddy KJ , Giles GG , MacInnis RJ , Southey MC , Le Marchand L , Wilkens LR , Haiman CA , Olsson H , Augustinsson A , Krüger U , Wagner P , Scott C , Winham SJ , Vachon CM , Perou CM , Olshan AF , Troester MA , Hunter DJ , Eliassen HA , Tamimi RM , Brantley K , Andrulis IL , Figueroa J , Chanock SJ , Ahearn TU , García-Closas M , Evans GD , Newman WG , van Veen EM , Howell A , Wolk A , Håkansson N , Anton-Culver H , Ziogas A , Jones ME , Orr N , Schoemaker MJ , Swerdlow AJ , Kitahara CM , Linet M , Prentice RL , Easton DF , Milne RL , Kraft P , Chang-Claude J , Lindström S
Affiliations
  • Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA. xwang23@fredhutch.org.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
  • Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
  • Department of Public Health Sciences, Cancer Research Institute, Queen's University, Kingston, ON, Canada.
  • School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
  • Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
  • BC Cancer, Cancer Control Research, Vancouver, BC, Canada.
  • Team Exposome and Heredity, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Saclay, Villejuif, France.
...show more
  • INSERM UMR-S1147, Université Paris Sorbonné, Paris, France.
  • Department of Population Science, American Cancer Society, Atlanta, GA, USA.
  • Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
  • Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
  • Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany.
  • Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
  • Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
  • Department of Oncology, Mayo Clinic, Rochester, MN, USA.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
  • Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
  • Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
  • Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Clinical Sciences, Department of Cancer Epidemiology, Lund University, Lund, Sweden.
  • Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
  • Division of Epidemiology, Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
  • Department of Epidemiology, Gillings School of Global Public Health, UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Nuffield Department of Population Health, University of Oxford, Oxford, UK.
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Fred A. Litwin Center for Cancer Genetics, Toronto, ON, Canada.
  • Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK.
  • Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
  • Division of Cancer Sciences, University of Manchester, Manchester, UK.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
  • Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Ireland, UK.
  • Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
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.

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