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

Xiaoliang Wang^{1

2}, Pooja Middha Kapoor^{3

4}, Paul L Auer^{5

6}, Joe Dennis⁷, Alison M Dunning⁸, Qin Wang⁷, Michael Lush⁷, Kyriaki Michailidou^{7

9

10}, Manjeet K Bolla⁷, Kristan J Aronson¹¹, Rachel A Murphy^{12

13}, Angela Brooks-Wilson^{14

15}, Derrick G Lee^{13

16}, Emilie Cordina-Duverger¹⁷, Pascal Guénel¹⁷, Thérèse Truong¹⁷, Claire Mulot¹⁸, Lauren R Teras¹⁹, Alpa V Patel¹⁹, Laure Dossus²⁰, Rudolf Kaaks³, Reiner Hoppe^{21

22}, Wing-Yee Lo^{21

22}, Thomas Brüning²³, Ute Hamann²⁴, Kamila Czene²⁵, Marike Gabrielson²⁵, Per Hall^{25

26}, Mikael Eriksson²⁵, Audrey Jung³, Heiko Becher²⁷, Fergus J Couch²⁸, Nicole L Larson²⁹, Janet E Olson²⁹, Kathryn J Ruddy³⁰, Graham G Giles^{31

32

33}, Robert J MacInnis^{31

32}, Melissa C Southey^{31

33

34}, Loic Le Marchand³⁵, Lynne R Wilkens³⁶, Christopher A Haiman³⁷, Håkan Olsson³⁸, Annelie Augustinsson³⁸, Ute Krüger³⁸, Philippe Wagner³⁸, Christopher Scott²⁹, Stacey J Winham³⁹, Celine M Vachon^{40

41}, Charles M Perou^{40

41}, Andrew F Olshan⁴², Melissa A Troester⁴², David J Hunter^{43

44}, Heather A Eliassen^{44

45}, Rulla M Tamimi^{44

46}, Kristen Brantley⁴⁵, Irene L Andrulis^{47

48}, Jonine Figueroa^{49

50

51}, Stephen J Chanock⁵¹, Thomas U Ahearn⁵¹, Montserrat García-Closas⁵¹, Gareth D Evans^{52

53}, William G Newman^{52

53}, Elke M van Veen^{52

53}, Anthony Howell⁵⁴, Alicja Wolk^{55

56}, Niclas Håkansson⁵⁵, Hoda Anton-Culver⁵⁷, Argyrios Ziogas⁵⁷, Michael E Jones⁵⁸, Nick Orr⁵⁹, Minouk J Schoemaker⁵⁸, Anthony J Swerdlow^{58

60}, Cari M Kitahara⁶¹, Martha Linet⁶¹, Ross L Prentice⁶², Douglas F Easton^{7

8}, Roger L Milne^{31

32

33}, Peter Kraft^{44

63}, Jenny Chang-Claude^{3

64}, Sara Lindström^{65

62}

Affiliations

¹ Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA. xwang23@fredhutch.org.
² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. xwang23@fredhutch.org.
³ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴ University of Heidelberg, Faculty of Medicine, Heidelberg, Germany.
⁵ Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁶ Division of Biostatistics, Institute for Health & Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
⁷ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
⁸ Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
⁹ Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
¹⁰ The Cyprus Institute of Neurology & Genetics, Cyprus School of Molecular Medicine, Nicosia, Cyprus.
¹¹ Department of Public Health Sciences, Cancer Research Institute, Queen's University, Kingston, ON, Canada.
¹² School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
¹³ BC Cancer, Cancer Control Research, Vancouver, BC, Canada.
¹⁴ Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
¹⁵ Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
¹⁶ Department of Mathematics and Statistics, St. Francis Xavier University, Antigonish, NS, Canada.
¹⁷ Team Exposome and Heredity, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Saclay, Villejuif, France.
¹⁸ INSERM UMR-S1147, Université Paris Sorbonné, Paris, France.
¹⁹ Department of Population Science, American Cancer Society, Atlanta, GA, USA.
²⁰ Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
²¹ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
²² University of Tÿbingen, Tÿbingen, Germany.
²³ Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany.
²⁴ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁶ Department of Oncology, Södersjukhuset, Stockholm, Sweden.
²⁷ Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁸ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
²⁹ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
³⁰ Department of Oncology, Mayo Clinic, Rochester, MN, USA.
³¹ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
³² Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
³³ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
³⁴ Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia.
³⁵ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
³⁶ Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
³⁷ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³⁸ Clinical Sciences, Department of Cancer Epidemiology, Lund University, Lund, Sweden.
³⁹ Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁴⁰ Division of Epidemiology, Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
⁴¹ Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴² 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.
⁴³ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁴⁴ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴⁵ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴⁶ Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA.
⁴⁷ Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Fred A. Litwin Center for Cancer Genetics, Toronto, ON, Canada.
⁴⁸ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁴⁹ Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK.
⁵⁰ Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK.
⁵¹ Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁵² 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.
⁵³ North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester Academic Health Science Centre, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
⁵⁴ Division of Cancer Sciences, University of Manchester, Manchester, UK.
⁵⁵ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁵⁶ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
⁵⁷ Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
⁵⁸ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁵⁹ Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Ireland, UK.
⁶⁰ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
⁶¹ Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁶² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁶³ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶⁴ Cancer Epidemiology Group, University Medical Center Hamburg-Eppendorf, University Cancer Center Hamburg (UCCH), Hamburg, Germany.
⁶⁵ Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.

PMID: 35418701
PMCID: PMC9007944
DOI: 10.1038/s41598-022-10121-2

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

Xiaoliang Wang et al. Sci Rep. 2022.

. 2022 Apr 13;12(1):6199.

doi: 10.1038/s41598-022-10121-2.

Authors

Affiliations

¹ Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA. xwang23@fredhutch.org.
² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. xwang23@fredhutch.org.
³ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴ University of Heidelberg, Faculty of Medicine, Heidelberg, Germany.
⁵ Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁶ Division of Biostatistics, Institute for Health & Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
⁷ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
⁸ Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
⁹ Biostatistics Unit, The Cyprus Institute of Neurology & Genetics, Nicosia, Cyprus.
¹⁰ The Cyprus Institute of Neurology & Genetics, Cyprus School of Molecular Medicine, Nicosia, Cyprus.
¹¹ Department of Public Health Sciences, Cancer Research Institute, Queen's University, Kingston, ON, Canada.
¹² School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
¹³ BC Cancer, Cancer Control Research, Vancouver, BC, Canada.
¹⁴ Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
¹⁵ Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
¹⁶ Department of Mathematics and Statistics, St. Francis Xavier University, Antigonish, NS, Canada.
¹⁷ Team Exposome and Heredity, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Saclay, Villejuif, France.
¹⁸ INSERM UMR-S1147, Université Paris Sorbonné, Paris, France.
¹⁹ Department of Population Science, American Cancer Society, Atlanta, GA, USA.
²⁰ Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
²¹ Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
²² University of Tÿbingen, Tÿbingen, Germany.
²³ Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany.
²⁴ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁵ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
²⁶ Department of Oncology, Södersjukhuset, Stockholm, Sweden.
²⁷ Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
²⁸ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
²⁹ Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
³⁰ Department of Oncology, Mayo Clinic, Rochester, MN, USA.
³¹ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
³² Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
³³ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
³⁴ Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia.
³⁵ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
³⁶ Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
³⁷ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³⁸ Clinical Sciences, Department of Cancer Epidemiology, Lund University, Lund, Sweden.
³⁹ Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁴⁰ Division of Epidemiology, Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
⁴¹ Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴² 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.
⁴³ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁴⁴ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴⁵ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴⁶ Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA.
⁴⁷ Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Fred A. Litwin Center for Cancer Genetics, Toronto, ON, Canada.
⁴⁸ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁴⁹ Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK.
⁵⁰ Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK.
⁵¹ Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁵² 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.
⁵³ North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester Academic Health Science Centre, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
⁵⁴ Division of Cancer Sciences, University of Manchester, Manchester, UK.
⁵⁵ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁵⁶ Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
⁵⁷ Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
⁵⁸ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
⁵⁹ Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Ireland, UK.
⁶⁰ Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
⁶¹ Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁶² Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁶³ Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁶⁴ Cancer Epidemiology Group, University Medical Center Hamburg-Eppendorf, University Cancer Center Hamburg (UCCH), Hamburg, Germany.
⁶⁵ Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.

PMID: 35418701
PMCID: PMC9007944
DOI: 10.1038/s41598-022-10121-2

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

**Figure 1**
Main effects of current menopausal hormone therapy use and breast cancer risk by study. **(A)** Current use of any menopausal hormone therapy. **(B)** Current use of combined estrogen–progesterone menopausal hormone therapy.

**Figure 2**
Manhattan plot of genome-wide interaction of current use of menopausal hormone therapy on breast cancer risk. **(A)** Current MHT use. **(B)** Current EPT use. Asterisk: red line: log-transformed genome-wide significant threshold at 5 × 10^–8; blue line: log-transformed suggestive threshold at 1 × 10^–5.

See this image and copyright information in PMC

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials