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

Wang, X. ; Olsson, H. LU orcid ; Augustinsson, A. LU ; Krüger, U. LU ; Wagner, P. LU and Lindström, S. (2022) In Scientific Reports 12(1).
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... (More)
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. © 2022, The Author(s). (Less)
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author collaboration
organization
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type
Contribution to journal
publication status
published
subject
keywords
adverse event, breast, breast tumor, estrogen therapy, female, genetics, hormone substitution, human, male, menopause, risk factor, Breast, Breast Neoplasms, Estrogen Replacement Therapy, Female, Hormone Replacement Therapy, Humans, Male, Menopause, Risk Factors
in
Scientific Reports
volume
12
issue
1
article number
6199
publisher
Nature Publishing Group
external identifiers
  • scopus:85128281436
  • pmid:35418701
ISSN
2045-2322
DOI
10.1038/s41598-022-10121-2
language
English
LU publication?
yes
id
9a80b98c-5fc0-49b6-bf25-f9df5f497ccd
date added to LUP
2022-09-12 09:07:13
date last changed
2022-09-13 03:00:06
@article{9a80b98c-5fc0-49b6-bf25-f9df5f497ccd,
  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 &lt; 5 × 10–8 as genome-wide significant, and p-values &lt; 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 &lt; 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. © 2022, The Author(s).}},
  author       = {{Wang, X. and Olsson, H. and Augustinsson, A. and Krüger, U. and Wagner, P. and Lindström, S.}},
  issn         = {{2045-2322}},
  keywords     = {{adverse event; breast; breast tumor; estrogen therapy; female; genetics; hormone substitution; human; male; menopause; risk factor; Breast; Breast Neoplasms; Estrogen Replacement Therapy; Female; Hormone Replacement Therapy; Humans; Male; Menopause; Risk Factors}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women}},
  url          = {{http://dx.doi.org/10.1038/s41598-022-10121-2}},
  doi          = {{10.1038/s41598-022-10121-2}},
  volume       = {{12}},
  year         = {{2022}},
}