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

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Wang, Xiaoliang 
Kapoor, Pooja Middha 
Auer, Paul L 
Dennis, Joe 
Dunning, Alison M 

jats:titleAbstract</jats:title>jats:pUse 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 × 10jats:sup–8</jats:sup> as genome-wide significant, and p-values < 1 × 10jats:sup–5</jats:sup> 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 × 10jats:sup5</jats:sup>. The strongest evidence was found for rs4674019 (p-value = 2.27 × 10jats:sup–7</jats:sup>), which showed genome-wide significant interaction (p-value = 3.8 × 10jats:sup–8</jats:sup>) 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.</jats:p>

Article, /631/208/205/2138, /692/499, /692/699/67/1347, /692/699/67/2324, article
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Scientific Reports
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Springer Science and Business Media LLC
National Cancer Institute (U19 CA148065-01)
European Union's Horizon 2020 Research and Innovation Programme (634935, 633784)
European Community´s Seventh Framework Programme (223175)
Cancer Research UK (C1287/A16563, C1287/A10118, C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565)
Canadian Institutes of Health Research (GPH-129344)
Science et Innovation du Québec (PSRSIIRI-701)
European Community's Seventh Framework Programme (HEALTH-F2-2009-223175)
Bundesministerium für Bildung, Wissenschaft und Forschung (01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114)
Swedish Research Council (VR 2017-00644)
National Institutes of Health (P01 CA87969, UM1 CA186107, U19 CA148065, UM1 CA176726, U19 CA148065)
Lon V Smith Foundation (LVS39420)
U.S. Department of Health and Human Services (HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C)