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Breast Cancer Research
Published in: Breast Cancer Research 1/2015

Open Access 01-12-2015 | Research article

A comprehensive evaluation of interaction between genetic variants and use of menopausal hormone therapy on mammographic density

Authors: Anja Rudolph, Peter A. Fasching, Sabine Behrens, Ursula Eilber, Manjeet K. Bolla, Qin Wang, Deborah Thompson, Kamila Czene, Judith S. Brand, Jingmei Li, Christopher Scott, V. Shane Pankratz, Kathleen Brandt, Emily Hallberg, Janet E. Olson, Adam Lee, Matthias W. Beckmann, Arif B. Ekici, Lothar Haeberle, Gertraud Maskarinec, Loic Le Marchand, Fredrick Schumacher, Roger L. Milne, Julia A. Knight, Carmel Apicella, Melissa C. Southey, Miroslav K. Kapuscinski, John L. Hopper, Irene L. Andrulis, Graham G. Giles, Christopher A. Haiman, Kay-Tee Khaw, Robert Luben, Per Hall, Paul D. P. Pharoah, Fergus J. Couch, Douglas F. Easton, Isabel dos-Santos-Silva, Celine Vachon, Jenny Chang-Claude

Published in: Breast Cancer Research | Issue 1/2015

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Abstract

Introduction

Mammographic density is an established breast cancer risk factor with a strong genetic component and can be increased in women using menopausal hormone therapy (MHT). Here, we aimed to identify genetic variants that may modify the association between MHT use and mammographic density.

Methods

The study comprised 6,298 postmenopausal women from the Mayo Mammography Health Study and nine studies included in the Breast Cancer Association Consortium. We selected for evaluation 1327 single nucleotide polymorphisms (SNPs) showing the lowest P-values for interaction (P int) in a meta-analysis of genome-wide gene-environment interaction studies with MHT use on risk of breast cancer, 2541 SNPs in candidate genes (AKR1C4, CYP1A1-CYP1A2, CYP1B1, ESR2, PPARG, PRL, SULT1A1-SULT1A2 and TNF) and ten SNPs (AREG-rs10034692, PRDM6-rs186749, ESR1-rs12665607, ZNF365-rs10995190, 8p11.23-rs7816345, LSP1-rs3817198, IGF1-rs703556, 12q24-rs1265507, TMEM184B-rs7289126, and SGSM3-rs17001868) associated with mammographic density in genome-wide studies. We used multiple linear regression models adjusted for potential confounders to evaluate interactions between SNPs and current use of MHT on mammographic density.

Results

No significant interactions were identified after adjustment for multiple testing. The strongest SNP-MHT interaction (unadjusted P int <0.0004) was observed with rs9358531 6.5kb 5′ of PRL. Furthermore, three SNPs in PLCG2 that had previously been shown to modify the association of MHT use with breast cancer risk were found to modify also the association of MHT use with mammographic density (unadjusted P int <0.002), but solely among cases (unadjusted P int SNP×MHT×case-status <0.02).

Conclusions

The study identified potential interactions on mammographic density between current use of MHT and SNPs near PRL and in PLCG2, which require confirmation. Given the moderate size of the interactions observed, larger studies are needed to identify genetic modifiers of the association of MHT use with mammographic density.
Appendix
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Metadata
Title
A comprehensive evaluation of interaction between genetic variants and use of menopausal hormone therapy on mammographic density
Authors
Anja Rudolph
Peter A. Fasching
Sabine Behrens
Ursula Eilber
Manjeet K. Bolla
Qin Wang
Deborah Thompson
Kamila Czene
Judith S. Brand
Jingmei Li
Christopher Scott
V. Shane Pankratz
Kathleen Brandt
Emily Hallberg
Janet E. Olson
Adam Lee
Matthias W. Beckmann
Arif B. Ekici
Lothar Haeberle
Gertraud Maskarinec
Loic Le Marchand
Fredrick Schumacher
Roger L. Milne
Julia A. Knight
Carmel Apicella
Melissa C. Southey
Miroslav K. Kapuscinski
John L. Hopper
Irene L. Andrulis
Graham G. Giles
Christopher A. Haiman
Kay-Tee Khaw
Robert Luben
Per Hall
Paul D. P. Pharoah
Fergus J. Couch
Douglas F. Easton
Isabel dos-Santos-Silva
Celine Vachon
Jenny Chang-Claude
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2015
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-015-0625-9

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