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