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- Title
Gene-Hormone Therapy Interaction and Fracture Risk in Postmenopausal Women.
- Authors
Wang, Youjin; Wactawski-Wende, Jean; Sucheston-Campbell, Lara E; Preus, Leah; Hovey, Kathleen M; Nie, Jing; Jackson, Rebecca D; Handelman, Samuel K; Nassir, Rami; Crandall, Carolyn J; Ochs-Balcom, Heather M
- Abstract
<bold>Context: </bold>Evidence supports a protective effect of menopausal hormone therapy (HT) on bone. However, whether genetic susceptibility modifies the association of HT and fracture risk is not sufficiently explored.<bold>Objective: </bold>The objective was to test an interaction between genetic susceptibility and HT on fracture risk.<bold>Design: </bold>We constructed two weighted genetic risk scores (GRSs) based on 16 fracture-associated variants (Fx-GRSs) and 50 bone mineral density variants (BMD-GRSs). We used Cox regression to estimate the main effects of GRSs and their interactions with HT on fracture risk. We estimated the relative excess risk due to interaction (RERI) as a measure of additive interaction. We also used the case-only approach to test for a multiplicative interaction.<bold>Setting: </bold>Forty US clinical centers.<bold>Participants: </bold>A total of 9922 genotyped white postmenopausal women (age, 50 to 79) from the Women's Health Initiative HT randomized trials.<bold>Main Outcome Measures: </bold>Adjudicated fracture incidence.<bold>Results: </bold>Both GRSs were associated with fracture risk per 1-unit increment in GRS (hazard ratio, 1.04 [95% confidence interval, 1.02 to 1.06] for Fx-GRS and hazard ratio, 1.03 [95% confidence interval,1.02-1.04] for BMD-GRS). We found no evidence for multiplicative interaction for either of the GRS. However, we observed a substantial additive interaction, where the highest quartile of both GRSs and randomization to placebo have excess fracture risk: Fx-GRS P for RERI = 0.047, BMD-GRS P for RERI = 0.046.<bold>Conclusions: </bold>These results suggest that HT reduces fracture risk in postmenopausal women, especially in those at highest genetic risk of fracture and low BMD.
- Publication
Journal of Clinical Endocrinology & Metabolism, 2017, pN.PAG
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/jc.2016-2936