Abstract | Context: 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.

Objective: The objective was to test an interaction between genetic susceptibility and HT on fracture risk.

Design: We constructed two weighted genetic risk scores (GRSs) based on 16 fracture-associated variants (Fx-GRS) and 50 bone mineral density (BMD) variants (BMD-GRS). 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 utilized the case-only approach to test for a multiplicative interaction.

Setting: 40 US clinical centers

Participants: 9,922 genotyped white postmenopausal women (age 50-79) from the Women’s Health Initiative HT randomized trials

Main outcome: Adjudicated fracture incidence

Results: Both GRSs were associated with fracture risk (hazard ratio (HR) (95% CI) per one-unit increment in GRS, 1.04 (1.02-1.06) for Fx-GRS and 1.03 (1.02-1.04) for BMD-GRS). We found no evidence for multiplicative interaction for either of the GRS. However, we observed a significant 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.

Conclusions: These results suggest that HT reduces fracture risk in postmenopausal women especially in those at highest genetic risk of fracture and low BMD.

Youjin Wang Jean Wactawski-Wende Lara E. Sucheston-Campbell Leah Preus Kathleen M. Hovey Jing Nie Rebecca D. Jackson Samuel K. Handelman Rami Nassir Carolyn J. Crandall

J Clin Endocrinol Metab jc.2016-2936. DOI:

Published: 06 March 2017

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