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
Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, The State University of New York, Buffalo, New York 14214.
College of Pharmacy, The Ohio State University, Columbus, Ohio 43210.
J Clin Endocrinol Metab. 2017 Jun 1;102(6):1908-1916. doi: 10.1210/jc.2016-2936.
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.
The objective was to test an interaction between genetic susceptibility and HT on fracture risk.
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.
Forty US clinical centers.
A total of 9922 genotyped white postmenopausal women (age, 50 to 79) from the Women's Health Initiative HT randomized trials.
Adjudicated fracture incidence.
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.
These results suggest that HT reduces fracture risk in postmenopausal women, especially in those at highest genetic risk of fracture and low BMD.
有证据支持绝经激素治疗（HT）对骨骼具有保护作用。然而，遗传易感性是否会改变HT与骨折风险之间的关联尚未得到充分研究。
旨在测试遗传易感性与HT对骨折风险的相互作用。
我们基于16个骨折相关变异构建了两个加权遗传风险评分（GRS）（Fx-GRS）和50个骨密度变异（BMD-GRS）。我们使用Cox回归来估计GRS的主要效应及其与HT对骨折风险的相互作用。我们估计了由于相互作用导致的相对超额风险（RERI）作为相加相互作用的指标。我们还使用病例对照法来测试相乘相互作用。
美国40个临床中心。
来自女性健康倡议HT随机试验的9922名基因分型的绝经后白人女性（年龄50至79岁）。
判定的骨折发生率。
每增加1个单位的GRS，两种GRS均与骨折风险相关（Fx-GRS的风险比为1.04 [95%置信区间，1.02至1.06]，BMD-GRS的风险比为1.03 [95%置信区间，1.02 - 1.04]）。我们没有发现两种GRS中任何一种存在相乘相互作用的证据。然而，我们观察到显著的相加相互作用，即两种GRS的最高四分位数与随机分配到安慰剂组均有额外的骨折风险：Fx-GRS的RERI为P = 0.047，BMD-GRS的RERI为P = 0.046。
这些结果表明，HT可降低绝经后女性的骨折风险，尤其是那些骨折遗传风险最高且骨密度低的女性。
