Hivert Marie-France, Christophi Costas A, Franks Paul W, Jablonski Kathleen A, Ehrmann David A, Kahn Steven E, Horton Edward S, Pollin Toni I, Mather Kieren J, Perreault Leigh, Barrett-Connor Elizabeth, Knowler William C, Florez Jose C
Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, Canada.
The Biostatistics Center, George Washington University, Rockville, MD.
Diabetes. 2016 Feb;65(2):520-6. doi: 10.2337/db15-0950. Epub 2015 Nov 2.
Large genome-wide association studies of glycemic traits have identified genetics variants that are associated with insulin resistance (IR) in the general population. It is unknown whether people with genetic enrichment for these IR variants respond differently to interventions that aim to improve insulin sensitivity. We built a genetic risk score (GRS) based on 17 established IR variants and effect sizes (weighted IR-GRS) in 2,713 participants of the Diabetes Prevention Program (DPP) with genetic consent. We tested associations between the weighted IR-GRS and insulin sensitivity index (ISI) at baseline in all participants, and with change in ISI over 1 year of follow-up in the DPP intervention (metformin and lifestyle) and control (placebo) arms. All models were adjusted for age, sex, ethnicity, and waist circumference at baseline (plus baseline ISI for 1-year ISI change models). A higher IR-GRS was associated with lower baseline ISI (β = -0.754 [SE = 0.229] log-ISI per unit, P = 0.001 in fully adjusted models). There was no differential effect of treatment for the association between the IR-GRS on the change in ISI; higher IR-GRS was associated with an attenuation in ISI improvement over 1 year (β = -0.520 [SE = 0.233], P = 0.03 in fully adjusted models; all treatment arms). Lifestyle intervention and metformin treatment improved the ISI, regardless of the genetic burden of IR variants.
对血糖性状进行的大规模全基因组关联研究已经确定了与普通人群胰岛素抵抗（IR）相关的基因变异。目前尚不清楚携带这些IR变异基因富集的人群对旨在改善胰岛素敏感性的干预措施的反应是否不同。我们基于17个已确定的IR变异和效应大小，在2713名获得基因同意的糖尿病预防计划（DPP）参与者中构建了一个遗传风险评分（GRS）（加权IR-GRS）。我们在所有参与者中测试了基线时加权IR-GRS与胰岛素敏感性指数（ISI）之间的关联，以及在DPP干预组（二甲双胍和生活方式干预）和对照组（安慰剂）中随访1年期间ISI的变化。所有模型均根据年龄、性别、种族和基线时的腰围进行了调整（对于1年ISI变化模型，还包括基线ISI）。较高的IR-GRS与较低的基线ISI相关（在完全调整模型中，每单位log-ISI的β=-0.754[SE = 0.229]，P = 0.001）。对于IR-GRS与ISI变化之间的关联，治疗没有差异效应；较高的IR-GRS与1年内ISI改善的减弱相关（在完全调整模型中，β=-0.520[SE = 0.233]，P = 0.03；所有治疗组）。无论IR变异的遗传负担如何，生活方式干预和二甲双胍治疗均可改善ISI。
