Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance.
Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance.
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综合基因组分析暗示有限的外周脂肪储存能力在人类胰岛素抵抗的发病机理中。
DOI：
10.1038/ng.3714
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发表时间：
2017-01
期刊：
影响因子：
30.8
通讯作者：
Scott RA
中科院分区：
文献类型：
--
作者：
Lotta LA;Gulati P;Day FR;Payne F;Ongen H;van de Bunt M;Gaulton KJ;Eicher JD;Sharp SJ;Luan J;De Lucia Rolfe E;Stewart ID;Wheeler E;Willems SM;Adams C;Yaghootkar H;EPIC-InterAct Consortium;Cambridge FPLD1 Consortium;Forouhi NG;Khaw KT;Johnson AD;Semple RK;Frayling T;Perry JR;Dermitzakis E;McCarthy MI;Barroso I;Wareham NJ;Savage DB;Langenberg C;O'Rahilly S;Scott RA
胰岛素抵抗是肥胖相关的心脏代谢疾病的关键介质，但这种联系的机制仍然不清楚。使用整合基因组方法，我们确定了53个与胰岛素抵抗表型相关的基因组区域（经BMI调整后的空腹胰岛素较高，HDL胆固醇较低，甘油三酯较高），并提供证据表明，它们与较高的心脏代谢风险的联系是由与外周室中较低的脂肪量的关联所支撑的。使用这53个基因座，我们显示了多基因的贡献，家族性部分脂肪代谢障碍1型，严重的胰岛素抵抗，并强调共同/轻度和罕见/严重的胰岛素抵抗之间的分子机制。群体水平的遗传分析结合细胞模型实验表明，CCDC 92、DNAH 10和L3 MBTL 3是以前未认识到的影响脂肪细胞分化的分子。我们的研究结果支持了外周脂肪组织储存能力有限是胰岛素抵抗性心脏代谢疾病的重要病因组成部分的观点，并强调了支持这种联系的基因和机制。
Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin adjusted for BMI, lower HDL cholesterol and higher triglycerides) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy-type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms between common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognised molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important aetiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.
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影响因子：
7.7
作者：
Gray, Sarah L.;Nora, Edoardo Dalla;Vidal-Puig, Antonio
通讯作者：
Vidal-Puig, Antonio
影响因子：
9.8
作者：
Dyment, David A.;Smith, Amanda C.;Innes, A. Micheil
通讯作者：
Innes, A. Micheil
影响因子：
4.5
作者：
Chasman DI;Paré G;Mora S;Hopewell JC;Peloso G;Clarke R;Cupples LA;Hamsten A;Kathiresan S;Mälarstig A;Ordovas JM;Ripatti S;Parker AN;Miletich JP;Ridker PM
通讯作者：
Ridker PM
影响因子：
15.9
作者：
Ginsberg, HN
通讯作者：
Ginsberg, HN
DOI：
10.1056/nejmoa1506930
发表时间：
2016-04-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Kernan WN;Viscoli CM;Furie KL;Young LH;Inzucchi SE;Gorman M;Guarino PD;Lovejoy AM;Peduzzi PN;Conwit R;Brass LM;Schwartz GG;Adams HP Jr;Berger L;Carolei A;Clark W;Coull B;Ford GA;Kleindorfer D;O'Leary JR;Parsons MW;Ringleb P;Sen S;Spence JD;Tanne D;Wang D;Winder TR;IRIS Trial Investigators
通讯作者：
IRIS Trial Investigators