Genetic Support for a Causal Role of Insulin Resistance on Circulating Branched-Chain Amino Acids and Inflammation.
Genetic Support for a Causal Role of Insulin Resistance on Circulating Branched-Chain Amino Acids and Inflammation.
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DOI：
10.2337/dc17-1642
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发表时间：
2017-12
期刊：
影响因子：
16.2
通讯作者：
Ala-Korpela M
中科院分区：
文献类型：
--
作者：
Wang Q;Holmes MV;Davey Smith G;Ala-Korpela M
胰岛素抵抗对心脏代谢疾病具有有害影响。我们使用孟德尔随机化分析来阐明胰岛素抵抗与循环血液代谢物的因果关系，以阐明胰岛素抵抗与心脏代谢疾病关系的潜在介质。我们从最近的一项全基因组关联研究中使用了53个与胰岛素抵抗相关的单核苷酸多态性，以探讨它们对循环脂质和代谢物的影响。我们使用了来自欧洲个体的两项全基因组关联研究（GWAS）的已发表摘要级数据;关于暴露（胰岛素抵抗）的数据来自188，577名个体的元GWAS，关于结果的数据（通过NMR评估的58项代谢指标）来自24，925名个体的GWAS。一个标准差（SD）遗传性胰岛素抵抗升高（相当于空腹胰岛素几何平均值升高55%，甘油三酯升高0.89 mmol/L，HDL-C降低0.46 mmol/L）与所有支链氨基酸、异亮氨酸（0.56 SD; 95%CI：0.43，0.70），亮氨酸（0.42 SD; 95%CI：0.28，0.55）和缬氨酸（0.26 SD; 95%CI：0.12，0.39）以及较高的糖蛋白乙酰基（炎症标志物; 0.47 SD; 95%CI：0.32，0.62）（每种P<0.0003）。当使用多重敏感性分析来解释潜在的遗传多效性时，结果大致一致。我们提供了强有力的证据表明，胰岛素抵抗对每个支链氨基酸和炎症产生因果影响。与现有的研究一起，这意味着支链氨基酸代谢是从肥胖和胰岛素抵抗到2型糖尿病的因果途径。
Insulin resistance has deleterious effects on cardiometabolic disease. We used Mendelian randomization analyses to clarify the causal relationships of insulin resistance on circulating blood-based metabolites to shed light on potential mediators of the insulin resistance to cardiometabolic disease relationship. We used 53 single nucleotide polymorphisms associated with insulin resistance from a recent genome-wide association study to explore their effects on circulating lipids and metabolites. We used published summary-level data from two genome-wide association studies (GWASs) of European individuals; data on the exposure (insulin resistance) were obtained from meta-GWASs of 188,577 individuals and data on the outcomes (58 metabolic measures assessed by NMR) were taken from a GWAS of 24,925 individuals. One standard deviation (SD) genetically elevated insulin resistance (equivalent to 55% higher geometric mean of fasting insulin, 0.89 mmol/L higher triglycerides and 0.46 mmol/L lower HDL-C) was associated with higher concentrations of all branched-chain amino acids, isoleucine (0.56 SD; 95%CI: 0.43, 0.70), leucine (0.42 SD; 95%CI: 0.28, 0.55) and valine (0.26 SD; 95%CI: 0.12, 0.39) as well as with higher glycoprotein acetyls (an inflammation marker; 0.47 SD; 95%CI: 0.32, 0.62) (P<0.0003 for each). Results were broadly consistent when using multiple sensitivity analyses to account for potential genetic pleiotropy. We provide robust evidence that insulin resistance causally impacts on each individual branched-chain amino acid and inflammation. Taken together with existing studies, this implies that branched-chain amino acid metabolism lies on a causal pathway from adiposity and insulin resistance to type 2 diabetes.
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影响因子：
7.7
作者：
Bowden J;Del Greco M F;Minelli C;Davey Smith G;Sheehan NA;Thompson JR
通讯作者：
Thompson JR
影响因子：
8.2
作者：
Gan W;Walters RG;Holmes MV;Bragg F;Millwood IY;Banasik K;Chen Y;Du H;Iona A;Mahajan A;Yang L;Bian Z;Guo Y;Clarke RJ;Li L;McCarthy MI;Chen Z;China Kadoorie Biobank Collaborative Group
通讯作者：
China Kadoorie Biobank Collaborative Group
影响因子：
9.9
作者：
Shaham, Oded;Wei, Ru;Wang, Thomas J.;Ricciardi, Catherine;Lewis, Gregory D.;Vasan, Ramachandran S.;Carr, Steven A.;Thadhani, Ravi;Gerszten, Robert E.;Mootha, Vamsi K.
通讯作者：
Mootha, Vamsi K.
腰围比与心脏代谢性状，2型糖尿病和冠状动脉疾病的遗传关联。
DOI：
10.1001/jama.2016.21042
发表时间：
2017-02-14
期刊：
JAMA
影响因子：
--
作者：
Emdin CA;Khera AV;Natarajan P;Klarin D;Zekavat SM;Hsiao AJ;Kathiresan S
通讯作者：
Kathiresan S
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。
影响因子：
30.8
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
通讯作者：
Scott RA