國家衛生研究院 NHRI:Item 3990099045/8025
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    题名: Genetic and Functional Analyses Identify NAT2 as a Human Insulin Sensitivity Gene
    作者: Knowles, JW;Hao, K;Xie, WJ;Weedon, MN;Zhang, ZY;Paaanen, J;Goodarzi, MO;Hansson, O;Pankow, JS;Chenemsetty, I;Carcamo-Orive, I;Assimes, T;Morris, A;Chen, YDI;Schadt, EE;Makinen, VP;Yang, X;Abbasi, F;Attie, A;Keller, M;Greenawalt, D;Rotter, JI;Sinako, A;Hsiung, A;Cordell, HJ;Reaven, G;Groop, L;Laakso, M;Ingelsson, E;Frayling, TM;Walker, M;Quertermous, T;Genesis;Risc;Eugene, U;Guardian;Consortia, SA
    贡献者: Division of Biostatistics and Bioinformatics
    摘要: Decreased tissue sensitivity to insulin (insulin resistance) is a fundamental abnormality in patients with type 2 diabetes, and a major risk factor for cardiovascular disease in nondiabetic individuals. The genetic basis of insulin resistance remains largely unknown as large genome-wide association studies of type 2 diabetes have mostly identified genes related to beta cell biology rather than insulin sensitivity. The GENEticS of Insulin Sensitivity (GENESIS) consortium conducted a genome wide association study for direct measures of insulin sensitivity (euglycemic clamp or insulin suppression test) in 2765 white/European individuals from four studies. Further, we performed in silico replication of five loci with P values < 10-6 in 1540 Hispanic individuals with euglycemic clamp data. The strongest association after in silico replication was found with two common tightly linked, non-synonymous SNPs in NAT2 [rs1208 (803A>G, R268K) and rs1801280 (341T>C, I114T)] white/European minor allele frequency (MAF) ~ 0.45] with the ancestral alleles at both positions associated with a greater degree of insulin resistance in analyses adjusted for age, gender and body mass index. Additional replication genotyping of N=1422 white/Europeans for the NAT2 SNPs from four independent cohorts with euglycemic clamp data demonstrated an overall fixed effects meta-analytic P value of 1.0khcy10-6 for rs1208 (Nmax = 5669). In a lookup in GWAS meta-analysis results from other consortia, the ancestral allele for the lead SNP (rs1208) has also been nominally associated with increased fasting glucose (P=0.007), hemoglobin A1C (P=0.02), triglyceride levels (P=0.00003) total cholesterol (P=0.0004), LDL cholesterol (P=0.02) and coronary artery disease (P=0.02) but not with fasting insulin or HDL. In 3T3-L1 adipocytes, silencing of Nat1 (the mouse homolog to NAT2) decreased insulin mediated glucose uptake. Furthermore, Nat1 silencing also decreased 3T3-L1 adipocyte differentiation and increased basal and isoproterenol stimulated lipolysis while decreasing insulin mediated suppression of lipolysis. Opposite effects were seen with Nat1 overexpression. Taken together, our results suggest a role for NAT2 in insulin sensitivity.
    日期: 2013-11
    關聯: Circulation. 2013 Nov;128(22 Suppl.):Meeting Abstract 10906.
    Link to: http://circ.ahajournals.org/cgi/content/meeting_abstract/128/22_MeetingAbstracts/A10906
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0009-7322&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000332162901245
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