Abstract 10906: Genetic and Functional Analyses Identify NAT2 as a Human Insulin Sensitivity Gene
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 1.0х10-6 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.
- © 2013 by American Heart Association, Inc.