DESCRIPTION:

List of positional candidate genes after correcting for multiple testing and controlling the false discovery rate from genome wide association studies (GWAS) retrieved from the NHGRI-EBI Catalog of published genome-wide association studies (http://www.ebi.ac.uk/gwas/). The disease/trait examined in this study, as reported by the authors, was Insulin resistance/response. The EFO term insulin resistance was annotated to this set after curation by NHGRI-EBI. Intergenic SNPS were mapped to both the upstream and downstream gene. P-value uploaded. This gene set was generated using gwas2gs v. 0.1.8 and the GWAS Catalog v. 1.0.1.

LABEL:

GWAS: insulin resistance

SCORE TYPE:

P-Value

DATE ADDED:

2017-05-02

DATE UPDATED:

2024-04-25

SPECIES:

AUTHORS:

JW Knowles, W Xie, Z Zhang, I Chennamsetty, I Chennemsetty, TL Assimes, J Paananen, O Hansson, J Pankow, MO Goodarzi, I Carcamo-Orive, AP Morris, YD Chen, VP Mäkinen, A Ganna, A Mahajan, X Guo, F Abbasi, DM Greenawalt, P Lum, C Molony, L Lind, C Lindgren, LJ Raffel, PS Tsao, EE Schadt, JI Rotter, A Sinaiko, G Reaven, X Yang, CA Hsiung, L Groop, HJ Cordell, M Laakso, K Hao, E Ingelsson, TM Frayling, MN Weedon, M Walker, T Quertermous

TITLE:

Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene.

JOURNAL:

The Journal of clinical investigation Apr 2015, Vol 125, pp. 1739-51

ABSTRACT:

Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity. PUBMED: 25798622
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