The association of the angiotensinogen gene with insulin sensitivity in humans: a tagging single nucleotide polymorphism and haplotype approach

Abstract

The purpose of this study was to clarify the association of the angiotensinogen gene (AGT) with insulin sensitivity using single nucleotide polymorphism (SNP) and haplotype analyses in a white cohort. A candidate gene association study was conducted in white persons with and without hypertension (N = 449). Seventeen SNPs of the AGT gene and their haplotypes were analyzed for an association with homeostasis model assessment of insulin resistance (HOMA-IR). Multivariate regression model accounting for age, sex, body mass index, hypertension status, study site, and sibling relatedness was used to test the hypothesis. Nine of the 17 SNPs were significantly associated with lower HOMA-IR levels. Homozygous minor allele carriers of the most significant SNP, rs2493134 (GG), a surrogate for the gain-of-function mutation rs699 (AGT p.M268T), had significantly lower HOMA-IR levels (P = .0001) than heterozygous or homozygous major allele carriers (AG, AA). Direct genotyping of rs699 in a subset of the population showed similar results, with minor allele carriers exhibiting significantly decreased HOMA-IR levels (P = .003). Haplotype analysis demonstrated that haplotypes rs2493137A|rs5050A|rs3789678G|rs2493134A and rs2004776G|rs11122576A|rs699T|rs6687360G were also significantly associated with HOMA-IR (P = .0009, P = .02), and these results were driven by rs2493134 and rs699. This study confirms an association between the AGT gene and insulin sensitivity in white humans. Haplotype analysis extends this finding and implicates SNPs rs2493134 and rs699 as the most influential. Thus, AGT gene variants, previously shown to be associated with AGT levels, are also associated with insulin sensitivity; suggesting a relationship between the AGT gene, AGT levels, and insulin sensitivity in humans.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Figure 1. Linkage Disequilibrium Plot of 17 SNPs

Numbers represent R2 values. Population includes participants with and without hypertension. SNP location along gene was determined using the NM_000029.3 AGT reference sequence.

Figure 2. Association of rs2493134 with Primary and Secondary Phenotypes

HOMA-IR and fasting plasma insulin values by SNP rs2493134 in entire population A) (All), individuals with hypertension only B) (HTN), and individuals without hypertension C) (NTN). Point estimates (least-square means), error bars (95% CI), and p values were obtained from the mixed model regression accounting for age, gender, BMI, sibling relatedness, and study site.