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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.

SUBMITTER: Underwood PC

PROVIDER: S-EPMC3115454 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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

Underwood Patricia C PC Sun Bei B Williams Jonathan S JS Pojoga Luminita H LH Raby Benjamin B Lasky-Su Jessica J Hunt Steven S Hopkins Paul N PN Jeunemaitre Xavier X Adler Gail K GK Williams Gordon H GH

Metabolism: clinical and experimental 20110208 8

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 ...[more]

PMID: 21306748

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Project description:Variation in the angiotensinogen gene, AGT, has been associated with variation in plasma angiotensinogen levels. In addition, the T235M polymorphism in the AGT product is associated with an increased risk of essential hypertension in multiple populations, making AGT a good example of a quantitative-trait locus underlying susceptibility to a common disease. To better understand genetic variation in AGT, we sequenced a 14.4-kb genomic region spanning the entire AGT and identified 44 single-nucleotide polymorphisms (SNPs). Forty-two SNPs were observed both in 88 white and in 77 Japanese unselected subjects. Six major haplotypes accounted for most of the variation in this region, indicating less allelic complexity than in many other genomic regions. Although the two populations were found to share all of the major AGT haplotypes, there were substantial differences in haplotype frequencies. Pairwise linkage disequilibrium (LD), measured by the D', r(2), and d(2) statistics, demonstrated a general pattern of decline with increasing distance, but, as expected in a small genomic region, individual LD values were highly variable. LD between T235M and each of the other 39 SNPs was assessed in order to model the usefulness of LD to detect a disease-associated mutation. Among the Japanese subjects, 13 (33%) of the SNPs had r(2) values >0.1, whereas this statistic was substantially higher for the white subjects (occurring in 35/39 [90%]). LD between a hypertension-associated promoter mutation, A-6G, and 39 SNPs was also measured. Similar results were obtained, with 33% of the SNPs showing r(2)>0.1 in the Japanese subjects and 92% of the SNPs showing r(2)>0.1 in the white subjects. This difference, which occurs despite an overall similarity in LD patterns in the two populations, reflects a much higher frequency of the M235-associated haplotype in the white sample. These results have important implications for the usefulness of LD approaches in the mapping of genes underlying susceptibility to complex diseases.

Dataset Information

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

Publications

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

Similar Datasets

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