Dataset Information

Association of TCF7L2 gene polymorphisms with reduced acute insulin response in Hispanic Americans.

ABSTRACT: Genetic variation at the transcription factor 7-like 2 locus has been linked to type 2 diabetes in predominantly European-derived populations. The biological basis of these associations remains to be determined.The objective of this study was to evaluate previously associated variants for association with measures of glucose homeostasis in Hispanic-Americans and African-Americans and determine the biological mechanism(s) through which these variants exert their effect.This study was the Insulin Resistance Atherosclerosis Family Study (IRAS-FS).The IRAS-FS is a community-based study of Hispanic-Americans (San Antonio, TX, and San Luis Valley, CO) and African-Americans (Los Angeles, CA).A total of 1040 Hispanic-American and 500 African-American individuals from the IRAS-FS formed the basis of this study. MAIN OUTCOMES MEASURES(S): The primary glucose homeostasis phenotypes of interest in this study were derived from the frequently sampled iv glucose tolerance test and include insulin sensitivity, acute insulin response, and disposition index.In Hispanic-Americans, significant evidence of association was observed between single-nucleotide polymorphisms rs7903146 and rs112255372 with reduced insulin secretion as measured by acute insulin response and adjusted for the degree of insulin sensitivity (P = 0.032 and 0.036, respectively). Other quantitative measures, e.g. insulin sensitivity or disposition index, were not associated with the single nucleotide polymorphisms examined. In African-Americans there was no evidence of association observed.These results suggest that transcription factor 7-like 2 variants could play a role in the pathogenesis of type 2 diabetes in the Hispanic-American population through a mechanism involving insulin secretion.

SUBMITTER: Palmer ND

PROVIDER: S-EPMC2190750 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Association of TCF7L2 gene polymorphisms with reduced acute insulin response in Hispanic Americans.

Palmer Nicholette D ND Lehtinen Allison B AB Langefeld Carl D CD Campbell Joel K JK Haffner Steven M SM Norris Jill M JM Bergman Richard N RN Goodarzi Mark O MO Rotter Jerome I JI Bowden Donald W DW

The Journal of clinical endocrinology and metabolism 20071030 1

<h4>Context</h4>Genetic variation at the transcription factor 7-like 2 locus has been linked to type 2 diabetes in predominantly European-derived populations. The biological basis of these associations remains to be determined.<h4>Objective</h4>The objective of this study was to evaluate previously associated variants for association with measures of glucose homeostasis in Hispanic-Americans and African-Americans and determine the biological mechanism(s) through which these variants exert their ...[more]

PMID: 17971425

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Project description:The SOCS3 gene product participates in the feedback inhibition of a range of cytokine signals. Most notably, SOCS3 inhibits the functioning of leptin and downstream steps in insulin signaling after being expressed by terminal transcription factors, such as STAT3 and c-fos. The SOCS3 gene is located in the chromosome region 17q24-17q25, previously linked to body mass index (BMI), visceral adipose tissue (VAT), and waist circumference (WAIST) in Hispanic families in the Insulin Resistance Atherosclerosis Family Study (IRASFS). A high density map of 1,536 single nucleotide polymorphisms (SNPs) was constructed to cover a portion of the 17q linkage interval in 1,425 Hispanic subjects from 90 extended families in IRASFS. Analysis of this dense SNP map data revealed evidence of association of rs9914220 (located 10 kb 5' of the SOCS3 gene) with BMI, VAT, and WAIST (P-value ranging from 0.003 to 0.017). Using a tagging SNP approach, rs9914220 and 22 additional SOCS3 SNPs were genotyped for genetic association analysis with measures of adiposity and glucose homeostasis. The adiposity phenotypes utilized in association analyses included BMI, WAIST, waist to hip ratio (WHR), subcutaneous adipose tissue, VAT, and visceral to subcutaneous ratio (VSR). Linkage disequilibrium calculations revealed three haplotype blocks near SOCS3. Haplotype Block 3 (5' of SOCS3) contained SNPs consistently associated with BMI, WAIST, WHR, and VAT (P-values ranging from 2.00 x 10(-4) to 0.036). Haplotype Block 1 contained single-SNPs that were associated with most adiposity traits except for VSR (P-values ranging from 0.002 to 0.047). When trait associated SNPs were included in linkage analyses as covariates, a reduction of VAT LOD score from 1.26 to 0.76 above the SOCS3 locus (110 cM) was observed. Multi-SNP haplotype testing using the quantitative pedigree disequilibrium test was broadly consistent with the single-SNP associations. In conclusion, these results support a role for SOCS3 genetic variants in human obesity.

Dataset Information

Association of TCF7L2 gene polymorphisms with reduced acute insulin response in Hispanic Americans.

Publications

Association of TCF7L2 gene polymorphisms with reduced acute insulin response in Hispanic Americans.

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