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Association of the Kir6.2 E23K variant with reduced acute insulin response in African-Americans.

ABSTRACT: ATP-sensitive potassium channels are composed of pore-forming (Kir6.x) and regulatory sulfonylurea receptor (SURx) subunits and have been implicated in the maintenance of glucose homeostasis. Kir6.2 and SUR1 are expressed in a broad range of tissues, and no contemporary studies have addressed the physiological impact of variants in Hispanic-Americans and African-Americans carefully phenotyped for components of glucose homeostasis.The objective of this study was to evaluate two nonsynonymous variants in Kir6.2 (E23K) and SUR1 (A1369S) and determine their role in vivo.The Insulin Resistance Atherosclerosis Family Study (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 1,040 Hispanic-Americans and 500 African-American individuals formed the basis of this study.The primary glucose homeostasis phenotypes of interest in this study were derived from the frequently sampled iv glucose tolerance test and included insulin sensitivity (S(I)), acute insulin response, and disposition index.In African-Americans, both variants were associated with a significant reduction in insulin secretion in glucose-tolerant carriers of the minor alleles (additive P = 0.00053). S(I), a measure of insulin sensitivity, was not associated. In Hispanic-Americans, there was no association with measures of glucose homeostasis.We conclude that variation marked by the Kir6.2 E23K and SUR1 A1369S mutations is associated with alterations in glucose-stimulated insulin secretion but not with other measures of glucose homeostasis in an African-American population.

SUBMITTER: Palmer ND

PROVIDER: S-EPMC2626454 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Association of the Kir6.2 E23K variant with reduced acute insulin response in African-Americans.

Palmer Nicholette D ND Langefeld Carl D CD Bryer-Ash Michael M Rotter Jerome I JI Taylor Kent D KD Bowden Donald W DW

The Journal of clinical endocrinology and metabolism 20080916 12

<h4>Context</h4>ATP-sensitive potassium channels are composed of pore-forming (Kir6.x) and regulatory sulfonylurea receptor (SURx) subunits and have been implicated in the maintenance of glucose homeostasis. Kir6.2 and SUR1 are expressed in a broad range of tissues, and no contemporary studies have addressed the physiological impact of variants in Hispanic-Americans and African-Americans carefully phenotyped for components of glucose homeostasis.<h4>Objective</h4>The objective of this study was ...[more]

PMID: 18796522

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Project description:BackgroundAfrican Americans have a high risk for type 2 diabetes (T2D) and insulin resistance. Studies among other population groups have identified DNA methylation loci associated with insulin resistance, but data in African Americans are lacking. Using DNA methylation profiles of blood samples obtained from the Illumina Infinium® HumanMethylation450 BeadChip, we performed an epigenome-wide association study to identify DNA methylation loci associated with insulin resistance among 136 non-diabetic, unrelated African American men (mean age 41.6 years) from the Howard University Family Study.ResultsWe identified three differentially methylated positions (DMPs) for homeostatic model assessment of insulin resistance (HOMA-IR) at 5% FDR. One DMP (cg14013695, HOXA5) is a known locus among Mexican Americans, while the other two DMPs are novel-cg00456326 (OSR1; beta = 0.027) and cg20259981 (ST18; beta = 0.010). Although the cg00456326 DMP is novel, the OSR1 gene has previously been found associated with both insulin resistance and T2D in Europeans. The genes HOXA5 and ST18 have been implicated in biological processes relevant to insulin resistance. Differential methylation at the significant HOXA5 and OSR1 DMPs is associated with differences in gene expression in the iMETHYL database. Analysis of differentially methylated regions (DMRs) did not identify any epigenome-wide DMRs for HOMA-IR. We tested transferability of HOMA-IR associated DMPs from five previous EWAS in Mexican Americans, Indian Asians, Europeans, and European ancestry Americans. Out of the 730 previously reported HOMA-IR DMPs, 47 (6.4%) were associated with HOMA-IR in this cohort of African Americans.ConclusionsThe findings from our study suggest substantial differences in DNA methylation patterns associated with insulin resistance across populations. Two of the DMPs we identified in African Americans have not been reported in other populations, and we found low transferability of HOMA-IR DMPs reported in other populations in African Americans. More work in African-ancestry populations is needed to confirm our findings as well as functional analyses to understand how such DNA methylation alterations contribute to T2D pathology.

Dataset Information

Association of the Kir6.2 E23K variant with reduced acute insulin response in African-Americans.

Publications

Association of the Kir6.2 E23K variant with reduced acute insulin response in African-Americans.

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