Many of the established genes for type 2 diabetes (T2D) identified via genome-wide association studies appear to increase risk via an effect on acute insulin secretory response to glucose (AIR). Although the AIR is highly heritable in Pima Indians, established T2D genes account for only a fraction of this heritability. We performed a genome-wide analysis to identify variants that associate consistently with 2 different measures of acute insulin secretory function and with T2D. Genotypic data on 491,288 SNPs tagging 92% of common variation identified in whole genome sequences of Pima Indians (minor allele frequency ≥0.05, r2 ≥0.85) were available on 3708 full heritage Pima Indians informative for T2D. Among these, 300 (193 men, age: 27±6 yr, body fat: 31±8%) also had a measure of AIR when they had normal glucose tolerance. AIR was measured after an overnight fast by infusion of 25 g dextrose for 3 minutes, and calculated as the average increment in plasma insulin concentration from the 3rd to the 5th min after the glucose bolus. The corrected insulin response (CIR) was calculated at 30’ during the OGTT. No SNP achieved genome-wide statistical significance (p=5x10-8) for AIR or CIR (451 and 438 SNPs, respectively, had p<10−3 after genomic control, adjusted for age, sex, body fat, insulin action assessed during a glucose clamp, the first 5 genetic principal components and sibship, with 19 SNPs associated with both traits with directional consistency). However, one intronic SNP in TMEM132D (rs4301843) was consistent for the 2 traits and T2D, where the C allele (frequency=0.72) associated with lower AIR (b=−20% per copy, p=10-4), lower CIR (b=−21%, p=10-4) and higher T2D prevalence (OR=1.32, 95% CI: 1.14-1.52, p=2×10-4). TMEM132D encodes the transmembrane protein 132D, which may have an indirect role in T2D onset by binding to PPP1CA and other established T2D genes such as KCNQ1. Our results suggest that common variation in TMEM132D may influence AIR and predispose Pima Indians to T2D.

A Genome-Wide Association Study of Acute Insulin Secretory Response in Pima Indians

Paolo Piaggi
Primo
;
2017-01-01

Abstract

Many of the established genes for type 2 diabetes (T2D) identified via genome-wide association studies appear to increase risk via an effect on acute insulin secretory response to glucose (AIR). Although the AIR is highly heritable in Pima Indians, established T2D genes account for only a fraction of this heritability. We performed a genome-wide analysis to identify variants that associate consistently with 2 different measures of acute insulin secretory function and with T2D. Genotypic data on 491,288 SNPs tagging 92% of common variation identified in whole genome sequences of Pima Indians (minor allele frequency ≥0.05, r2 ≥0.85) were available on 3708 full heritage Pima Indians informative for T2D. Among these, 300 (193 men, age: 27±6 yr, body fat: 31±8%) also had a measure of AIR when they had normal glucose tolerance. AIR was measured after an overnight fast by infusion of 25 g dextrose for 3 minutes, and calculated as the average increment in plasma insulin concentration from the 3rd to the 5th min after the glucose bolus. The corrected insulin response (CIR) was calculated at 30’ during the OGTT. No SNP achieved genome-wide statistical significance (p=5x10-8) for AIR or CIR (451 and 438 SNPs, respectively, had p<10−3 after genomic control, adjusted for age, sex, body fat, insulin action assessed during a glucose clamp, the first 5 genetic principal components and sibship, with 19 SNPs associated with both traits with directional consistency). However, one intronic SNP in TMEM132D (rs4301843) was consistent for the 2 traits and T2D, where the C allele (frequency=0.72) associated with lower AIR (b=−20% per copy, p=10-4), lower CIR (b=−21%, p=10-4) and higher T2D prevalence (OR=1.32, 95% CI: 1.14-1.52, p=2×10-4). TMEM132D encodes the transmembrane protein 132D, which may have an indirect role in T2D onset by binding to PPP1CA and other established T2D genes such as KCNQ1. Our results suggest that common variation in TMEM132D may influence AIR and predispose Pima Indians to T2D.
2017
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/960882
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