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PCLO variants are nominally associated with early-onset type 2 diabetes and insulin resistance in Pima Indians.

ABSTRACT: A prior genome-wide association (GWA) study in Pima Indians identified variants within PCLO that were associated with early-onset type 2 diabetes. PCLO encodes a presynaptic cytomatrix protein that functions as a Ca(2+) sensor that may be involved in insulin secretion and/or insulin action. Therefore, PCLO was analyzed as a candidate gene for type 2 diabetes.Sequencing of PCLO identified four nonsynonymous variants and a 10-amino acid insertion. These variants, together with 100 additional variants identified by sequencing or chosen from databases, were genotyped for association analysis in the same 895 subjects analyzed in the prior GWA study (300 case subjects with diabetes onset at aged <25 years, 334 nondiabetic control subjects aged >45 years, and 261 discordant siblings of the case or control subjects for within-family analyses), as well as 415 nondiabetic Pima Indians who had been metabolically phenotyped for predictors of diabetes. Selected variants were further genotyped in a population-based sample of 3,501 Pima Indians.Four variants were modestly associated with early-onset type 2 diabetes in both general and within-family analyses (P = 0.004-0.04, recessive model), where the diabetes risk allele was also nominally associated with a lower insulin-mediated glucose disposal rate (P = 0.009-0.14, recessive model) in nondiabetic Pima Indians. However, their association with diabetes in the population-based sample was weaker (P = 0.02-0.20, recessive model).Variation within PCLO may have a modest effect on early-onset type 2 diabetes, possibly as a result of reduced insulin action, but has minimal, if any, impact on population-based risk for type 2 diabetes.

SUBMITTER: Ma L

PROVIDER: S-EPMC2570415 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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PCLO variants are nominally associated with early-onset type 2 diabetes and insulin resistance in Pima Indians.

Ma Lijun L Hanson Robert L RL Que Lorem N LN Guo Yan Y Kobes Sayuko S Bogardus Clifton C Baier Leslie J LJ

Diabetes 20080722 11

<h4>Objective</h4>A prior genome-wide association (GWA) study in Pima Indians identified variants within PCLO that were associated with early-onset type 2 diabetes. PCLO encodes a presynaptic cytomatrix protein that functions as a Ca(2+) sensor that may be involved in insulin secretion and/or insulin action. Therefore, PCLO was analyzed as a candidate gene for type 2 diabetes.<h4>Research design and methods</h4>Sequencing of PCLO identified four nonsynonymous variants and a 10-amino acid inserti ...[more]

PMID: 18647954

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Project description:The type 2 deiodinase gene (DIO2) encodes a deiodinase that converts the thyroid prohormone, thyroxine, to the biologically active triiodothyronine. Thyroid hormones regulate energy balance and may also influence glucose metabolism. Therefore, we hypothesized that variations in DIO2 could contribute to obesity or type 2 diabetes mellitus (T2DM) in Pima Indians.Sequencing of the DIO2 gene in DNA from 83 Pima Indians identified 12 single-nucleotide polymorphisms (SNPs). Several of these SNPs were in perfect genotypic concordance among the 83 samples that were sequenced, and all 12 could be divided into five linkage disequilibrium groups. One representative SNP from each group (Thr92Ala, rs225011, rs225015, rs6574549, and a rare 5' flanking SNP) was selected for further genotyping for association analyses. In this study, the five selected variants in DIO2, as described above, were genotyped in three groups of Pima Indians: (i) a case (n=150)/control (n=150) group for early-onset T2DM (onset age <25 years); (ii) a case (n=362)/control (n=127) group for obesity; (iii) a large (n=1,311, cases n=810/controls n=501) family-based group, of which 256 nondiabetic subjects had undergone detailed metabolic phenotyping.The Thr92Ala variant common in Pima Indians, rs225011, and rs225015 were modestly associated with early-onset T2DM (p=0.01-0.04) in the case-control study, but were not associated with obesity in the obesity case-control study, nor associated with T2DM (at any age) or body-mass index (BMI; as a quantitative trait) in the family-based analysis. Thr92Ala, rs225011, rs225015, and rs6574549 were also nominally associated with hepatic glucose output (p=0.02). rs6574549 was associated with fasting insulin (p=0.02), insulin action (p=0.04), and energy expenditure (p=0.02). None of these nominal associations remained statistically significant after corrections for multiple testing.We propose that variation in DIO2 may have a subtle role in altering metabolic processes that lead to early-onset T2DM, but this gene does not have a large impact on T2DM at older ages, nor does DIO2 influence BMI in the Pima Indian population.

Project description:ObjectivePrior genome-wide association and exon array expression studies both provided suggestive evidence that apoptosis signal regulating kinase 1 (ASK1) may influence in vivo insulin action in Pima Indians. Genetic variants in or near ASK1 were analyzed to assess the role of this gene in insulin action and type 2 diabetes.Research design and methodsGenotypic data from 31 variants were used to determine the linkage disequilibrium pattern across ASK1 in Pima Indians. Eight tag SNPs were initially genotyped in 3,501 full-heritage Pima Indians. Replication for association with diabetes was assessed in a second population-based sample of 3,723 Native Americans and the published DIAGRAM study. Quantitative traits were analyzed in 536 nondiabetic Native Americans, and ASK1 expression was examined in skeletal muscle of 153 nondiabetic Native Americans.ResultsThree tag SNPs were associated with type 2 diabetes (rs35898099, P = 0.003, odds ratio [95% CI] 1.27 [1.08-1.47]; rs1570056, P = 0.007, 1.19 [1.05-1.36]; rs7775356, P = 0.04, 1.14 [1.01-1.28]) in the full-heritage Pima Indians. The association with rs35898099 was replicated in a second sample of Native Americans (P = 0.04, 1.22 [1.01-1.47]), while that for rs1570056 was replicated in the DIAGRAM study of Caucasians (Z statistic based P = 0.026; fixed-effect model, 1.06 [1.00-1.12]). The diabetes risk allele for rs1570056 was associated with reduced insulin action as assessed by either HOMA-IR in 2,549 nondiabetic full-heritage Pima Indians (P = 0.027) or a hyperinsulinemic-euglycemic clamp among 536 nondiabetic Native Americans (P = 0.02). Real-time PCR identified a positive correlation between ASK1 expression in skeletal muscle biopsies and in vivo insulin action (P = 0.02, r = 0.23), and the risk allele for rs1570056 was associated with lower ASK1 expression (P = 0.003, r = -0.22).ConclusionsASK1 variants may increase susceptibility to type 2 diabetes by decreasing insulin sensitivity via reduced ASK1 expression.

Dataset Information

PCLO variants are nominally associated with early-onset type 2 diabetes and insulin resistance in Pima Indians.

Publications

PCLO variants are nominally associated with early-onset type 2 diabetes and insulin resistance in Pima Indians.

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