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Functional variants in MBL2 are associated with type 2 diabetes and pre-diabetes traits in Pima Indians and the old order Amish.

ABSTRACT: MBL2 encodes the mannose-binding lectin, which is a key player in the innate immune system and has recently been found to play a role in insulin resistance and development of type 1 diabetes and gestational diabetes mellitus. To assess the role of MBL2 in diabetes susceptibility, this gene was analyzed in the Pima Indian population, which has a high prevalence of type 2 diabetes.Nineteen tag single nucleotide polymorphisms (SNPs) were genotyped in a population-based sample of 3,501 full-heritage Pima Indians, and selected SNPs were further genotyped in independent samples of Native American (n = 3,723) and Old Order Amish (n = 486) subjects.Two variants, a promoter SNP (rs11003125) at -550 bp with a risk allele frequency of 0.77 and a Gly54Asp (rs1800450) with a risk allele frequency of 0.83, were associated with type 2 diabetes in the full-heritage Pima Indians (odds ratio 1.30 per copy of the G allele for rs1103125, P = 0.0007, and 1.30 per copy of the glycine allele for rs1800450, P = 0.002, adjusted for age, sex, birth year, and family membership). These associations replicated in an independent Native American sample (1.19, P = 0.04, for rs11003125) and a Caucasian sample, the Old Order Amish (1.51, P = 0.004, for rs1103125 and 2.38, P = 0.003, for rs1800450). Among Pima Indians with normal glucose tolerance, the diabetes risk allele glycine of Gly54Asp was associated with a decreased acute insulin response to an intravenous glucose bolus infusion (P = 0.004, adjusted for age, sex, percent body fat, glucose disposal under physiological insulin stimulation, and family membership).Our data suggest that the functional variants in MBL2 contribute to type 2 diabetes susceptibility in both Native Americans and the Old Order Amish.

SUBMITTER: Muller YL

PROVIDER: S-EPMC2911048 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Functional variants in MBL2 are associated with type 2 diabetes and pre-diabetes traits in Pima Indians and the old order Amish.

Muller Yunhua L YL Hanson Robert L RL Bian Li L Mack Janel J Shi Xiaolian X Pakyz Ruth R Shuldiner Alan R AR Knowler William C WC Bogardus Clifton C Baier Leslie J LJ

Diabetes 20100603 8

<h4>Objective</h4>MBL2 encodes the mannose-binding lectin, which is a key player in the innate immune system and has recently been found to play a role in insulin resistance and development of type 1 diabetes and gestational diabetes mellitus. To assess the role of MBL2 in diabetes susceptibility, this gene was analyzed in the Pima Indian population, which has a high prevalence of type 2 diabetes.<h4>Research design and methods</h4>Nineteen tag single nucleotide polymorphisms (SNPs) were genotyp ...[more]

PMID: 20522590

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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.

Dataset Information

Functional variants in MBL2 are associated with type 2 diabetes and pre-diabetes traits in Pima Indians and the old order Amish.

Publications

Functional variants in MBL2 are associated with type 2 diabetes and pre-diabetes traits in Pima Indians and the old order Amish.

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