Evaluation of DLG2 as a positional candidate for disposition index in African-Americans from the IRAS family study

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Abstract

Aims

Evaluate discs large homolog 2 (DLG2) as a positional candidate gene for disposition index (DI) in the Insulin Resistance Atherosclerosis Family Study (IRAS-FS) African-American sample.

Methods

SNPs (n = 193) were selected for genotyping in 580 African-American individuals using a modified tagging algorithm. Follow-up genotyping was carried out within regions associated with DI. A subset of highly associated, uncorrelated SNPs was used as covariates in the linkage analysis to assess their contribution to linkage.

Results

Evidence of association with DI was observed at the DLG2 locus (admixture-adjusted P = 0.050–8.7 × 10−5) with additional signals observed in follow-up genotyping of 17 SNPs (P = 0.033–0.0012). Inclusion of highly associated, uncorrelated SNPs as covariates in the linkage analysis explained linkage at the DLG2 locus (90.8 cM) and reduced the maximal LOD score (72.0 cM) from 4.37 to 3.71.

Conclusions

Evidence of association and an observed contribution to evidence for linkage to DI was observed for SNPs in DLG2 genotyped on the African-American individuals from the IRAS-FS. Although not the only gene in the region, these results suggest that variation at the DLG2 locus contributes to maintenance of glucose homeostasis through regulation of insulin sensitivity and β-cell function as measured by DI.

Introduction

Maintenance of glucose homeostasis encompasses both peripheral insulin sensitivity and β-cell function. It has been widely observed that insulin-resistant subjects have markedly increased insulin secretory function compared with insulin-sensitive subjects. This compensatory relationship or negative feedback loop has been quantified experimentally and demonstrated to function as a hyperbolic relationship between insulin sensitivity and β-cell function [1]. The disposition index (DI) quantifies the relationship between insulin sensitivity (SI) and pancreatic β-cell function (AIR); DI = SIxAIR [2]. Type 2 diabetes (T2D) is characterized by the failure of this compensatory relationship and reduced DI is a strong predictor of T2D [3]. Through investigation of the relationship between SI and AIR quantified by DI, we aim to identify molecular mechanism(s) that detrimentally modulate glucose homeostasis.

In a genome-wide scan based on 284 nondiabetic African-Americans from 21 pedigrees recruited by the Insulin Resistance Atherosclerosis Family Study (IRAS-FS), evidence for linkage to DI on chromosome 11q was observed with a LOD score of 3.21 at 81.0 cM flanked by markers D11S2371 and D11S2002 [4]. Following fine mapping with microsatellite markers in the initial family sample (Set 1) and in an independent set of 214 African-American subjects in 21 pedigrees (Set 2), the resulting linkage signal increased to a LOD score of 4.80 at 80.0 cM near marker D11S937. Suggestive evidence for linkage to acute insulin response (AIR) at two separate locations flanking the DI peak (64.0 cM, LOD 2.77, flanked by markers D11S4076 and D11S981; and 85.0 cM, LOD 2.54, flanked by markers D11S4172 and D11S2002) was also observed, but no evidence of linkage to the insulin sensitivity index (SI) [5]. The goal of this study was to evaluate the DLG2 locus as a positional candidate gene for DI and assess its contribution to the observed linkage signal.

Section snippets

Subjects

Study design, recruitment and phenotyping for the IRAS-FS have been described in detail [6]. Briefly, the IRAS-FS is a multi-center study designed to identify the genetic determinants of quantitative measures of glucose homeostasis and adiposity in African-Americans and Hispanic Americans. A clinical examination was performed that included an interview, a frequently sampled intravenous glucose tolerance test (FSIGT), anthropometric measurements, and blood collection. The Institutional Review

Genotyping

SNPs were chosen for genotyping within the DLG2 gene (longest annotated transcript; Chr11:82843701-85015962, NCBI Build 36.1 hg18) using a modified tagging algorithm. SNPs were identified for genotyping based on binning Illumina-designable SNPs according to a threshold linkage disequilibrium score (r2) [11]. This algorithm specifically tagged SNPs (as opposed to haplotypes) and was agnostic towards haplotype block structure, although larger bins were likely to encompass haplotype block regions.

Results

This study evaluated genetic data from 580 African-Americans in the IRAS-FS of whom 499 had FSIGT-derived measures of glucose homeostasis. Table 1 summarizes the descriptive statistics of the sample. In general, the sample included more women than men (59.2% women) and was overweight (BMI = 30.0 ± 6.8 kg/m2).

SNP genotyping from the Illumina Custom Bead Array platform at CIDR, was >99% efficient (0.045% missing data rate) and after Mendelian error corrections using PedCheck blind duplicate samples

Discussion

Using a positional cloning approach, evidence of DI linked to chromosome 11q has been observed. This result has been replicated in additional study samples and fine mapping resulted in a significant LOD score of 4.80 at 80 cM near marker D11S937 in African-Americans from the IRAS-FS [5]. The purpose of the current study was to evaluate discs large homolog 2 (DLG2) as a positional candidate gene for DI.

The longest of six DLG2 transcripts spans greater than 2.1Mb of chromosome 11q (Chr11:

Conflict of interest

There are no conflicts of interest.

Acknowledgements

We wish to thank participants of the IRAS Family Study. The IRAS Family Study was supported in part by NIH grants HL060894, HL060931, HL060944, HL061019, and HL061210. Genotyping services were provided by CIDR. CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract Number N01-HG-65403.

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    Genetic mapping of disposition index and acute insulin response loci on chromosome 11q. The Insulin Resistance Atherosclerosis Study (IRAS) Family Study

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