Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action - PubMed (original) (raw)

Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action

Inês Barroso et al. PLoS Biol. 2003 Oct.

Erratum in

Abstract

Type 2 diabetes is an increasingly common, serious metabolic disorder with a substantial inherited component. It is characterised by defects in both insulin secretion and action. Progress in identification of specific genetic variants predisposing to the disease has been limited. To complement ongoing positional cloning efforts, we have undertaken a large-scale candidate gene association study. We examined 152 SNPs in 71 candidate genes for association with diabetes status and related phenotypes in 2,134 Caucasians in a case-control study and an independent quantitative trait (QT) cohort in the United Kingdom. Polymorphisms in five of 15 genes (33%) encoding molecules known to primarily influence pancreatic beta-cell function-ABCC8 (sulphonylurea receptor), KCNJ11 (KIR6.2), SLC2A2 (GLUT2), HNF4A (HNF4alpha), and INS (insulin)-significantly altered disease risk, and in three genes, the risk allele, haplotype, or both had a biologically consistent effect on a relevant physiological trait in the QT study. We examined 35 genes predicted to have their major influence on insulin action, and three (9%)-INSR, PIK3R1, and SOS1-showed significant associations with diabetes. These results confirm the genetic complexity of Type 2 diabetes and provide evidence that common variants in genes influencing pancreatic beta-cell function may make a significant contribution to the inherited component of this disease. This study additionally demonstrates that the systematic examination of panels of biological candidate genes in large, well-characterised populations can be an effective complement to positional cloning approaches. The absence of large single-gene effects and the detection of multiple small effects accentuate the need for the study of larger populations in order to reliably identify the size of effect we now expect for complex diseases.

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Conflict of interest statement

Portions of the research were supported by Incyte Corporation (formerly Incyte Genomics). This collaboration provided access to certain technologies and scientific expertise for basic research in the genetics of diabetes in return for possible shared intellectual property. The work described here is not subject to any patent filings or intellectual property protection and restrictions from free use of the information. IB and AJS were employees of Incyte at the time the research took place.

Figures

Figure 1

Figure 1. Study Design

Candidate genes were selected based on known or putative function. A de novo polymorphism discovery step was undertaken to identify novel variants for association studies. We selected 152 SNPs and tested them in a case-control study and a QT study. Association analysis with Type 2 diabetes was done for SNPs and haplotypes under multiple genetic models. Only SNPs and haplotypes associated with disease were evaluated for association with five diabetes-related QTs under the same model in the QT study.

Figure 2

Figure 2. Power Calculations

Power of the current Cambridgeshire Case-Control Study to detect associations with risk allele of varying frequencies and with a Type 1 error rate of 5%. Abbreviations: p0, frequency of the predisposing allele; chr, number of chromosomes. Graphs were plotted with the PS power and sample-size program (available at

http://www.mc.vanderbilt.edu/prevmed/ps

; DuPont and Plummer 1997).

Figure 3

Figure 3. Genes with Haplotypes Associated with Type 2 Diabetes

Genomic organization with exons (black boxes or vertical lines) and with genotyped SNPs and SNPs utilised in the haplotype reconstructions (in blue boxes) is shown. The most common haplotypes with population prevalence greater than 5% in the control population are shown, and the measure of LD (r2) is shown for a subset of the SNPs. (A) ABCC8–KCNJ11. (B) HNF4A. (C) INSR.

Figure 4

Figure 4. Size of Case-Control Study Required to Detect Small Risk Effects

The number is shown of the case chromosomes (assuming an equal number of control chromosomes) required to attain 80% power to detect associations with the OR varying between 1.0 and 1.5 and with a Type 1 error rate of 0.01%. Abbreviations: p0, frequency of the predisposing allele; chr, number of chromosomes. Graphs were plotted with the PS power and sample-size program (DuPont and Plummer 1997).

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