Candidate Gene Studies

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Candidate genes for type 2 diabetes are selected based on their involvement in pancreatic P-cell function, insulin action/glucose metabolism, or other metabolic conditions that increase type 2 diabetes risk (e.g. energy intake/expenditure and lipid metabolism) (Barroso et al, 2003). To date, more than 50 candidate genes for type 2 diabetes have been studied in various populations worldwide. However, most candidate gene studies for diabetes typically tested a limited number of genetic variants and often in only small samples or in cases and controls that were poorly matched or diagnosed, frequently resulting in lack of replication of the weak associations detected (Moore and Florez, 2008). In this section, we focus on a few of the most promising candidate genes (PPARG, KCNJ11 and WFS1) for which the results are most convincing and the samples sizes are large.

The PPARG (peroxisome proliferatoracti-vated receptor-y) gene has been widely studied because of its importance in adipocyte and lipid metabolism (Tontonoz and Spiegelman, 2008). In addition, it is a target for hypoglycemic drugs known as thiazolidinediones. A proline-to-alanine (Pro12Ala) change in codon 12 of PPARG was the first genetic variant to be definitively implicated in the common form of type 2 diabetes. The rare Ala allele is present in ~15% of white Europeans and was shown to be associated with increased insulin sensitivity. A study that combined data on a Finnish and a second generation Japanese cohort (Deeb et al, 1998) found that Pro allele homozygotes had 4.35 times higher risk for developing type 2 diabetes compared to those who do not carry the allele (p = 0.028). Although a number of subsequent small studies were not able to replicate this initial finding, a meta-analysis combining the results from 16 studies published before 2000 confirmed the association with type 2 diabetes (Altshuler et al, 2000). In addition, a meta-analysis of data from 57 studies comprising approximately 32,000 non-diabetic individuals further established the role of Pro12Ala variant in association with greater insulin sensitivity (standardized effect size 0.227, P = 0.0067) (Tonjes et al, 2006).

The beta-cell adenosine triphosphate-sensitive potassium (KATP) channel plays a critical role in insulin secretion. The channel is composed of two subunits: the sulfonylurea receptor-1 (SURl) and an inward rectifying potassium channel (Kir6.2) that are encoded on chromosome lp15.1 by genes ABCC8 and KCNJII, respectively. SNP E23K of KCNJ11 has been shown to be associated with type 2 diabetes. Although initial smaller studies failed to replicate the association of the E23K polymorphism with type 2 diabetes, large-scale studies and meta-analyses have consistently associated the lysine variant with type 2 diabetes, showing a 1.15 times higher risk for developing type 2 diabetes compared to those who do not carry this variant (Florez et al, 2004; Gloyn et al, 2003; Van Dam et al, 2005). Genome-wide association studies have further confirmed the association of PPARG and KCNJ11 variants in association with type 2 diabetes (Diabetes Genetics Initiative of Broad Institute of Harvard and MIT et al, 2007; Scott et al, 2007; Zeggini et al, 2007).

WFS1 gene encodes wolframin, a protein that is defective in individuals with the Wolfram syndrome. This syndrome is characterized by diabetes insipidus, juvenile diabetes, optic atrophy and deafness. Disruption of Wfs1 in mice causes overt diabetes or impaired glucose tolerance, depending on genetic background (Ishihara et al, 2004; Riggs et al, 2005). Both humans and mice deficient in Wolframin show pancreatic P-cell loss, possibly as a result of an enhanced endoplasmic reticulum stress response leading to increased P-cell apoptosis (Riggs et al, 2005; Yamada et al, 2006). Hence, WFS1 is critical for survival and function of insulin-producing pancreatic beta cells. The first evidence that variation in the WFS1 gene influences susceptibility to type 2 diabetes was shown in a family-based association study (Minton et al, 2002). A study on 1,536 SNPs in 84 candidate genes using a gene-centric approach showed that only WFS1 gene was associated with type 2 diabetes (Sandhu et al, 2007). This finding was further replicated in 9533 cases and 11,389 controls. Following this study, a meta-analysis of 11 studies (Franks et al, 2008), comprising up to 12,979 cases and 14,937 controls, further confirmed association between the WFS1 gene variant, rs10010131 and type 2 diabetes (OR: 0.89, 95% CI 0.86-0.92; p = 4.9 x 10-11).

In summary, large-scale studies and meta-analyses have identified only three candidate genes to be robustly associated with type 2 diabetes traits.

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