The genetic basis of type 2 diabetes in a multi-ethnic population in Singapore

Abstract

Type 2 diabetes occurs when the body is unable to regulate blood glucose levels as a result of insulin resistance and impaired insulin secretion. Type 2 diabetes mellitus exhibits significant heritability and the aim of my research is to examine the basis of this heritability. In the first study, we evaluate the effect of a family history of type 2 diabetes on risk of type 2 diabetes and related metabolic traits. We found that subjects with a positive family history had an increased risk of developing type 2 diabetes with an odds-ratio of 2.25 (95% CI: 1.85 ¿ 2.75). This increased risk appears to be mediated through increased obesity, insulin resistance and ß-cell dysfunction. The year 2007 brought the advent of genome wide association studies, which lead to the identification of over a dozen novel type 2 diabetes susceptibility loci. As these initial studies were carried out in populations of European ancestry, the relevance of these genetic variants in Asian populations remain less well-characterized. To gain a greater appreciation of the genetic basis of type 2 diabetes in Asians, we have investigated the association between recently identified type 2 diabetes susceptibility loci with risk of diabetes in the Chinese, Malay and Asian-Indian populations in Singapore. We also examined their associations with traits that appear to be involved in the pathogenesis of type 2 diabetes; namely obesity, insulin resistance and ß-cell dysfunction. In the second study, we examine the effect of genetic variants at the FTO locus in the Singapore Chinese and Malay populations. We found statistically significant association between FTO variants with type 2 diabetes which appeared to be mediated through its effect on BMI (p=10^4¿10^6). In the third study, to characterize the effect of a newly identified susceptibility locus (KCNQ1), we investigate the association between polymorphisms at the locus with quantitative traits relevant to the pathogenesis of type 2 diabetes. We found that the increased risk for type 2 diabetes associated with KCNQ1 is likely through a reduction in pancreatic ß-cell function/insulin secretion (p=0.013). In the fourth study, we examine the effects of genetic variants at eight type 2 diabetes susceptibility loci (CDKAL1, CDKN2A/B, IGF2BP2, HHEX, SLC30A8, PKN2, LOC387761) and conduct a meta-analysis with studies in East Asians. This study demonstrated that type 2 diabetes susceptibility loci identified through genome wide association studies in populations of European ancestry show similar effects in East Asian populations. This suggest that failure to detect these effects across different populations are likely due to issues of power owing to limited sample size, lower minor allele frequency, or differences in genetic effect sizes. Our studies examined several type 2 diabetes susceptibility loci and demonstrate a genetic basis/predisposition of type 2 diabetes in Asians. As several groups worldwide are currently undertaking re-sequencing studies to identify causative variants at these loci, the examination of multiple ethnic groups may allow us to exploit differences in the patterns of linkage disequilibrium between ethnic groups, in order to refine the genomic region of interest and aid in this effort. While many susceptibility loci continue to be identified, much of the disease variability still remains unaccounted for; further studies examining gene-environment interaction as well as a more detailed interrogation of human genetic variation will provide further insight to the genetics of type 2 diabetes.