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Until recently, genome-wide association study (GWAS)-based findings have provided a substantial genetic contribution to type 2 diabetes mellitus (T2DM) or related glycemic traits. However, identification of allelic heterogeneity and population-specific genetic variants under consideration of potential confounding factors will be very valuable for clinical applicability. To identify novel susceptibility loci for T2DM and glycemic traits, we performed a two-stage genetic association study in a Korean population.
We performed a logistic analysis for T2DM, and the first discovery GWAS was analyzed for 1,042 cases and 2,943 controls recruited from a population-based cohort (KARE,
A combined meta-analysis for T2DM identified two new (rs11065756 and rs2074356) loci reaching genome-wide significance in CCDC63 and C12orf51 on the 12q24 region. In addition, these variants were significantly associated with fasting plasma glucose and homeostasis model assessment of β-cell function. Interestingly, two independent single nucleotide polymorphisms were associated with sex-specific stratification in this study.
Our study showed a strong association between T2DM and glycemic traits. We further observed that two novel loci with multiple diverse effects were highly specific to males. Taken together, these findings may provide additional insights into the clinical assessment or subclassification of disease risk in a Korean population.
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Genome wide association analyses have revealed large numbers of common variants influencing predisposition to type 2 diabetes and related phenotypes. These studies have predominantly featured European populations, but are now being extended to samples from a wider range of ethnic groups. The transethnic analysis of association data is already providing insights into the genetic, molecular and biological causes of diabetes, and the relevance of such studies will increase as human discovery genetics increasingly moves towards sequencing-based approaches and a focus on low frequency and rare variants.
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Type 2 diabetes mellitus (T2DM) is caused by complex interplay between multiple genetic and environmental factors. The three major approaches used to identify the genetic susceptibility include candidate gene approach, familial linkage analysis and genome- wide association analysis. Recent advance in genome-wide association studies have greatly improved our understanding of the pathophysiology of T2DM. As of the end of 2010, there are more than 40 confirmed T2DM-associated genetic loci. Most of the T2DM susceptibility genes were implicated in decreased β-cell function. However, these genetic variations have a modest effect and their combination only explains less than 10% of the T2DM heritability. With the advent of the next-generation sequencing technology, we will soon identify rare variants of larger effect as well as causal variants. These advances in understanding the genetics of T2DM will lead to the development of new therapeutic and preventive strategies and individualized medicine.
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