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Review

Challenges in studies of the genetic basis of Type 2 diabetes

Pages 451-459 | Published online: 10 Jan 2014
 

Abstract

The prevalence of diabetes is increasing worldwide in epidemic proportions. This increase is mainly due to increased incidence and prevalence of Type 2 diabetes, which accounts for 80–90% of all cases of diabetes. The susceptibility to develop Type 2 diabetes is determined by genetic and environmental factors. Major genes responsible for Type 2 diabetes have not yet been identified. The most replicated susceptibility gene for Type 2 diabetes is TCF7L2, recently published by investigators from Iceland. The second most widely replicated association between a genetic variation and the risk of Type 2 diabetes is that of the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor γ2 gene. Furthermore, the common E23K polymorphism in the KCJN11 gene, encoding the ATP-sensitive potassium-channel subunit Kir6.2, and variants in the calpain-10 gene have been associated with increased susceptibility to Type 2 diabetes in meta-analyses. Several studies have investigated the possibility that rare, highly penetrant mutations in the maturity-onset diabetes of the young genes lead to monogenic diabetes, while common polymorphisms increase the susceptibility to Type 2 diabetes. Indeed, there is increasing evidence that single nucleotide polymorphisms in hepatic nuclear factor-4α are significantly associated with the risk of Type 2 diabetes. In this review, different approaches to identify susceptibility genes for Type 2 diabetes are discussed. In particular, the importance of prospective population-based cohort studies and prospective intervention studies are emphasized. Finally, genome-wide association studies using single nucleotide polymorphisms randomly spaced across the entire genome may be useful in the identification of susceptibility genes for Type 2 diabetes.

Acknowledgement

This review was supported by a grant from the European Community’s FP6 EUGENE (LSHM-CT-2004–5122013) and the Academy of Finland.

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