Identification of susceptibility genes for type 2 diabetes in the Japanese using affected sib pair analysis

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It has been suggested that most of type, 2 diabetes is likely to be a polygenic, multifactorial disorder, although one or more major genes could be involved. In this study, we aimed to identify the susceptibility genes using affected sib-pair analysis, which is thought to be suitable for detecting susceptibility loci for such polygenic, multifactorial disorders. We have already, genotyped highly polmorphic markers on several chromosomes. Whole genome will be investigated and several loci would be mapped by the end of fiscal 2000.We also tried to detect the susceptibility genes for type 2 diabetes using population association studies with candidate genes. We have generated PPARγ deficient mice to investigate the physiological role of PPARγ in adipocyte hypertrophy arid insulin resistance under a high-fat diet. Heterozygous PPARγ deficient mice were protected from fat accumulation, body weight gain and insulin resistance under a high-fat diet (Mol Cell 4: 597-609, 1999). Therefore we proposed that PPARγ is one of the important thrifty genes and associated with 'multifactorial' type 2 diabetes. To investigate whether PPARγ serves as a thrifty gene in humans, we investigated the association between Pro12Ala polymorphism in PPARγ gene and type2 diabetes. In obese subjects, Alal2 allele of PPARγ2 gene protects against insulin resistance. Allele of Alal2 was, significantly less frequent in type2 diabetic subjects than in non-diabetic, suggesting that the Alal2 polymorphism in PPARγ2 may protect against type2 diabetes (Diabetologia, in press).We have also found that the Gln27Glu β2 adrenergic receptor variant is associated with obesity due to subcutaneous fat accumulation (Biochem Biophys Res Commun 258 : 138-140, 1999).