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

大多数2型糖尿病可能是一种多基因、多因素的疾病，尽管可能涉及一个或多个主基因。在这项研究中，我们的目的是确定易感基因，受影响的同胞对分析，这被认为是适合检测易感基因的多基因，多因素的疾病。我们已经对几条染色体上的高度多态性标记进行了基因分型。2000年年底将完成全基因组调查和多个位点的定位。我们还尝试用候选基因进行群体关联研究，以检测2型糖尿病的易感基因。我们已经产生了PPARγ缺陷小鼠，以研究在高脂饮食下，PPARγ在脂肪细胞肥大和胰岛素抵抗中的生理作用。在高脂肪饮食下，杂合的PPARγ缺陷小鼠免受脂肪积累、体重增加和胰岛素抵抗（Mol Cell 4：597-609，1999）。因此，我们认为PPARγ是一个重要的节俭基因，与2型糖尿病的发生有着“多因素”的关系。为了探讨过氧化物酶体增殖物激活受体γ（PPARγ）是否是一个节俭基因，我们研究了PPARγ基因Pro 12 Ala多态性与2型糖尿病的关系。在肥胖者中，PPARγ2基因的Ala 1 2等位基因可保护胰岛素抵抗。Ala 12的等位基因在2型糖尿病受试者中的频率显著低于非糖尿病受试者，这表明PPARγ2中的Ala 12多态性可以防止2型糖尿病（Diabetologia，出版中）。我们还发现Gln 27 Glu β2肾上腺素能受体变体与由于皮下脂肪积累引起的肥胖有关（Biochem Biophys Res Commun 258：138-140，1999）。

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).