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

有研究表明，大多数2型糖尿病可能是一种多基因、多因子疾病，尽管可能涉及一个或多个主要基因。在这项研究中，我们的目的是利用受影响的兄弟姐妹对分析来确定易感基因，这种分析被认为适用于检测此类多基因、多因素疾病的易感位点。我们已经在几条染色体上对高度多态性标记进行了基因分型。到2000财政年度末，将对全基因组进行调查，并绘制若干位点。我们还试图通过候选基因的群体关联研究来检测2型糖尿病的易感基因。我们制造了PPARγ缺乏的小鼠，以研究高脂肪饮食下PPARγ在脂肪细胞肥大和胰岛素抵抗中的生理作用。杂合子PPARγ缺乏小鼠在高脂肪饮食下免受脂肪积累、体重增加和胰岛素抵抗的影响（Mol Cell 4: 597- 609,1999）。因此，我们提出PPARγ是一个重要的节俭基因，与“多因素”2型糖尿病有关。为了研究PPARγ是否在人类中作为一种节俭基因，我们研究了PPARγ基因Pro12Ala多态性与2型糖尿病的关系。肥胖人群PPARγ2基因Alal2等位基因对胰岛素抵抗具有保护作用。Alal2等位基因在2型糖尿病患者中的频率明显低于非糖尿病患者，这表明PPARγ2中的Alal2多态性可能对2型糖尿病有保护作用（diabologia, in press）。我们还发现Gln27Glu β2肾上腺素能受体变异与皮下脂肪堆积引起的肥胖有关（Biochem Biophys comm258: 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).