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

使用受影响的同胞对分析鉴定日本人 2 型糖尿病的易感基因

基本信息

批准号：
09557078
负责人：
KADOWAKI Takashi
金额：
$ 7.62万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09557078/
关键词：
type 2 diabetes a polygenic, multifactorial disorder affected sib-pair analysis susceptibility loci PPARγ insulin resistance high-fat diet thrifty genes β2 adrenergic receptor Common NIDDM 全ゲノムマッピング罹患同胞対候補遺伝子アプローチインスリン分泌低下ア

项目摘要

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).

有人认为，大多数 2 型糖尿病可能是一种多基因、多因素疾病，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同胞对分析来鉴定易感基因，该分析被认为适合检测此类多基因、多因素疾病的易感位点。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。整个基因组将被研究，几个位点将在 2000 财年末绘制图谱。我们还尝试利用候选基因的群体关联研究来检测 2 型糖尿病的易感基因。我们培育了 PPARγ 缺陷小鼠，以研究 PPARγ 在高脂肪饮食下脂肪细胞肥大和胰岛素抵抗中的生理作用。杂合 PPARγ 缺陷小鼠在高脂肪饮食下免受脂肪堆积、体重增加和胰岛素抵抗（Mol Cell 4: 597-609, 1999）。因此，我们提出 PPARγ 是重要的节俭基因之一，与“多因素”2 型糖尿病相关。为了研究 PPARγ 是否作为人类的节俭基因，我们研究了 PPARγ 基因中 Pro12Ala 多态性与 2 型糖尿病之间的关联。在肥胖受试者中，PPARγ2 基因的 Alal2 等位基因可防止胰岛素抵抗。 Alal2 等位基因在 2 型糖尿病受试者中的出现频率明显低于非糖尿病受试者，表明 PPARγ2 中的 Alal2 多态性可以预防 2 型糖尿病（Diabetologia，出版中）。我们还发现 Gln27Glu β2 肾上腺素能受体变体与皮下脂肪堆积导致的肥胖相关（Biochem Biophys Res Commun 258： 138-140，1999）。