Genetic analysis of type II diabetes in Finnish populati

芬兰人群 II 型糖尿病的遗传分析

• 批准号: 6829436
• 负责人: FRANCIS S. COLLINS
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6829436
• 关键词: Scandinavian; biotechnology; chromosome aberrations; clinical research; diabetes mellitus genetics; diabetic retinopathy; family genetics; genetic promoter element; genetic susceptibility; genotype; human genetic material tag; human population genetics; human subject; linkage mapping; mass spectrometry; matrix assisted laser desorption ionization; noninsulin dependent diabetes mellitus; single nucleotide polymorphism

Type 2 diabetes (T2D) is one of the major causes of morbidity and mortality in the developed world. While environmental factors such as diet play a significant role, familial clustering indicates that there must be significant genetic suscepibility factors at work. For ten years we have been engaged in a large collaborative study entitled FUSION (Finland - United States Investigation of NIDDM), in which over 5000 individuals with diabetes (and suitable controls) from Finland are being studied, using careful phenotyping of diabetes and diabetes associated traits, and genome-wide genetic linkage and association. We have developed new approaches in the laboratory to achieve high throughput microsatellite and SNP genotyping, which has allowed the collection of a massive amount of data from these Finnish diabetics and their families. During FY 2002 this project has made significant progress, focusing on fine mapping of regions on chromosomes 6, 11, 14, 20, and 22 where prior linkage analyses have shown evidence for susceptibility genes for diabetes or related traits. In particular, we have identified a small region on chromosome 22 which contains a haplotype conferring an odds ratio of 1.5 for T2D, and which has been confirmed and narrowed by studying a West African diabetic population. On the long arm of chromosome 20, a region where a dozen groups have independently shown evidence of linkage for T2D, we have identified susceptibility variants in a small region of the promoter of an excellent candidate gene. These variants seem to account for most or all of the linkage signal, and have just been confirmed in an independent study of Ashkenazi diabetics. We have also identified an attractive candidate gene on chromosome 11 that carries a P-value <0.001 for T2D association. With this kind of substantial progress, and the emerging haplotype map of the human genome to guide additional SNP selection, we are confident that the "geneticist's nightmare" (Jim Neel's description of the genetics of diabetes) may be coming to an end.

2型糖尿病（T2D）是发达国家发病率和死亡率的主要原因之一。尽管饮食等环境因素起着重要作用，但家族性聚类表明，工作中必须有重要的遗传可疑因素。十年来，我们一直从事一项题为“融合 - 美国对NIDDM的调查”的大型合作研究，其中使用糖尿病和糖尿病相关的糖尿病表型来研究芬兰的5000多名糖尿病患者（和适当的对照）。特征和全基因组遗传联系与关联。我们已经开发了实验室中的新方法，以实现高通量的微卫星和SNP基因分型，从而允许从这些芬兰糖尿病患者及其家人那里收集大量数据。在2002财年期间，该项目取得了重大进展，重点是对6、11、14、20和22染色体区域的精细映射，其中先前的链接分析显示了证据证明了糖尿病或相关性状的易感基因的证据。特别是，我们已经确定了22号染色体上的一个小区域，该区域包含单倍型，T2D的优势比为1.5，并且通过研究西非糖尿病人群来确认和缩小。在20号染色体的长臂上，该区域具有独立的T2D链接证据的区域，我们已经确定了优秀候选基因启动子的一小部分中的敏感性变体。这些变体似乎解释了大多数或全部连锁信号，并且刚刚在Ashkenazi糖尿病患者的独立研究中得到了证实。我们还确定了11号染色体上有吸引力的候选基因，该基因的P值<0.001对于T2D关联。随着这种实质性进展，人类基因组的新兴单倍型图可以指导其他SNP选择，我们相信“遗传学家的噩梦”（吉姆·尼尔（Jim Neel）对糖尿病遗传学的描述）可能会结束。