METABOLIC BASIS OF NIDDM-- A SIB-PAIR ANALYSIS

描述：此修订后的申请旨在更新一个正在进行的项目， 建议定义相对胰岛素缺乏位点的代谢基础， 2型糖尿病的遗传基础。的重点 申请是在德系犹太人，一个基因独特的高加索人口。 有待验证的假设是，少数几个主要基因是负责类型 2糖尿病.共有289个家庭有两个或两个以上受影响的人， 收藏于以色列使用9.5 cM STR标记进行初始基因组扫描 间隔已经完成。六个染色体区域有名义上的证据表明 连锁（多点LOD大于1.0）。三个具体目标 被提议。首先，他们将完成家庭中的连锁分析， 在6个区域用更密集的标记对另外的个体进行基因分型。 此外，将对非糖尿病对照组（n=150）进行基因分型， 问题研究第二，基于德系犹太人染色体20 q的连锁结果， FUSION研究的芬兰人中，与MSP的协作关联研究 并将进行SNP标记以缩小区域。另外基于 连锁和关联的结果，其他染色体区域可以精细定位 在无关个体中进行LD分析。这将需要建造 该地区的物理地图，识别多达300个SNP在30 kb 的间隔将对糖尿病和对照以及不一致的同胞进行基因分型。因为 德系犹太人独特的基因组成， 对复杂疾病进行这种类型的分析。 第三，从通过LD缩小到小于1Mb的任何区域，定位克隆 将进行。候选基因将通过以下方法在区域内鉴定： 完成基因组测序，然后进行突变分析。一旦 在这个高加索人群体中鉴定出基因，然后可以评估该基因的 它对其他种族糖尿病的影响。在过去3年中 专家组已接近其最初宣布的目标， 2型糖尿病的基因确定这些基因缺陷的性质将提高 努力实现确定代谢基础的长期目标 2型糖尿病通过确定其遗传学来了解病因 基础将有助于早期诊断，治疗和预防。 该基金旨在通过阐明其遗传基础来确定T2DM代谢缺陷的病因。

DESCRIPTION: This revised application seeks to renew an ongoing project that proposes to define the metabolic basis for the relative insulin deficiency loci of type 2 diabetes by exploring its genetic basis. The focus of this application is on Ashkenazi Jews, a genetically distinct Caucasian Population. The hypothesis to be tested is that a few major genes are responsible for type 2 diabetes. A total of 289 families with two or more affected individuals were collected in Israel. An initial genome scan with STR markers at 9.5 cM intervals was completed. Six chromosomal regions with nominal evidence for linkage (multipoint LOD greater than 1.0) were identified. Three specific aims are proposed. First, they will complete linkage analysis in families by genotyping additional individuals with more dense markers across the 6 regions. In addition, nondiabetic controls (n=150) will be genotyped for association studies. Second, based on linkage results for chromosome 20q in Ashkenazi Jews and in Finns of the FUSION study, collaborative association studies with MSP and SNP markers will be conducted to narrow the region. In addition, based on linkage and association results, other chromosomal regions may be fine mapped by LD analysis in unrelated individuals. This will require construction of physical maps on the regions, identification of as many as 300 SNPs at 30 kb intervals. Diabetes and controls and discordant sibs will be genotyped. Because of its unique genetic composition, Ashkenazi Jews may represent the best cohort of patients in which to conduct this type of analysis for a complex disease. Third, from any region narrowed to less than 1 Mb by LD, positional cloning will be undertaken. Candidate genes will be identified within the region by completion of genomic sequencing, followed by mutational analysis. Once the gene is identified in this Caucasian group, the gene can then be assessed for its contribution to diabetes in other racial groups. In the preceding 3 years the group has moved closer to their original stated goal of identification of type 2 diabetes genes. Defining the nature of these gene defects will enhance efforts toward achieving the long-range goal of determining the metabolic basis of type 2 diabetes. Knowledge of the etiology through identifying its genetic basis will serve to facilitate early diagnosis, treatment and prevention. This grant seeks to define the etiology of the metabolic defects in T2DM by clarifying its genetic basis.