METABOLIC BASIS OF NIDDM-- A SIB-PAIR ANALYSIS

描述：此修订申请旨在续签一个正在进行的项目 建议确定相对胰岛素缺乏基因座的代谢基础 通过探索2型糖尿病的遗传基础。这件事的重点是 申请对象是德系犹太人，这是一个基因上截然不同的高加索人群。 需要检验的假设是，几个主要基因对类型有影响 2糖尿病。共有289个家庭有两个或更多受影响的个人被感染 在以色列收集的。初始基因组扫描，STR标记位于9.5 cM 时间间隔已完成。六个染色体区域，名义上有证据 鉴定出连锁(多点LOD大于1.0)。三个具体目标 都被提出了。首先，他们将通过以下方式完成家庭中的连锁分析 用更密集的标记对6个地区的其他个体进行基因分型。 此外，还将对非糖尿病对照组(n=150)进行基因分型以进行关联。 学习。第二，基于德系犹太人染色体20Q的连锁结果 在芬兰的Fusion研究中，与MSP的协作关联研究 并将进行SNP标记以缩小区域范围。此外，基于 连锁和关联结果，其他染色体区域可能被精细定位 对无血缘关系的个体进行LD分析。这将需要建造 这些地区的物理地图，在30kb处识别多达300个SNP 间隔时间。糖尿病和对照组以及不和谐的兄弟姐妹将进行基因分型。因为 在其独特的遗传构成中，德系犹太人可能代表了最好的群体 对一种复杂疾病进行这种类型的分析的患者。 第三，通过LD、位置克隆从任何区域缩小到小于1Mb 将会被承担。候选基因将通过以下方式在该区域内识别 完成基因组测序，然后进行突变分析。一旦 在这个高加索人群中发现了基因，然后可以对该基因进行评估 它在其他种族群体中对糖尿病的贡献。在过去3年内 该组织已经更接近他们最初宣布的确定 2型糖尿病基因。确定这些基因缺陷的性质将增强 为实现确定代谢基础的长期目标所作的努力 2型糖尿病患者。通过对其基因的识别来认识其病因 这将有助于早期诊断、治疗和预防。这项资助旨在通过阐明T2 DM的遗传基础来确定T2 DM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.