GENETICS OF NONINSULIN DEPENDENT DIABETES MELLITUS

说明：非胰岛素依赖型糖尿病（NIDDM）有很强的 家族成分，但无论是生理或候选基因的研究 确定了从正常葡萄糖稳态到 易患糖尿病的个体。 申请人提出了一种基因 一种定位NIDDM易感基因的方法，其目标是 定义NIDDM发病机制。 在正在进行的19个多重家族的研究中， 根据统一的标准确定，他们确定了几个地区， 可能的兴趣包括NIDDM和禁食的不同潜在位点 在多点分析中接近统计学显著性的葡萄糖。 然而，在两点分析中，没有一个区域在家庭中达到显著性， 这表明一个单一的基因座不太可能解释超过70%的家庭， 在这个统一的人口。 申请人建议继续进行研究，以确定主要的 通过增加研究的功效在NIDDM家族亚群中的遗传位点 在一个大大扩大，但类似确定的家庭集，不包括已知的 NIDDM表型的原因，测试推定的易感基因座， 在一个独立的家系队列中的连锁，并通过关联，并通过 将最新的数据分析方法应用于这一扩大的日期集。 具体来说，他们建议完成10 cM的基因组筛选， 在62个家系（43个新家系，464个核心成员）中， 家庭成员）。 将进一步评价显示可能连锁的标记 通过（1）键入剩余的家庭成员，（2）键入紧密间隔的相邻 标记，以及（3）通过在一组独立的家庭中测试连锁， 230个同胞对。 将使用2点和多点参数和同胞分析数据 配对方法 遗传亚群的证据将被寻找， 通过混合和根据发病年龄对家庭进行分层来标记， 肥胖 将通过分子生物学方法检测早发性（MODY-3）突变。 筛选 申请人将寻找控制中间体的基因座， 空腹胰岛素表型、胰岛素分泌和空腹和 使用多点定量性状分析的攻毒后血糖 非糖尿病家庭成员

DESCRIPTION: Non-insulin dependent diabetes mellitus (NIDDM) has a strong familial component, but neither physiologic nor candidate gene studies have identified the events that lead from normal glucose homeostasis to the diabetic state in predisposed individuals. The applicants propose a genetic approach to localize genes that predispose to NIDDM with the goal of defining NIDDM pathogenesis. In ongoing studies of 19 multiplex families ascertained under uniform criteria, they identified several regions of possible interest including different potential loci for NIDDM and fasting glucose which approach statistical significance on multipoint analysis. However, no region achieves significance in families on two-point analysis, suggesting that a single locus is unlikely to explain over 70% of families in this uniform population. The applicants propose a continuation of studies aimed at identifying major genetic loci in subsets of NIDDM families by increasing the power of studies in a greatly expanded but similarly ascertained family set, excluding known causes of the NIDDM phenotype, testing putative susceptibility loci by linkage in an independent pedigree cohort and by association, and by applying the most recent data analysis methods to this expanded date set. Specifically, they propose to complete a 10 cM genome screen with highly informative markers in key members of 62 families (43 new families with 464 family members). Markers showing possible linkage will be further evaluated by (1) typing remaining family members, (2) typing closely spaced adjacent markers, and (3) by testing linkage in an independent set of families with 230 sib pairs. Data will be analyzed using both 2-point and multipoint parametric and sib pair methods. Evidence for genetic subgroups will be sought for linked markers by admixture and by stratifying families based on age of onset and obesity. Early onset (MODY-3) mutations will be detected by molecular screening. The applicants will search for loci controlling intermediate phenotypes of fasting insulin, insulin secretion, and fasting and post-challenge glucose using multipoint quantitative trait analysis in nondiabetic family members.