GENETICS OF NONINSULIN DEPENDENT DIABETES MELLITUS

描述：非胰岛素依赖型糖尿病(NIDDM)有很强的 家族性成分，但生理学和候选基因研究都没有 确定了导致正常血糖动态平衡到 易患糖尿病的个体的糖尿病状态。申请者提出了一种基因 定位易患NIDDM的基因的方法，目标是 明确NIDDM的发病机制。正在进行的对19个多户型家庭的研究 在统一的标准下，他们确定了几个区域 可能的兴趣包括NIDDM和空腹的不同潜在基因座 葡萄糖在多点分析中接近统计学意义。 然而，没有一个地区的家庭在两点分析上达到显著水平， 这表明单个基因座不太可能解释超过70%的家庭 在这个统一的人群中。 申请者提议继续研究，目的是确定主要专业 通过增加研究力量来研究NIDDM家系亚群中的遗传位点 在一个大大扩展但相似确定的家庭集合中，不包括已知的 NIDDM表型的原因，通过检测推测的易感基因座 在一个独立的系谱队列中，通过关联和通过 将最新的数据分析方法应用于此扩展数据集。 具体地说，他们建议完成一个10 cM的基因组筛查，高度 62个家庭关键成员的信息性标记(43个新家庭，464个 家庭成员)。将对显示可能连锁的标记进行进一步评估 通过(1)输入剩余的家庭成员，(2)输入间隔很近的相邻成员 标记，以及(3)在一组独立的家系中测试连锁 230对兄弟姐妹。 数据将使用两点和多点参数和SIB进行分析 配对方法。将寻找遗传亚群的证据以寻找关联 按混合物和根据发病年龄和年龄对家庭进行分层的标记物 肥胖。早发性(MODY-3)突变将通过分子检测 放映。申请者将寻找控制中间体的基因座。 空腹胰岛素、胰岛素分泌和空腹及 攻击后血糖的多点数量性状分析 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.