METABOLIC BASIS OF NIDDM--A SIB PAIR ANALYSIS

描述（改编自申请人摘要）：一般公认 NIDDM不是一种单一的疾病，而是一组异质性疾病， 葡萄糖耐受不良的代谢紊乱。 精确的新陈代谢 缺陷仍然是未知的，缺陷胰岛素的相对首要性 胰岛素分泌与胰岛素作用缺陷仍有争议 NIDDM的病因可能有助于早期诊断， 治疗和预防。 这项补助金旨在确定病因的 通过阐明NIDDM的遗传基础，研究NIDDM的代谢缺陷。 的焦点 这是德系犹太人，一个独特的民族群体， 基因上相对同质 有待检验的假设是， NIDDM中的代谢缺陷是有限数量的 糖尿病基因，每一个都有中等的影响，而且检测的能力 在德系犹太人这样的同质群体中， 犹太人 NIDDM基因将在该组中鉴定如下：1） 将收集400名受影响患者的临床/人口统计学数据和基因组DNA 德系犹太同胞对（800名NIDDM受试者），通过糖尿病 Haddasah医院诊所和联合国普通疾病基金诊所 以色列的历史 入学标准包括要求， 受影响的一对中至少有一个成员必须在55岁之前被诊断出来， 增加遗传风险。 这一人群相对较高， NIDDM的患病率，目前的基因库是从一个小的 700年前的原始人口。 此外，还可以轻松访问 在以色列相对稳定的人群中， 环境背景，以及糖尿病治疗集中在 （2）专业化程度低;（3）。 全基因组搜索 （定位克隆）将使用基于以下内容的方案完成： 简单重复序列多态性标记（SSRPs）的多重PCR， 自动DNA片段分析 将开发SSRP用于多重PCR 荧光标记引物和自动评分，以确保最大 人类基因组的可能覆盖范围，间隔不大于10 cM。 将使用按州划分的非参数恒等式进行数据分析 (IBS)分析所有受影响的同胞对。 任何符合 随访标准（标称p值小于0.05），将遵循 随访分析，包括参数分析和侧翼分型 标记。 （德系犹太人的积极发现将在其他地区复制。 种族/族裔群体）。通过上述研究，他预计 在四年内他将收集到一个有价值的基因 用于鉴定NIDDM基因的资源，并将鉴定区域 糖尿病基因所在的基因组。 界定这些问题的性质 基因缺陷将增强实现他的长期目标的努力， 确定NIDDM的代谢基础。

DESCRIPTION (Adapted from applicant's abstract): It is generally recognized that NIDDM is not a single disease, but rather a heterogeneous group of metabolic disorders that share glucose intolerance. The precise metabolic defects are still unknown, and the relative primacy of defective insulin secretion vs. defective insulin action is still controversial Knowledge of the etiology of NIDDM would likely serve to facilitate early diagnosis, treatment, and prevention. This grant seeks to define the etiology of the metabolic defects in NIDDM by clarifying their genetic basis. The focus of this grant is on Ashkenazi Jews, a distinct ethnic group which is genetically, relatively homogeneous. The hypothesis to be tested is that the metabolic defects in NIDDM are the result of a limited number of diabetogenic genes, each with moderate effect, and that the power to detect these genes is greater in a homogeneous population such as the Ashkenazi Jews. NIDDM genes will be identified in this group as follows: 1) Clinical/demographic data, and genomic DNA will be collected on 400 affected Ashkenazi Jewish sib pairs (800 NIDDM subjects), through the Diabetes Clinics of the Haddasah Hospital and of the General Sick Fund of the Histadrut in Israel. Admission criteria includes the requirement that at least one member of an affected pair must have been diagnosed before age 55, to enhance the genetic risk. This population has a relatively high prevalence of NIDDM, and the current gene pool developed from a small initial population about 700 years ago. Furthermore, there is easy access to patients in Israel in a relatively stable population, with similar environmental backgrounds, and where diabetes treatment is concentrated in a limited number of specialized centers; 2). A whole genome search (positional cloning) will be accomplished using a protocol based on multiplex PCR of simple sequence repeat polymorphic markers (SSRPs) and automated DNA fragment analysis. SSRPs will be developed for multiplex PCR with fluorescent labeled primers and automated scoring to assure maximum possible coverage of the human genome with intervals no larger than 10 cM. Data analysis will be conducted using the nonparametric identity by state (IBS) analysis on all affected sib pairs. Any locus which meets the follow-up criteria (nominal p-value less than 0.05), will be subject to follow-up analysis including parametric analyses and typing of flanking markers. (Positive findings in Ashkenazi will be replicated in other racial/ethnic groups.) Through the studies outlined above, he anticipates that within a four year period he will have collected a valuable genetic resource for identification of NIDDM genes and will have identified regions of the genome where diabetogenic genes reside. Defining the nature of these gene defects will enhance efforts toward achieving his long range goal of determining the metabolic basis of NIDDM.