GENETICS OF TYPE II DIABETES

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。一个显着的非胰岛素依赖型糖尿病（NIDDM）的遗传易感性位点是由一个高一致性的同卵双胞胎，强大的家族聚集性，并从一个主要的疾病和中间表型的基因分离分析的证据。尽管进行了广泛的研究，但尚未确定任何诱发性生化缺陷。已知的基因位点解释了<1%的遗传性糖尿病。位置搜索策略提供了一个强大的替代方法来确定糖尿病易感基因和了解NIDDM的早期病理生理学阶段。我们的数据否定了NIDDM是一种单一的高发病率的同质性疾病的假设。这一建议是我们寻求NIDDM发病机制的重要遗传基础的逻辑演变，考虑到我们的基因组筛选结果，我们大大扩展的谱系资源，人类连锁和物理图谱的巨大进步，以及复杂疾病分析中不断发展的想法。我们假设，NIDDM易感性是由一个基因座与主要临床影响的寡基因疾病模型，这个基因座将导致一个可识别的表型亚组的家系与一个强大的家族史的NIDDM发病年龄在65岁之前。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A significant inherited susceptibility locus for non-insulin dependent diabetes (NIDDM) is suggested by a high concordance in identical twins, strong familial aggregation, and evidence from segregation analysis for a major gene for both the disease and intermediate phenotypes. Despite extensive study, no predisposing biochemical defect has been identified conclusively. Known loci explain <1% of inherited diabetes. The positional search strategy offers a powerful alternative approach to identify diabetes susceptibility genes and to understand the early stages of NIDDM pathophysiology. Our data reject the hypothesis that NIDDM represents a single homogeneous disease with high penetrance. This proposal is the logical evolution of our quest for an important genetic basis to NIDDM pathogenesis, given the results of our genome screen, our greatly expanded pedigree resource, the tremendous advances in both the human linkage and physical maps, and the evolving ideas in complex disease analysis. We hypothesize that NIDDM susceptibility is determined by a locus with major clinical impact in an oligogenic disease model, and that this locus will result in an identifiable phenotypic subgroup of pedigrees with a strong family history of NIDDM onset before age 65.