Mapping Genes for Nephropathy in Type 2 Diabetes

有强有力的证据表明，遗传易感性是糖尿病肾病的发展所必需的。 我们迄今的研究表明，1型和2型糖尿病中与糖尿病肾病易感性相关的基因可能不同。 这项研究旨在确定染色体7q上的一个推定基因，该基因似乎特别有助于2型糖尿病患者对糖尿病肾病的易感性。 此外，我们还将寻找2型糖尿病肾病的主要易感基因所在的其他染色体区域。 研究设计基于糖尿病肾病（DSP）不一致的2型糖尿病同胞对。 这些家庭将被用于连锁分析，以及使用同胞传递不平衡检验（S-TDT）方法的关联研究。 拟议研究的具体目标是：1）建立两个兄弟姐妹对小组，这两个小组对2型糖尿病一致，对糖尿病肾病（DSP）不一致：已经招募了一个由89个大家庭组成的筛查小组，以进一步检查以提高肾病诊断的特异性;将招募至少200个具有DSP的核心家庭的扩展小组，以及用于糖尿病肾病遗传学研究的病例组和对照组。2)3）在DSPs中寻找与糖尿病肾病相关的其他染色体区域;四、通过DSP的基因分型面板缩小染色体区域中具有连锁证据的区域，以确定这些区域中的其他标记，并启动易感性的定位克隆糖尿病肾病的基因在最有希望的区域。鉴于目前美国人群中2型糖尿病导致的终末期肾衰竭的"流行病"，这项研究具有重要意义。 此外，根据我们现有的数据，在2型糖尿病中鉴定糖尿病肾病易感基因的概率非常高。 该提案的创新之处在于使用DSP研究设计研究2型糖尿病患者糖尿病肾病的遗传易感性。 该研究设计似乎比传统的ASP（受累同胞对）设计更有效地检测肾病的连锁。

There is strong evidence that genetic susceptibility is necessary for the development of diabetic nephropathy. Our research so far showed that genes involved in susceptibility to diabetic nephropathy may be different in type 1 and type 2 diabetes. The proposed research aims to identify a putative gene on chromosome 7q that seems to contribute specifically to susceptibility to diabetic nephropathy in type 2 diabetes. In addition, we will search for other chromosomal regions that harbor a major susceptibility locus for diabetic nephropathy in type 2 diabetes. The study design is based on sib-pairs with type 2 diabetes that are discordant for diabetic nephropathy (DSP). These families will be used for linkage analysis as well as for association studies using the Sibling Transmission Disequilibrium Test (s-TDT) approach. The specific aims of the proposed research are: 1) To establish two panels of sibling pairs that are concordant for type 2 diabetes and discordant for diabetic nephropathy (DSP): Already recruited is a Screening Panel of 89 extended families to be examined further to increase the specificity of nephropathy diagnoses; To be recruited is an Extension Panel of at least 200 nuclear families having a DSP, and groups of cases and controls for studies of the genetics of diabetic nephropathy. 2) To examine the promising chromosomal region on chromosome 7q for a locus contributing to susceptibility to diabetic nephropathy in type 2 diabetes; 3) To search for other chromosomal regions segregating with diabetic nephropathy in the Panels of DSPs using a chromosome specific panel of genetic markers; 4) To narrow chromosomal regions with evidence of linkage by genotyping panels of DSPs for additional markers in those regions and to initiate positional cloning of susceptibility genes for diabetic nephropathy in the most promising regions. The research has great significance given the current "epidemic" of end-stage renal failure due to type 2 diabetes in the U.S. population. Further, based upon our existing data, the probability of identifying genes for susceptibility to diabetic nephropathy in type 2 diabetes is very high. The innovation of this proposal is the study of genetic susceptibility for diabetic nephropathy in type 2 diabetes using a DSPs study design. This study design seems to be more efficient in detecting linkage for nephropathy than the traditional ASP (affected sib-pair) design.