Mapping Genes for Nephropathy in Type 2 Diabetes

有强有力的证据表明，遗传易感性在糖尿病肾病的发展中是必要的。到目前为止，我们的研究表明，在1型糖尿病和2型糖尿病中，与糖尿病肾病易感性相关的基因可能不同。这项拟议的研究旨在确定染色体7q上的一个假定基因，该基因似乎特定地与2型糖尿病患者患糖尿病肾病的易感性有关。此外，我们还将寻找包含2型糖尿病肾病主要易感基因的其他染色体区域。该研究设计基于与糖尿病肾病(DSP)不一致的2型糖尿病同胞配对。这些家系将用于连锁分析以及使用同胞传递不平衡检验(S-TDT)方法进行关联研究。拟议研究的具体目标是：1)建立两个符合2型糖尿病和糖尿病肾病的同胞对小组：已经招募了大家庭筛查小组进行进一步检查，以增加肾病诊断的特异性；将招募至少200个具有糖尿病肾病核心家庭的扩展小组，以及糖尿病肾病遗传学研究的病例组和对照小组。2)检查染色体7q上有希望的染色体区域，以寻找与2型糖尿病肾病易感性有关的基因；3)使用染色体特异遗传标记组在数字信号处理器组中寻找与糖尿病肾病分离的其他染色体区域；4)通过在数字信号处理器组中寻找额外标记的基因分型，缩小有连锁证据的染色体区域，并在最有希望的区域启动糖尿病肾病易感基因的定位克隆。鉴于目前美国人群中因2型糖尿病导致的终末期肾功能衰竭的“流行病”，这项研究具有重大意义。此外，根据我们现有的数据，在2型糖尿病中识别糖尿病肾病易感性基因的可能性非常高。该方案的创新之处在于利用DSPs研究设计对2型糖尿病患者糖尿病肾病的遗传易感性进行了研究。这项研究设计似乎比传统的ASP(受影响的同胞对)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.