Genetic Association Studies of Diabetic Nephropathy

描述（由申请人提供）：糖尿病肾病（DN）是糖尿病的一种破坏性并发症，是美国终末期肾脏疾病的主要原因。目前的治疗策略只能减缓这种疾病的进展，而不是预防或逆转这种疾病。虽然严格控制血糖可降低包括DN在内的糖尿病并发症的发生率，但对DN的易感性存在差异，这不能单独用血糖控制来解释。对兄弟姐妹患有糖尿病的家庭的研究强烈表明遗传因素在DN的发展中起作用；然而，影响DN风险的具体遗传因素在很大程度上仍然未知。揭示DN风险的遗传基础有望更好地理解DN的生物学发病机制，并确定预防和治疗的新靶点。遗传研究的进步使全基因组分析研究（GWAS）成为可能，它提供了对整个基因组的无偏扫描，能够检测适度大小的影响。DN的初始GWAS确定了几个潜在的风险位点，但这些研究受到低变异密度或样本量太小而无法检测适度影响的阻碍。迄今为止最大的DN GWAS是一个国际T1D队列联盟，无法复制大多数先前与DN相关的遗传关联；随后的荟萃分析确定了GWAS与ESRD的几种关联。该分析的一个值得注意的发现是，与传统的基于蛋白尿的DN定义相比，使用更严格的ESRD表型，明显存在更强的遗传关联。该项目将建立在目前扩大的GWAS工作的基础上，由青少年糖尿病研究基金会资助，总计约20,000例病例和对照，通过使用替代表型定义，评估定量DN相关特征和限制分析极端表型来探索发现的信号。此外，将使用最新的基因负担测试来评估不常见和罕见的变异，该测试将基因内的所有变异统称为一组。最后，我们横断面分析的结果将是

DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) is a devastating complication of diabetes, and the leading cause of end-stage renal disease in the United States. Current treatment strategies only slow progression of, rather than prevent or reverse, this disease. Although tight control of blood glucose reduces the rate of diabetic complications including DN, there is variability in susceptibility to DN that is not explained by glycemic contro alone. Studies of families of siblings with diabetes strongly suggest a role for heritable factors n the development of DN; however, the specific genetic factors influencing DN risk remain largely unknown. Uncovering the genetic basis of DN risk holds the promise of better understanding the biology of the pathogenesis of DN, and identifying novel targets for prevention and treatment. Advances in genetic research have enabled genome-wide analysis studies (GWAS), which offer an unbiased scan of the entire genome, powered to detect effects of modest size. Initial GWAS of DN identified several potential risk loci, but these studies were hindered by low variant densities or sample sizes too small to detect modest effects. The largest GWAS of DN to date, an international consortium of T1D cohorts, was unable to replicate most of the previously associated genetic associations for DN; a subsequent meta-analysis identified several GWAS associations for ESRD. A notable finding of this analysis was that stronger genetic associations were apparent using the more stringent ESRD phenotype compared to the traditional proteinuria-based definition of DN. This project will build on a current expanded GWAS effort, totaling ~20,000 cases and controls, funded by the Juvenile Diabetes Research Foundation, to explore signals uncovered by using alternate phenotype definitions, evaluating quantitative DN- associated traits, and restricting analysis to extreme phenotypes. Additionally, uncommon and rare variants will be evaluated using the most current gene-burden tests, which group all variants within a gene collectively. Finally, the results from our cross-sectional analysis will be integrated with longitudinal data from our collaborators to further explore suggestive signals; thi data will be further leveraged to explore the causality of heritable risk factors (e.g. obesity or hypertension) with epidemiologic association with DN. The advanced analytic approaches outlined in this proposal have the promise to uncover new genetic variants associated with development of renal disease in patients with T1D.