Genetic Association Studies of Diabetic Nephropathy

描述(申请人提供)：糖尿病肾病是糖尿病的一种破坏性并发症，也是美国终末期肾病的主要原因。目前的治疗策略只减缓这种疾病的进展，而不是预防或逆转。尽管严格控制血糖可降低包括糖尿病肾病在内的糖尿病并发症的发生率，但糖尿病肾病的易感性存在变异性，仅靠血糖控制并不能解释这一点。对糖尿病兄弟姐妹家庭的研究有力地表明了遗传因素在糖尿病肾病发生中的作用；然而，影响糖尿病肾病风险的具体遗传因素在很大程度上仍不清楚。揭示糖尿病肾病风险的遗传基础有望更好地理解糖尿病肾病发病的生物学机制，并确定预防和治疗的新靶点。基因研究的进步使全基因组分析研究(GWAS)成为可能，这种研究提供了对整个基因组的无偏见扫描，有能力检测适度大小的影响。最初的糖尿病肾病研究确定了几个潜在的风险基因座，但这些研究因变异密度低或样本量太小而无法检测到适度的影响。迄今为止最大的糖尿病肾病GWAS是一个由T1D队列组成的国际联盟，它无法复制大多数以前与糖尿病肾病相关的遗传关联；随后的荟萃分析发现了几个与终末期肾病相关的GWAS关联。这项分析的一个值得注意的发现是，与传统的基于蛋白尿的糖尿病肾病定义相比，使用更严格的ESRD表型更明显地具有更强的遗传相关性。该项目将建立在目前扩大的GWAS努力的基础上，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，以探索通过使用替代表型定义、评估量化的糖尿病肾病相关特征以及将分析限制在极端表型上所发现的信号。此外，不常见和罕见的变异将使用最新的基因负担测试进行评估，该测试将所有变异集中在一个基因内。最后，我们横截面分析的结果将是 整合来自我们合作者的纵向数据以进一步探索提示信号；这些数据将被进一步利用来探索可遗传风险因素(例如肥胖或高血压)与糖尿病肾病的流行病学关联的因果关系。这项提案中概述的先进分析方法有望发现与T1D患者肾脏疾病发展相关的新基因变异。

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.