GENETIC REGULATION OF RENAL DISEASE PROGRESSION

流行病学数据表明，进行性肾病(CRF)是由基因决定的。然而，慢性肾功能衰竭是复杂的，有多个基因参与疾病表型。糖尿病肾病是工业化世界中CRF的主要原因，占终末期肾病病例的40%-50%。为了限制遗传异质性，我们启动了一项资助的多中心研究，以确定多个家庭中的2型糖尿病肾病易感基因。解剖复杂的疾病，如慢性肾功能衰竭，可以通过将表型解构为中间的数量性状来促进。我们假设中间CRF表型、蛋白尿和GFR改变是遗传的，它们分别预测和衡量糖尿病肾病的进展。结合正在进行的横断面家系研究的ESRD全基因组扫描，我们将识别控制CRF表型的连续、定量成分的基因座。数量性状可能更接近突变基因，而不是像ESRD这样的离散诊断类别。此外，调节中间表型的基因数量可能会更少，环境因素对分析的影响也会更小。我们的方法是前瞻性地研究终末期肾病先证者的同胞，分离调节蛋白尿和GFR下降的基因座。具体目的：1.为了表征蛋白尿的中间表型和GFR的变化，对2型糖尿病肾病所致终末期肾病(ESRD)患者的兄弟姐妹进行纵向追踪，包括有(协调性)或无(协调性)肾脏病变的表型。SIB，以及可能的父母，不受糖尿病或肾脏疾病影响的将作为对照。预计的队列将包括250名兄弟姐妹和另外100名未受糖尿病影响的家庭成员。主要的依赖结果将包括尿白蛋白排泄量和每6个月测量一次的GFR。还将确定特定的社会经济、人口、环境和临床变量在该人群和每个个体中的基因分型。2.为了评估基因组区域与蛋白尿和GFR变化的中间、定量表型的联系，将使用分子和统计学方法来检查全基因组扫描或由ESRD基因组扫描确定的候选区域或通过与模式生物中控制蛋白尿的区域的同源性来确定。基于兄弟姐妹对的无模型方法将被强调，并用单变量和多变量方法进行分析。

Epidemiological data indicate that progressive renal disease (CRF) is genetically determined. However, CRF is complex, with multiple genes contributing to disease phenotype. Diabetic nephropathy is the leading cause of CRF in the industrialized world, accounting for 40-50 percent of incident ESRD cases. To limit genetic heterogeneity, we have initiated a funded, multicenter study to identify type 2 diabetes nephropathy susceptibility genes in multiplex families. Dissecting complex diseases, like CRF, can be facilitated by deconstructing phenotypes into intermediate, quantitative traits. We hypothesize that the intermediate CRF phenotypes, proteinuria and GFR change, which respectively predict and measure progression of diabetic nephropathy, are inherited. In conjunction with an ESRD whole genome scan from the ongoing, cross-sectional family study, we will identify loci which control continuous, quantitative components of the CRF phenotype. Quantitative traits may be more proximal to mutated genes than a discrete diagnostic category like ESRD. In addition, genes regulating intermediate phenotypes are likely to be fewer in number, with less environmental factors confounding the analysis. Our approach is to prospectively study sibs of ESRD probands, to isolate loci that regulate proteinuria and GFR decline. Specific aims: 1. To characterize intermediate phenotypes of proteinuria and GFR change, carefully phenotyped diabetic siblings of index patients with ESRD due to type 2 diabetic nephropathy, with (concordant) or without (discordant) kidney disease, will be followed longitudinally. Sibs, and where possible parents, unaffected by diabetes or renal disease will serve as controls. The projected cohort will include 250 sibships and an additional 100 family members unaffected by diabetes. Primary, dependent outcomes will include urinary albumin excretion and GFR measured every 6 months. Specific socioeconomic, demographic, environmental and clinical variables will also be ascertained in this population and each individual genotyped. 2. To assess linkage of genomic regions with the intermediate, quantitative phenotypes of proteinuria and GFR change, molecular and statistical methods will be used to examine either a genome-wide scan or candidate regions identified by the ESRD genome scan or by synteny with regions that control proteinuria in model organisms. Model-free approaches based on sibling pairs will be emphasized and analyzed by both univariate and multivariate approaches.