GENETIC REGULATION OF RENAL DISEASE PROGRESSION

流行病学数据表明，进行性肾病（CRF）是由遗传决定的。 然而，CRF是复杂的，多个基因导致疾病表型。 糖尿病肾病是工业化国家CRF的主要原因，占事件ESRD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2型糖尿病肾病易感基因的多重家庭。 通过将表型分解为中间的数量性状，可以促进对CRF等复杂疾病的剖析。 我们假设，分别预测和测量糖尿病肾病进展的中间CRF表型、蛋白尿和GFR变化是遗传的。 结合正在进行的横断面家族研究的ESRD全基因组扫描，我们将确定控制CRF表型的连续定量组分的基因座。 数量性状可能比ESRD等离散诊断类别更接近突变基因。 此外，调节中间表型的基因可能在数量上更少，环境因素混淆分析的可能性更小。 我们的方法是前瞻性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。 具体目标：1.为了表征蛋白尿和GFR变化的中间表型，将对因2型糖尿病肾病导致ESRD的索引患者的糖尿病兄弟姐妹进行仔细的表型分析，伴（一致）或不伴（不一致）肾脏疾病。 未受糖尿病或肾脏疾病影响的同胞和可能的父母将作为对照。 预计队列将包括250名同胞和另外100名未受糖尿病影响的家庭成员。 主要、依赖性结局将包括每6个月测量一次的尿白蛋白排泄和GFR。 还将在该人群和每个个体基因分型中确定特定的社会经济、人口统计学、环境和临床变量。 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通过ESRD基因组扫描或通过与模型生物体中控制蛋白尿的区域的同线性鉴定的候选区域。 基于兄弟对的无模型方法将被强调，并通过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.