Mapping genes for proteinuria in type II diabetes

描述（由申请人提供）：遗传易感性似乎对2型糖尿病（T2DM）蛋白尿的发展至关重要。在最近的一项家庭研究中，我们发现了尿白蛋白排泄变异与染色体区域5q、7q、21p和22q之间联系的证据。我们假设这些染色体区域含有促进2型糖尿病蛋白尿发展的基因。在这个项目中，我们的目标是确定位于这些关键染色体区域的蛋白尿易感基因。具体目的是：1)在230例蛋白尿患者和230例超对照（正常蛋白尿和长期T2DM患者）筛选组中，在检测蛋白尿相关单倍型的四个关键染色体区域中鉴定-6200个信息性snp，并对其进行基因分型。2)对扩展组（470例和470例超级对照）进行-780个蛋白尿相关snp的基因分型，以确认筛选组中发现的蛋白尿相关单倍型。3)通过生物信息学和分子技术研究已确诊的蛋白尿相关单倍体块，鉴定蛋白尿易感基因。4)通过在一组病例和对照中对这些基因座进行测序，对筛选和扩展面板进行基因分型，以确定蛋白尿易感基因的因果多态性，并验证Joslin家族收集中的发现。在这项研究中，我们将采用多学科方法，包括与生物信息学、人类遗传学和临床研究专家的互动，以确定与蛋白尿易感性相关的基因，蛋白尿是T2DM终末期肾脏疾病的一个强有力的预测因子。一种新的两阶段基因分型方法将被用于通过关联图谱识别基因，并在欧洲多样性小组和发现这种联系的家庭中进行验证。这些验证方法是本提案的独特之处，将有助于消除关联的假阳性结果。乔斯林诊所的独特资源将允许选择记录良好的病例和“超级控制”。经验丰富的研究团队，使用最先进的基因组方法，进一步保证了这项拟议研究的成功。此外，虽然拟议的研究旨在限制遗传和表型异质性以提高有效性，但研究结果的普遍性将通过检查多中心收集（如GoKinD和FIND）来验证。

DESCRIPTION (provided by applicant): Genetic susceptibility appears to be critical for the development of proteinuria in type 2 diabetes (T2DM). In a recent family study we found evidence for linkage between variation in urinary albumin excretion and chromosomal regions 5q, 7q, 21 p, and 22q. We postulate that these chromosomal regions harbor genes contributing to the development of proteinuria in T2DM. In this project we aim to identify the proteinuria susceptibility genes located in these critical chromosomal regions. The specific aims are to: 1) Identify -6200 informative SNPs in the four critical chromosomal regions for detecting proteinuria-associated haplotypes and genotype them in the screening panel of 230 cases with proteinuria and 230 super-controls (patients with normoalbuminuria and long duration of T2DM). 2) Genotype the extension panel (470 cases and 470 super-controls) for -780 proteinuria associated SNPs to confirm the proteinuria-associated haplotypes found in the screening panel. 3) Investigate the confirmed proteinuria-associated haplo-blocks to identify proteinuria susceptibility genes through bioinformatics and molecular protocols. 4) Identify the causal polymorphisms in proteinuria-susceptibility genes by sequencing these loci in a group of cases and controls and genotyping the screening and extension panels for potential causal polymorphisms and validating the findings in the Joslin Family Collection. In the proposed research we will use a multidisciplinary approach including interactions with experts in bioinformatics, human genetics and clinical research to identify genes responsible for susceptibility to proteinuria, a phenotype that is a strong predictor of end stage renal disease in T2DM. A novel two-stage genotyping approach will be used to identify the genes through association mapping with validation in a European Diversity Panel and in families in which the linkage was discovered. These validation approaches are unique features of this proposal, and will help eliminate the false positive findings of the association. The unique resources of the Joslin Clinic will allow selection of well-documented cases and also "super controls". The experienced team of investigators, using state-of-the-art genomic approaches, further assures the success of this proposed research. Furthermore while the proposed study aims to limit genetic and phenotypic heterogeneity to increase effectiveness, the generalizability of the findings will be verified by examining multi-center collections such as GoKinD and FIND.