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（T2 DM）蛋白尿的发生至关重要。在最近的一项家族研究中，我们发现了尿白蛋白排泄变异与染色体区域5 q、7 q、21 p和22 q之间存在联系的证据。我们推测这些染色体区域含有导致2型糖尿病蛋白尿发生的基因。在这个项目中，我们的目标是确定蛋白尿易感基因位于这些关键的染色体区域。具体目标是：1）鉴定四个关键染色体区域中的~ 6200个信息SNP以用于检测蛋白尿相关单倍型，并在230个蛋白尿病例和230个超级对照（具有正常白蛋白尿和长期T2 DM的患者）的筛选组中对其进行基因分型。2)对延伸组（470个病例和470个超级对照）的约780个蛋白尿相关SNP进行基因分型，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生物学方法，对已证实的蛋白尿相关单倍块进行研究，以确定蛋白尿易感基因。4)通过对一组病例和对照组中的这些位点进行测序，对筛选和延伸组中潜在的因果多态性进行基因分型，并验证Joslin家族标本中的发现，从而确定蛋白尿易感基因的因果多态性。在拟议的研究中，我们将使用多学科方法，包括与生物信息学，人类遗传学和临床研究专家的互动，以确定负责蛋白尿易感性的基因，蛋白尿是T2 DM终末期肾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来确定基因，通过关联映射与验证在欧洲多样性小组和家庭中的连锁被发现。这些验证方法是本提案的独特之处，将有助于消除该关联的假阳性结果。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”。经验丰富的研究人员团队使用最先进的基因组方法，进一步确保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，但将通过检查GoKinD和FIND等多中心集合来验证研究结果的普遍性。

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.