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.