SNP Haplotyping to Detect Diabetic Nephropathy Risk

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DESCRIPTION (provided by applicant): The initiation/progression of diabetic nephropathy (DN) is partly genetic in origin. Candidate gene and genomic scanning studies failed so far to identify powerful effects verified in replicate populations, suggesting that DN may be polygenic rather than oligogenic. Family Investigation of Nephropathy and Diabetes (FIND) is an NIDDK consortium to identify DN risk loci using linkage analysis or mapping by admixture linkage disequilibrium (MALD). Single nucleotide polymorphism (SNP) haplotyping was not available at FIND's inception, but may have greater power to discern risk loci in polygenic disorders than linkage analysis. Using the Mexican-American (MA) case-control cohort from the PI's FIND center, we propose an ancillary study to FIND with these Specific Aims: 1. Use Perlegen Science's SNP haplotyping method in an association study by: a) testing samples for population stratification; b) estimating allele frequency differences of 250,000 SNPs using pooled genotyping; and c) distinguishing true associations from false positives by identifying the 6,000 SNPs exhibiting the most significant allele frequency differences for follow-up evaluation by individual genotyping; 2. perform full genome-wide SNP haplotyping on the MA MALD cohort with results within 6 months; 3. Determine a set of SNP marker alleles which identifies individual DN susceptibility; 4. Share the data with FIND; 5. Validate SNP haplotyping technique and results in two independent cohorts of subjects under-represented (European -Americans (EA)) and unrepresented (Chinese) in FIND; and 6. Provide genome-wide confirmatory SNP haplotyping to ascertain similarities and differences across ethnicities. This application uses SNP haplotyping genomic scanning methods not used in FIND on a FIND MA case-control cohort. It synergizes with FIND by enhancing inclusion for groups not adequately represented in FIND. This data may confirm FIND results, and/or identify previously unsuspected loci.