SNP Haplotyping to Detect Diabetic Nephropathy Risk

描述(由申请人提供)：糖尿病肾病的发生/发展部分是遗传的。到目前为止，候选基因和基因组扫描研究未能确定在复制群体中验证的强大效应，这表明糖尿病肾病可能是多基因的，而不是少基因的。肾病和糖尿病家族调查(FIND)是一个NIDDK联盟，通过混合连锁不平衡(MALD)的连锁分析或作图来确定糖尿病肾病的危险基因。单核苷酸多态(SNP)单倍型在FIND开始时是不可用的，但可能比连锁分析更有能力识别多基因疾病中的危险基因。利用来自PI‘s Find中心的墨西哥裔美国人(MA)病例对照队列，我们提出了一项辅助研究，以寻找具有这些特定目标的：1.在关联研究中使用PerLegen Science的SNP单倍型方法：a)测试样本以进行群体分层；b)使用混合基因分型估计250,000个SNP的等位基因频率差异；以及c)通过识别6000个表现出最显著等位基因频率差异的SNP来区分真阳性和假阳性，用于通过个体基因分型进行后续评估；2.对MA MALD队列进行全基因组范围的SNP单倍型分析，结果在6个月内；3.确定一组识别个体糖尿病肾病易感性的SNP标记等位基因；4.与FIND共享数据；5.验证SNP单倍型技术，并在FIND中产生代表不足(欧洲-美国人(EA))和未代表(中国)的两个独立队列；以及6.提供全基因组验证性SNP单倍型分析，以确定不同种族之间的相似和差异。该应用程序使用的SNP单倍型基因组扫描方法在Find on a Find MA病例对照队列中没有使用。它通过加强对未在FIND中充分代表的群体的包容，与FIND协同工作。该数据可以确认查找结果，和/或识别先前未怀疑的基因座。

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.