SNP Haplotyping to Detect Diabetic Nephropathy Risk

描述（由申请人提供）：糖尿病肾病（DN）的开始/进展部分是遗传的。到目前为止，候选基因和基因组扫描研究未能确定在重复群体中验证的强大效应，这表明DN可能是多基因的，而不是寡基因的。肾病和糖尿病家族调查（FIND）是一个NIDDK联盟，通过连锁分析或混合连锁不平衡（MALD）作图来识别DN风险位点。单核苷酸多态性（SNP）单倍型在FIND开始时是不可用的，但可能比连锁分析更能识别多基因疾病的风险位点。使用来自PI的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，以达到以下具体目的：在关联研究中使用Perlegen Science的SNP单倍型方法：a)测试样本进行群体分层；b)利用混合基因分型估计25万个snp的等位基因频率差异；c)通过识别6000个表现出最显著等位基因频率差异的snp来区分真实关联和假阳性，以便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SNP单倍型分析，并在6个月内获得结果；3. 确定一组SNP标记等位基因，确定个体DN易感性；4. 与FIND共享数据；5. 验证SNP单倍型技术，并在两个独立的队列中验证结果，这些队列的受试者在FIND中代表性不足（欧洲-美国人（EA））和未代表性（中国人）；和6。提供全基因组确认SNP单倍型，以确定种族之间的相似性和差异性。该应用程序在FIND MA病例对照队列中使用FIND未使用的SNP单倍型基因组扫描方法。它通过加强对在寻找新方法中没有充分代表的群体的包容，与寻找新方法协同作用。该数据可以证实FIND结果，和/或识别以前未被怀疑的位点。

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.