SNP Haplotyping to Detect Diabetic Nephropathy Risk

描述（由申请人提供）：糖尿病肾病（DN）的发生/进展部分源于遗传。候选基因和基因组扫描研究未能确定强大的影响，验证了重复人口，这表明DN可能是多基因，而不是寡基因。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）作图来确定DN风险位点。单核苷酸多态性（SNP）单倍型在FIND的开始是不可用的，但可能有更大的权力来辨别多基因疾病的风险位点比连锁分析。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FIND为这些特定目的：1。在关联研究中使用Perlegen Science的SNP单体型分析方法，通过：a）测试样本用于人群分层; B）使用合并的基因分型估计250，000个SNP的等位基因频率差异;以及c）通过鉴定6，000个表现出最显著等位基因频率差异的SNP来区分真实关联与假阳性，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SNP单体型分析，6个月内得到结果; 3.确定一组SNP标记等位基因，其鉴定个体DN易感性; 4.与FIND共享数据; 5. 6.使用SNP单体型分型技术，并在FIND中代表不足（欧洲-美国人（EA））和未代表（中国人）的两个独立受试者队列中产生结果;提供全基因组确证性SNP单体型分析，以确定不同种族之间的相似性和差异性。本申请使用FIND MA病例对照队列中未在FIND中使用的SNP单体型基因组扫描方法。它与FIND协同增效，加强了对FIND中没有充分代表的群体的包容。该数据可以确认FIND结果，和/或鉴定先前未被怀疑的基因座。

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.