Gene discoveries in subjects with Crohn's disease of African descent

描述(申请人提供)：克罗恩病(CD)是一种高度遗传性疾病。全基因组关联研究已被证明是非常成功的识别易感基因座，其中许多定义以前未知的通路在发病机制中发挥重要作用。几乎所有的基因研究都只关注欧洲血统的高加索人，他们只占美国人口的70%左右。因此，这些遗传标记是否对混杂个体具有预测作用还有待观察，例如占美国人口约15%的非裔美国人(AAs)，他们的每条染色体很可能是来自不同祖先群体的DNA块的马赛克。此外，来自HapMap和其他疾病研究的变异数据表明，再生障碍性贫血人群中CD的等位基因结构可能与高加索人显著不同。对非洲裔美国人的研究仍然严重不足。有必要通过招募大量的AA来扩大这些基因发现的研究范围，以增加样本量，增强发现的能力。在NIDDK IBDGC的这份R01辅助提案中，我们的目标是招募额外的1485名AA CD受试者，这些受试者可用于扩大IBDGC的发现队列和复制研究。我们的目标将是；目标1：非洲裔CD的详细表型特征(AA)。将在3年内招募至少1000名CD受试者：目标2：与IBDGC联合进行基因组广泛关联研究，利用病例对照分析、路径分析和拷贝数变异分析发现CD中的CD(IBD)基因/基因座：目标3：通过对AA患者和对照中常见的SNP进行靶向测序，发现群体特异性SNP，然后进行Illumina基因分型，提炼全基因组关联峰。对CD与欧洲血统的全基因组关联扫描发现，有40多个确认的变异影响了CD的发展风险。然而，悬而未决的问题是，在欧洲人中发现的变异与再生障碍性贫血人群有多大相关性？总之，我们强大的研究加上高通量的基因分型、最先进的分析和CD对AA人群的测序，将发现、比较和对比欧洲人在CD方面已经获得的知识。 公共卫生相关性：对欧洲血统的CD进行全基因组扫描，发现40多个确认的变异影响发展为克罗恩病(CD)的风险。然而，一个悬而未决的问题是，在欧洲人中发现的变异与非裔美国人(AA)人口有多大相关性？我们的强大研究与高通量基因分型、最先进的分析和CD的非裔美国人(AA)人群测序将发现、比较和对比欧洲人在CD中已经获得的知识。

DESCRIPTION (provided by applicant): Crohn's disease (CD) is a highly heritable disorder. Genome wide association studies (GWAS) have proved to be highly successful at identifying susceptibility loci, many of which define previously unsuspected pathways as playing an important role in pathogenesis. Nearly all genetic studies focused exclusively on Caucasians of European descent who represents only ~70% of the US population. Thus, it remains to be seen whether these genetic markers will have prognostic utility in admixed individuals, such as African Americans (AAs) who constitute about 15% of the US population and in whom each chromosome is likely to be a mosaic of blocks of DNA from different ancestral populations. Furthermore, variation data from the HapMap and other disease studies suggest the possibility that the allelic architecture of CD in AA populations may significantly differ from that in Caucasians. African American populations remain dramatically understudied. There is a great need to extend these gene discovery studies in AA with CD by recruiting a large numbers of AA to increase the sample size and to enhance the power of discovery. In this ancillary R01 proposal to NIDDK IBDGC, we aim to recruit additional 1485 AA CD subjects that can be used to augment the discovery cohort and for the replication studies to the IBDGC efforts. Our aims will be; Aim 1: Detailed phenotypic characterization of CD with African descent (AA). A minimum of 1000 AA subjects with CD will be recruited in 3 year period: Aim 2: Perform Genome Wide Association Study (GWAS) jointly with IBDGC to discover CD (IBD) genes / loci in CD with African descent (AA) using case control analysis, pathway analysis and CNV (copy number variation) analysis: Aim 3: Refine genome-wide association peaks by conducting targeted sequencing for population specific SNP discovery followed by Illumina genotyping of common SNPs in AA cases and controls. Genome-wide association scans in CD with European ancestry found more than 40 confirmed variants affecting the risk of developing CD. Open question, however, is how relevant the variants discovered in Europeans, are to AA population? Together, our well powered studies with high-throughput genotyping, state of the art analysis and sequencing in AA population with CD will discover, compare and contrast the already gained knowledge in Europeans in CD. PUBLIC HEALTH RELEVANCE: Genome-wide association scans in CD with European ancestry found more than 40 confirmed variants affecting the risk of developing Crohn's disease (CD). An open question, however, is how relevant the variants discovered in Europeans are to African American (AA) population? Together, our well powered studies with high-throughput genotyping, state of the art analysis and sequencing in African American (AA) population with CD will discover, compare and contrast the already gained knowledge in Europeans in CD.