Mapping Chromosome 3q Inflammatory Bowel Disease Genes

描述（由申请人提供）：炎症性肠病（IBD）由克罗恩病（CD）和溃疡性结肠炎（UC）组成，是一种复杂的多基因疾病。IBD的一个主要流行病学特征是其在德系犹太人血统个体中的患病率增加了几倍。NOD2/CARD15基因的相关变异不能解释德系犹太人中CD患病率的增加，OCTN基因簇和MDR1的相关变异在德系犹太人CD中没有显著相关性。这些意想不到的发现表明，疾病发病机制在犹太人和非犹太人CD中存在根本不同。对IBD所有连锁研究的荟萃分析提供了染色体3q27-28的显著连锁证据的支持。在我们的大型IBD队列和德系犹太人亚群中，在该地区观察到最重要的关联证据。鉴于犹太人群中疾病患病率明显较高，确定与cd相关的风险等位基因将为疾病机制提供重要见解。1 .对德系犹太人3q染色体186,600,000 - 191,700,000之间的CD进行全面的基于snp的病例对照关联研究。在300名德系犹太人CD和300名德系犹太人对照中，对该地区的snp进行基因分型标记。将进行单点和多点分析，以测试确定值得复制努力的标记和基因。2。在独立的德系犹太人和非德系犹太人欧洲血统的CD队列中，测试证明与CD相关的最重要证据的snp。确定100个独立的犹太UC病例。复制队列将包括独立的犹太CD病例和犹太对照，非德系犹太人欧洲血统CD病例和对照。将确定德系犹太人和非德系犹太人欧洲血统病例和对照中疾病关联和连锁不平衡的比较模式。确定另外100个独立的犹太UC病例将允许在功能、疾病相关snp方面进行强有力的关联研究。3。鉴定3q27-28染色体上与IBD易感性相关的功能变异。全面定义这些功能变异与IBD关联的本质。将在关联的复制区域开发和分型标记，以评估哪些基因有助于复制关联。物种之间的序列保守分析在识别保守的功能基序（例如microRNA靶点）方面非常有效。将在最可能包含功能改变的区域对CD患者进行重测序。基因活性和表达的基因型依赖性改变将在原代细胞中定义。将在犹太和非犹太CD和UC中对该地区所有假定的功能snp进行基因分型，以全面定义该地区功能变异导致的IBD关联的性质。

DESCRIPTION (provided by applicant): The inflammatory bowel diseases (IBD), comprised of Crohn's disease (CD) and ulcerative colitis (UC), are complex, multigenic disorders. A central epidemiologic feature of IBD is its several-fold increased prevalence in individuals of Ashkenazi Jewish ancestry. Associated variants in the NOD2/CARD15 gene do not account for the increased CD prevalence among the Ashkenazim and implicated variants in the OCTN gene cluster and MDR1 are not significantly associated in Ashkenazim CD. These unexpected findings demonstrate that mechanisms of disease pathogenesis are fundamentally different in Jewish and non-Jewish CD. Support for significant linkage evidence on chromosome 3q27-28 is provided by a meta-analysis of all linkage studies in IBD. In our large IBD cohort and in the Ashkenazim subset, the most significant evidence for linkage is observed in this region. Identifying CD-associated risk alleles, given the markedly higher disease prevalence in Jewish populations, will provide significant insight into mechanisms of disease. I. To perform a comprehensive SNP-based case-control association study in Ashkenazi Jewish CD between 186,600,000 and 191,700,000 on chromosome 3q. A case-control study genotyping tagging SNPs in the region in 300 Ashkenazim CD and 300 Ashkenazi controls is proposed. Single and multipoint analyses will be performed to test identify markers and genes meriting replication efforts. II. To test SNPs demonstrating the most significant evidence for CD association in independent Ashkenazi and non-Ashkenazi European ancestry CD cohorts. To ascertain 100 independent Jewish UC cases. Replication cohorts will include independent Jewish CD cases and Jewish controls, non-Ashkenazim European ancestry CD cases and controls. Comparative patterns of disease association and linkage disequilibrium in Ashkenazim and non-Ashkenazim European ancestry cases and controls will be defined. Ascertainment of 100 additional independent Jewish UC cases will allow for well-powered association studies in functional, disease-associated SNPs. III. To identify functional variants contributing to IBD susceptibility on chromosome 3q27-28. To comprehensively define the nature of IBD association for these functional variants. Markers will be developed and typed in replicated regions of association to assess which genes contribute to the replicated association. Sequence conservation analyses between species are highly effective in identifying conserved functional motifs (e.g. microRNA targets). Resequencing will be performed in CD patients in those regions most likely to contain functional alterations. Genotype-dependent alterations in gene activity and expression will be defined using primary cells. Genotyping of all putative functional SNPs in the region will be performed in Jewish and non-Jewish CD and UC to comprehensively define the nature of IBD association contributed by functional variants in this region.