Mapping Chromosome 3q Inflammatory Bowel Disease Genes

描述(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血统的个人中的流行率增加了数倍。NOD2/CARD15基因的相关变异不能解释德系病患病率的增加，而OCTN基因簇和mdr1的相关变异在德系群中并不显著相关。这些意想不到的发现表明，犹太CD和非犹太CD的发病机制是根本不同的。对IBD中所有连锁研究的荟萃分析提供了对染色体3q27-28上显著连锁证据的支持。在我们庞大的IBD队列和阿什肯纳齐姆亚群中，在该地区观察到了最显著的连锁证据。鉴于犹太人群的疾病患病率明显较高，识别与CD相关的风险等位基因将为疾病机制提供重要的洞察力。I.在染色体3Q上186,600,000至191,700,000之间的德系犹太人CD中进行一项基于SNP的病例对照关联研究。建议进行病例对照研究，在300名德裔CD和300名德裔对照中对该地区的SNP进行基因分型标记。将进行单点和多点分析，以测试识别值得复制的标记和基因。测试SNPs，证明在独立的德系和非德系欧洲血统的Cd队列中存在Cd关联的最重要证据。以确定100个独立的犹太人UC病例。复制队列将包括独立的犹太CD盒和犹太控制件、非德系欧洲血统CD盒和控制件。将确定在德系和非德系系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例独立的犹太UC病例将允许对功能性的、与疾病相关的SNPs进行强有力的关联研究。确定染色体3q27-28上导致IBD易感性的功能变异。全面界定IBD与这些功能变异的关联性。将在复制的关联区域中开发和分型标记，以评估哪些基因对复制的关联有贡献。物种间的序列保守分析在识别保守的功能基序(例如microRNA靶标)方面非常有效。将在CD患者中对最有可能包含功能改变的区域进行重新测序。基因活性和表达的基因依赖于基因型的改变将使用原代细胞来定义。将在犹太人和非犹太人的CD和UC中对该地区所有可能的功能性SNPs进行基因分型，以全面确定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.