Mapping Chromosome 3q Inflammatory Bowel Disease Genes

描述（由申请人提供）：炎症性肠病（IBD）包括克罗恩病（CD）和溃疡性结肠炎（UC），是复杂的多基因疾病。IBD的一个中心流行病学特征是其在德系犹太血统个体中的患病率增加数倍。NOD 2/CARD 15基因中的相关变体不能解释Ashkenazim中CD患病率的增加，并且OCTN基因簇和MDR 1中的相关变体在Ashkenazim CD中不显著相关。这些意想不到的发现表明，犹太人和非犹太人CD的发病机制是根本不同的。IBD所有连锁研究的荟萃分析提供了染色体3q 27 -28上显著连锁证据的支持。在我们的大IBD队列和Ashkenazim亚组中，在该地区观察到了最重要的联系证据。鉴于犹太人群中疾病患病率明显较高，确定CD相关的风险等位基因将为疾病机制提供重要的见解。I.在染色体3q上186，600，000和191，700，000之间的德系犹太CD中进行全面的基于SNP的病例对照关联研究。一项病例对照研究，基因分型标签的SNP在该地区的300德系犹太人CD和300德系犹太人控制的建议。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。二.在独立的德系犹太人和非德系犹太人欧洲血统CD队列中检测证明CD相关性最显著证据的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的疾病关联和连锁不平衡的比较模式。另外100例独立犹太UC病例的确定将允许在功能性疾病相关SNP中进行充分的关联研究。三.确定染色体3q 27 -28上导致IBD易感性的功能性变异。全面定义IBD与这些功能性变体相关的性质。标记将被开发和分型在复制的关联区域，以评估哪些基因有助于复制的关联。物种之间的序列保守性分析在鉴定保守的功能基序（例如microRNA靶标）方面非常有效。将在CD患者中最有可能包含功能改变的区域进行重新测序。将使用原代细胞定义基因活性和表达的基因型依赖性改变。将在犹太人和非犹太人CD和UC中对该区域所有推定的功能性SNP进行基因分型，以全面定义该区域功能性变体促成的IBD相关性的性质。

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.