IBD Gene Mapping by Clinical and Population Subsets

描述（由申请人提供）：炎症性肠病（IBD），克罗恩病和溃疡性结肠炎，是一种复杂的遗传疾病，具有遗传和环境原因。疾病基因的分布因种族血统而异。尽管在北美有大量的非裔美国人（AA）患有IBD，但相对于白人甚至亚洲人群，对该人群遗传原因的确定还处于起步阶段。我们开发了最大的AA IBD病例队列（目前有258例确诊病例）和种族匹配的对照。这些已被纳入NIDDK IBD遗传联盟库，以便在未来的遗传研究中广泛使用。我们还分析了AA人群中IBD的表型，并确定其表型模式与白人人群中IBD的表型模式有显著差异。然而，我们也发现AAs中的IBD通常是家族性的，这表明与白人人群一样，存在潜在的易感基因。我们发现，与白种人不同，NOD2在aa患者的克罗恩病发病中没有显著作用。然而，我们已经复制了IBD5-OCTN1/2单倍型的重要作用。正如预测的那样，AA群体的连锁不平衡（LD）大大减少，这表明AA患者的IBD基因定位可能在高LD区域提供更有限的分辨率。此外，我们发现了独特的NOD2多态性，这表明AA群体中更大的遗传多样性可能为人类基因组中引起疾病的变异提供更多的知识。我们现在建议在第5年将AA队列扩大到800例和匹配的对照。与DCC联盟合作，我们将在四年级进行全基因组关联研究，以确定IBD基因。我们还将招募一个AA IBD复制群体来证实GWA研究的遗传发现。我们将使用更大的人群来确定独特的非洲祖先NOD2变异的重要性，进一步减少IBD5单倍型，确定IBD3连锁的原因，减少其单倍型，并进行关联测试，并为我们的NIDDK联盟合作者在白人人群中发现的任何候选基因确定独特的非洲祖先变异。

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, is a complex genetic disorder with both genetic and environmental causes. The distribution of disease genes varies by ethnic ancestry. Despite the large African American (AA) population with IBD in North America, determination of genetic causes in this population is only in its infancy relative to that of white and even Asian populations. We have developed the largest cohort of AA IBD cases (presently 258 confirmed cases) and ethnically matched controls. These have been enrolled into the NIDDK IBD Genetics Consortium Repository for broad use in future genetic studies. We have also analyzed the phenotype of IBD in the AA population and determined that the phenotype pattern is significantly different from that of IBD in the white population. However, we also found that IBD among AAs is frequently familial, suggesting that like the white population, there are underlying susceptibility genes. We found that unlike whites, NOD2 does not play a significant role in causing Crohn's disease in AAs. However we have replicated a significant role for the IBD5-OCTN1/2 haplotype. As predicted, linkage disequilibrium (LD) was greatly reduced for the AA population, suggesting that the IBD gene mapping in AA patients may allow more finite resolution in areas of high LD. Also, we found unique NOD2 polymorphisms suggesting that the greater genetic diversity within the AA population may provide greater knowledge of disease causing variations in the human genome. We now propose to enlarge the AA cohort to 800 cases and matched controls by year 5. Working with the consortiums DCC, we will perform a whole genome association study in Year 4, to identify IBD genes. We will also recruit an AA IBD replication population to confirm genetic findings from the GWA studies. We will use the larger population to determine the significance of unique African ancestral NOD2 variants, further reduce the IBD5 haplotype, determine the cause of IBD3 linkage and reduce its haplotype and test for association and identify unique African ancestral variants for any candidate genes identified in the white population by our NIDDK consortium collaborators.