IBD Gene Mapping by Clinical and Population Subsets

按临床和人群亚群划分的 IBD 基因图谱

• 批准号: 7500267
• 负责人: Steven R Brant
• 金额: $ 36.91万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7500267
• 关键词: 13q; ABCB1 gene; Admixture; African; African American; Algorithms; American; Antibodies; Area; Asians; Behavior; Bioinformatics; Biological Markers; Candidate Disease Gene; Caucasians; Caucasoid Race; Chairperson; Characteristics; Child; Childhood; Chromosome Mapping; Classification; Classification Scheme; Clinical; Clinical Data; Clinical Management; Collaborations; Collection; Communication; Community Health Centers; Complex; Crohn' s disease; DNA; Data; Data Collection; Development; Disease; Disease Association; Disease Pathway; Disease susceptibility; District of Columbia; Economic Factors; Enrollment; Environment; Environmental Risk Factor; European; Exposure to; Future; Gastroenterology; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Genome; Haplotypes; Head; Hereditary Disease; Heterogeneity; Human Genome; Infectious Agent; Inflammation; Inflammatory Bowel Diseases; Joints; Knowledge; Lead; Linkage Disequilibrium; Location; Maps; Measurement; Measures; Medical center; Methods; Modeling; Molecular; National Institute of Diabetes and Digestive and Kidney Diseases; North America; Numbers; Onset of illness; Pathogenesis; Patients; Pattern; Phase; Phenotype; Play; Population; Principal Investigator; Puerto Rican; Quality Control; Questionnaires; Recruitment Activity; Relative (related person); Research Personnel; Resolution; Resources; Risk; Role; Sampling; Serum; Severities; Severity of illness; Smoking; Statistical Models; Susceptibility Gene; Symptoms; Testing; Ulcerative Colitis; Variant; Work; base; case control; clinical Diagnosis; clinically relevant; cohort; disorder risk; disorder subtype; early onset; follow-up; gene interaction; genetic variant; genome wide association study; infancy; lymphoblastoid cell line; microorganism antigen; novel; nutrition; programs; repository; trait

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.

描述(申请人提供)：炎症性肠病(IBD)，克罗恩病和溃疡性结肠炎，是一种复杂的遗传性疾病，有遗传和环境两方面的原因。疾病基因的分布因种族血统而异。尽管北美有大量患有IBD的非裔美国人(AA)，但相对于白人甚至亚洲人群，对这一群体遗传原因的确定还处于初级阶段。我们开发了最大的AA IBD病例队列(目前258例确诊病例)和种族匹配的对照。这些基因已被NIDDK IBD遗传学联盟资料库登记，以便在未来的遗传学研究中广泛使用。我们还分析了AA人群中IBD的表型，并确定了其表型模式与白人人群中IBD的表型模式显著不同。然而，我们也发现AA中的IBD通常是家族性的，这表明像白人人群一样，存在潜在的易感基因。我们发现，与白人不同，NOD2在引起AAS克罗恩病方面没有发挥重要作用。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人群的连锁不平衡(LD)大大减少，这表明AA患者的IBD基因定位可能在LD高的地区允许更有限的分辨率。此外，我们还发现了独特的NOD2多态，这表明AA群体中更大的遗传多样性可能会提供更多关于导致人类基因组变异的疾病的知识。我们现在建议将AA病例队列扩大到800例，并在第5年之前匹配对照。我们将与DCC财团合作，在第4年进行全基因组关联研究，以确定IBD基因。我们还将招募AA IBD复制人群，以确认GWA研究的遗传发现。我们将使用更大的群体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连锁的原因并减少其单倍型，并测试关联性，并为我们的NIDDK联盟合作者在白人群体中发现的任何候选基因识别独特的非洲祖先变异。