IBD Gene Mapping by Clinical and Population Subsets

按临床和人群亚群划分的 IBD 基因图谱

基本信息

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
项目类别：
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&apos 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

项目摘要

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（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性疾病，具有遗传和环境原因。疾病基因的分布因种族血统而异。尽管北美有大量非裔美国人 (AA) 人群患有 IBD，但相对于白人甚至亚洲人群，对该人群遗传原因的确定仍处于起步阶段。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。这些已被登记到 NIDDK IBD 遗传学联盟存储库中，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，并确定其表型模式与白人人群中 IBD 的表型模式显着不同。然而，我们还发现 AA 中的 IBD 通常具有家族性，这表明与白人一样，也存在潜在的易感基因。我们发现，与白人不同，NOD2 在引起 AA 克罗恩病方面并没有发挥重要作用。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 基因图谱可能允许高 LD 区域的有限分辨率。此外，我们还发现了独特的 NOD2 多态性，这表明 AA 群体内更大的遗传多样性可能会提供更多关于人类基因组中引起疾病的变异的知识。我们现在建议到第 5 年将 AA 队列扩大到 800 例并匹配对照。我们将与 DCC 联盟合作，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 复制群体来确认 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，并测试关联并识别在我们的 NIDDK 联盟合作者所研究的白人人口。