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：
7936453
负责人：
Steven R Brant
金额：
$ 16.4万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7936453
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 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 non-genetic 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，是一种复杂的遗传疾病，既有遗传和环境原因。疾病基因的分布因种族血统而异。尽管北美IBD的非裔美国人（AA）人口众多，但与白人甚至亚洲人口相比，该人群中遗传原因的确定仅处于婴儿期。我们已经开发了最大的AA IBD病例（目前为258例已确认的病例）和种族匹配的对照组。这些已被纳入NIDDK IBD遗传学财团存储库，以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，并确定表型模式与白人人口中的IBD明显不同。但是，我们还发现，AAS中的IBD经常是家族性的，这表明像白人人口一样，有基本的易感基因。我们发现，与白人不同，NOD2在引起克罗恩病的AAS中并不发挥重要作用。但是，我们已经复制了IBD5-OCTN1/2单倍型的重要作用。如前所述，AA人群大大降低了连锁不平衡（LD），这表明AA患者的IBD基因映射可能允许在高LD领域提供更多有限的分辨率。同样，我们发现独特的NOD2多态性表明，AA人群中较大的遗传多样性可能会提供更多关于疾病的知识，从而导致人类基因组的变化。现在，我们建议将AA队列扩大到800个病例，并在5年级之前匹配对照。与财团DCC合作，我们将在4年级进行整个基因组协会研究，以识别IBD基因。我们还将招募AA IBD复制人群，以确认GWA研究中的遗传发现。我们将使用较大的人群来确定独特的非洲祖先NOD2变体的重要性，进一步降低IBD5单倍型，确定IBD3链接的原因，减少其单倍型并测试关联并确定非洲祖先变异的独特候选基因，以通过我们的NIDDK Comportium Complorators在白人人群中确定的任何候选基因。