NIDDK IBD Genetics Consortium Genetic Research Center

NIDDK IBD 遗传学联盟遗传研究中心

• 批准号: 9146333
• 负责人: Richard H Duerr
• 金额: $ 37.11万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9146333
• 关键词: Affect; Age; Alleles; Amino Acid Sequence; Ancillary Study; Ankylosing spondylitis; Autophagocytosis; Behcet Syndrome; Biological; Biology; Candidate Disease Gene; Charge; Clinical; Cluster Analysis; Code; Collection; Complement; Complex; Computing Methodologies; Crohn' s disease; DNA Resequencing; Data; Dinoprostone; Disease; Disease susceptibility; Environment; Epidemiologic Studies; European; Frequencies; Functional disorder; Funding; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Research; Genetic Variation; Genetic study; Genomic Segment; Genotype; Goals; Heritability; Human Biology; Human Resources; Immune; Incidence; Individual; Inflammation Mediators; Inflammatory Bowel Diseases; Intercistronic Region; Interleukin-1; International; Investigation; Learning; Leprosy; Life; Lighting; Manuscripts; Meta-Analysis; National Institute of Diabetes and Digestive and Kidney Diseases; Pathogenesis; Pathway interactions; Patient Care; Phenotype; Population; Prevalence; Psoriasis; Publications; Publishing; Reporting; Research; Research Infrastructure; Resources; Risk; Risk Factors; Role; Signal Transduction; Single Nucleotide Polymorphism; Statistical Methods; Study Subject; Susceptibility Gene; T memory cell; Tissue-Specific Gene Expression; Tissues; Training; Translating; Translations; Twin Studies; Ulcerative Colitis; Universities; Variant; cell type; design; follow-up; genetic risk factor; genetic variant; genome wide association study; genome-wide; interleukin-23; member; non-genetic; overexpression; patient population; protein structure; risk variant; trait; Affect; Age; Alleles; Amino Acid Sequence; Ancillary Study; Ankylosing spondylitis; Autophagocytosis; Behcet Syndrome; Biological; Biology; Candidate Disease Gene; Charge; Clinical; Cluster Analysis; Code; Collection; Complement; Complex; Computing Methodologies; Crohn' s disease; DNA Resequencing; Data; Dinoprostone; Disease; Disease susceptibility; Environment; Epidemiologic Studies; European; Frequencies; Functional disorder; Funding; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Research; Genetic Variation; Genetic study; Genomic Segment; Genotype; Goals; Heritability; Human Biology; Human Resources; Immune; Incidence; Individual; Inflammation Mediators; Inflammatory Bowel Diseases; Intercistronic Region; Interleukin-1; International; Investigation; Learning; Leprosy; Life; Lighting; Manuscripts; Meta-Analysis; National Institute of Diabetes and Digestive and Kidney Diseases; Pathogenesis; Pathway interactions; Patient Care; Phenotype; Population; Prevalence; Psoriasis; Publications; Publishing; Reporting; Research; Research Infrastructure; Resources; Risk; Risk Factors; Role; Signal Transduction; Single Nucleotide Polymorphism; Statistical Methods; Study Subject; Susceptibility Gene; T memory cell; Tissue-Specific Gene Expression; Tissues; Training; Translating; Translations; Twin Studies; Ulcerative Colitis; Universities; Variant; cell type; design; follow-up; genetic risk factor; genetic variant; genome wide association study; genome-wide; interleukin-23; member; non-genetic; overexpression; patient population; protein structure; risk variant; trait

DESCRIPTION (provided by applicant): Genome-wide association studies (GWASs) and follow-up studies of the most promising GWAS hits by the NIDDK Inflammatory Bowel Disease Genetics Consortium (IBDGC) and other members of the International IBDGC (IIBDGC) have been highly successful, as judged by the number of regions (>150) with genome-wide significant association signals in Crohn's disease (CD), ulcerative colitis (UC), or both forms of IBD; and their illumination of the probable involvement of specific biological pathways such as the IL-23/T helper 17 (Th17) immune pathway, autophagy, and mucosal barrier function in IBD pathogenesis. However, few of the genetic variants with the strongest association signals are predicted to change amino acid sequence or have other effects on protein structure. Most are in intronic or intergenic regions where they do not have immediately obvious functional effects. Together, they explain a modest proportion of the estimated heritability of CD and UC. Since effect sizes of individual risk-associated alleles are generally small, disease susceptibility probably arises from an accumulation of multiple small effects on biological pathways. Additional genetic studies that aim to fill in gaps in our understanding of the heritability should be complemented with the application of new statistical and computational methods to identify the strongest candidate IBD-causal variants in a gene network context. Coordinated investigation of the effects of candidate risk alleles on specific biological pathways in relevant tissues and cell types by NIDDK IBDGC Genetic Research Centers (GRCs) and other groups conducting ancillary studies is an essential strategy to dissect disease pathogenesis. IBD GWAS hits in multiple IL-23/Th17 immune pathway genes; GWAS hits that also implicate IL-23 signaling in ankylosing spondylitis, Behcet's disease, leprosy, and psoriasis; and a strong IL-23/Th17 immune pathway research environment at the University of Pittsburgh prompted us to begin exploration of the role of IBD-associated genetic variants in Th17 biology. Our Specific Aims are: Aim 1. Maintain an infrastructure for recruitment of study subjects, phenotyping, and biosample collection for NIDDK IBDGC Steering Committee-approved consortium-wide, GRC-specific, and ancillary studies; Aim 2. Participate in the design and execution of NIDDK IBDGC and IIBDGC genetic studies that aim to identify the strongest candidate IBD-causal variants; Aim 3. Examine the relationship between IBD-associated genetic variants and differential gene expression traits induced in activated effector memory T cells by inflammatory mediators (IL-23, IL-1�, and PGE2) known to be overexpressed in inflamed IBD tissues, to modulate Th17 function, and to be related to IBD-associated genes.

DESCRIPTION (provided by application): Genome-wide association studies (GWASs) and follow-up studies of the most promising GWAS hits by the NIDDK Inflammatory Bowel Disease Genetics Consortium (IBDGC) and other members of the International IBDGC (IIBDGC) have been highly successful, as judged by the number of regions (>150) with genome-wide significant association signals in Crohn's disease (CD), ulcerative colitis （UC）或两种形式的IBD；以及它们对特定生物学途径的可能参与（例如IL-23/T助手17（Th17）免疫途径，自噬和粘膜屏障功能在IBD发病机理中的可能参与。但是，很少有具有强关联信号的遗传变异能够改变氨基酸序列或对蛋白质结构具有其他影响。大多数人处于内含子或基因间区域，它们没有立即明显的功能效应。他们一起解释了CD和UC的估计遗传力的一定比例。由于单个风险相关等位基因的效果大小通常很小，因此疾病的敏感性可能是由于对生物学途径的多种影响产生的。旨在填补我们对遗传力的理解中差距的其他遗传研究应 通过应用新的统计和计算方法来完成，以在基因网络环境中识别强大的候选IBD-CAUSAL变体。 NIDDK IBDGC遗传研究中心（GRC）和其他进行辅助研究的组是对候选风险等位基因对特定生物学途径的影响的协调研究是剖析疾病发病机理的重要策略。 IBD GWAS命中多个IL-23/TH17免疫病基因基因； GWAS命中也暗示着连直鼻炎，Behcet病，麻风病和牛皮癣中的IL-23信号传导；匹兹堡大学的强大IL-23/TH17免疫病研究环境促使我们开始探索与IBD相关的遗传变异在TH17生物学中的作用。我们的具体目的是：目标1。维持NIDDK IBDGC指导委员会批准的整个财团，GRC特异性和辅助研究的研究对象，表型和生物样品收集的基础设施； AIM 2。参与NIDDK IBDGC和IIBDGC遗传学研究的设计和执行，旨在确定强大的候选人IBD-Causal变体； AIM 3。检查与IBD相关的遗传变异和鉴别基因表达性状之间的关系，通过炎症介质（IL-23，IL-1和PGE2）在激活的效应记忆T细胞中诱导的鉴定效应记忆T细胞中诱导的关系，已知在发炎的IBD组织中过表达IBD组织，以调节TH17功能，以调节TH17功能，并与IBD鉴定基因相关。