HLA and KIR Genomics in Inflammatory Bowel Disease

炎症性肠病中的 HLA 和 KIR 基因组学

• 批准号: 8306933
• 负责人: HENRY A ERLICH
• 金额: $ 175.5万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-20 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306933
• 关键词: Affect; Alleles; Antibodies; Ashkenazim; Autoimmune Diseases; Autoimmune Process; Autophagocytosis; Bioinformatics; Biological Assay; Caucasians; Caucasoid Race; Cell Surface Receptors; Cells; Chemistry; Chronic; Clinical; Colectomy; Communities; Complex; Crohn' s disease; Data; Data Analyses; Development; Dideoxy Chain Termination DNA Sequencing; Disease; Disease Association; Disease susceptibility; Doctor of Philosophy; Epitopes; Ethnic group; Exons; Family; Functional RNA; Functional disorder; Gastrointestinal tract structure; Gene Family; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Grant; HLA-A gene; Haplotypes; Healthcare; Heterozygote; Hispanics; Immune; Immune system; Immunogenetics; Immunologics; Immunology; Immunophenotyping; Inflammatory; Inflammatory Bowel Diseases; Intestines; Laboratories; Length; Ligands; Location; Meta-Analysis; Methods; Microbe; Molecular; National Institute of Allergy and Infectious Disease; Natural History; Natural Immunity; Natural Killer Cells; Nucleotides; Parents; Pathway interactions; Patients; Phenotype; Play; Principal Component Analysis; Principal Investigator; Publishing; Puerto Rican; Reading; Recording of previous events; Refractory; Refractory Disease; Relapse; Research Personnel; Resolution; Risk; Role; Sampling; Sampling Studies; Software Tools; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stratification; Support Contracts; Susceptibility Gene; System; Testing; Titania; Titanium; Ulcerative Colitis; Validation; Variant; Work; adaptive immunity; aggressive therapy; base; case control; cohort; data management; design; follower of religion Jewish; genome wide association study; human leukocyte antigen gene; improved; killer inhibitory receptor; method development; next generation; novel; proband; programs; public health relevance; response; tool; trait; transmission process

DESCRIPTION (provided by applicant): The two common inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are chronic relapsing, remitting conditions of the gastrointestinal tract. Association studies have identified a number of susceptibility genes for both diseases, implicating both adaptive and innate immunity in response to intestinal microbes and, for CD, the autophagy pathway in disease susceptibility. As with virtually all autoimmune and inflammatory disease, allelic variation at the HLA class I and class II loci has been associated with both UC and CD. Based on our previous work, the association of specific HLA haplotypes (eg. DRB1*0103-DQB1*0301) is particularly strong and, based on our recent GWAS, the strongest SNP association is with particular clinical subtypes (eg. medically refractory UC). The contribution of the natural killer cells (NK) in innate immunity to the risk of IBD has not been as well examined. NK cells are controlled by several gene families that encode cell surface receptors. The stimulatory and/or inhibitory KIR receptors use polymorphic epitopes on HLA class I as their cognate ligands. In a recent study of CD, we found inhibitory KIR heterozygotes (KIR2DL2/KIR2DL3) significantly associated with protection in the absence of their HLA ligand (CI), and predisposing in the presence of CI ligand homozygosity. We propose to expand this work by examining the role of HLA and KIR alleles, haplotypes and KIR gene-HLA ligand pairs with clinically well-defined CD and UC cohorts of Caucasian and Hispanic-Puerto Rican ancestry. We will use our newly developed Roche 454 GS FLX sequencing system for allelic HLA resolution, and will finish development and validation on our KIR (16 gene) 454 assays to sequence both gene complexes in our cohorts. Caucasian (1300 patients/550 controls and 100 family trios) and Puerto Rican (300 patients/200 controls) CD cohorts, and Caucasian (300 patients with medically refractory disease/550 controls) and Puerto Rican (200 patients/200 controls) UC cohorts will be examined. We will also develop bioinformatic tools to deal with the complex analysis of the highly polymorphic HLA and KIR genes, and make these data management and analysis tools available through NIAID's ImmPort in partnership with BISC. PUBLIC HEALTH RELEVANCE: Ulcerative colitis and Crohn's disease are serious and common inflammatory diseases, involving adaptive and innate immunity and requiring long term and expensive health care. A deeper understanding of the role of HLA and KIR polymorphism in these diseases and in specific clinical subtypes of UC and CD may prove clinically valuable in patient stratification for choice of therapy; patients whose genotype indicates a more severe and rapid disease course may benefit from more aggressive therapy.

描述（由申请人提供）：两种常见的炎症性肠病（IBD），克罗恩病（CD）和溃疡性结肠炎（UC）是胃肠道的慢性复发缓解性疾病。相关研究已经确定了这两种疾病的一些易感基因，涉及适应性和先天免疫对肠道微生物的反应，以及CD，疾病易感性中的自噬途径。与几乎所有的自身免疫性和炎症性疾病一样，HLA I类和II类基因座的等位基因变异与UC和CD均相关。基于我们以前的工作，特定的HLA单倍型（例如，DRB 1 *0103-DQB 1 *0301）特别强，并且基于我们最近的GWAS，最强的SNP关联是与特定的临床亚型（例如DRB 1 * 0103-DQB 1 *0301）。医学难治性UC）。天然杀伤细胞（NK）在先天免疫中对IBD风险的贡献尚未得到很好的研究。NK细胞由编码细胞表面受体的几个基因家族控制。刺激性和/或抑制性KIR受体使用HLA I类上的多态性表位作为其同源配体。在最近的CD研究中，我们发现抑制性KIR杂合子（KIR 2DL 2/KIR 2DL 3）在其HLA配体（CI）缺失时与保护显著相关，并且在CI配体纯合性存在时与易感性显著相关。我们建议通过研究HLA和KIR等位基因、单倍型和KIR基因-HLA配体对在临床明确定义的高加索人和西班牙裔波多黎各人的CD和UC队列中的作用来扩展这项工作。我们将使用我们新开发的Roche 454 GS FLX测序系统进行等位基因HLA解析，并将完成我们的KIR（16基因）454检测试剂盒的开发和验证，以对我们队列中的两种基因复合物进行测序。将检查高加索人（1300例患者/550例对照和100个家庭三人组）和波多黎各人（300例患者/200例对照）CD队列，以及高加索人（300例难治性疾病患者/550例对照）和波多黎各人（200例患者/200例对照）UC队列。我们还将开发生物信息学工具来处理高度多态性HLA和KIR基因的复杂分析，并通过NIAID与BISC合作的ImmPort提供这些数据管理和分析工具。 公共卫生关系：溃疡性结肠炎和克罗恩病是严重和常见的炎症性疾病，涉及适应性和先天免疫，需要长期和昂贵的医疗保健。更深入地了解HLA和KIR多态性在这些疾病中的作用以及UC和CD的特定临床亚型可能在患者分层中对治疗选择具有临床价值;基因型指示更严重和快速病程的患者可能从更积极的治疗中获益。