HLA and KIR Genomics in Inflammatory Bowel Disease

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）是胃肠道慢性复发，缓解性疾病。相关研究已经确定了这两种疾病的许多易感基因，暗示了对肠道微生物的适应性免疫和先天免疫，以及对乳糜泻的自噬途径在疾病易感性中的作用。与几乎所有的自身免疫性和炎症性疾病一样，HLA I类和II类位点的等位基因变异与UC和CD都有关联。DRB1*0103-DQB1*0301)特别强，根据我们最近的GWAS，最强的SNP关联与特定的临床亚型(例如：难治性UC)。自然杀伤细胞（NK）在先天免疫中对IBD风险的贡献尚未得到很好的研究。NK细胞受几个编码细胞表面受体的基因家族控制。刺激和/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。在最近的一项CD研究中，我们发现抑制性KIR杂合子（KIR2DL2/KIR2DL3）在缺乏HLA配体（CI）时具有显著的保护作用，而在存在HLA配体纯合性时具有易感性。我们建议通过研究HLA和KIR等位基因、单倍型和KIR基因-HLA配体对在临床上明确定义的白种人和西班牙裔波多黎各血统的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罗氏454 GS FLX测序系统进行等位基因HLA分辨率，并将完成我们的KIR（16基因）454测定的开发和验证，以在我们的队列中对这两个基因复合物进行测序。将检查白种人（1300名患者/550名对照和100名家庭三人组）和波多黎各人（300名患者/200名对照）CD队列，白种人（300名医学难治性疾病患者/550名对照）和波多黎各人（200名患者/200名对照）UC队列。我们还将开发生物信息学工具，以处理高度多态性的HLA和KIR基因的复杂分析，并通过NIAID与BISC合作的进口提供这些数据管理和分析工具。

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.