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: 9116404
• 负责人: HENRY A ERLICH
• 金额: $ 48.78万
• 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 2016-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116404
• 关键词: HLA; KIR; Genomics; Inflammatory; Bowel

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.

描述(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和缓解性疾病。相关研究已经确定了这两种疾病的一些易感基因，涉及对肠道微生物的适应性免疫和先天免疫，对于CD，涉及疾病易感性的自噬途径。与几乎所有的自身免疫性和炎症性疾病一样，人类白细胞抗原I类和II类基因座上的等位基因变异与UC和CD都有关联。在我们以前工作的基础上，特定的人类白细胞抗原单倍型(例如，DRB1*0103-DQB1*0301)特别强，根据我们最近的GWAS，最强的SNP与特定的临床亚型(例如。医学上难治性UC)。天然免疫中的自然杀伤细胞(NK)对IBD风险的贡献还没有得到很好的研究。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受体使用人类白细胞抗原I类分子上的多态表位作为同源配体。在最近对CD的一项研究中，我们发现抑制性KIR杂合子(KIR2DL2/KIR2DL3)在缺乏其HLA配体(CI)的情况下与保护显著相关，而在CI配体纯合性存在的情况下易患。我们建议通过研究人类白细胞抗原和KIR等位基因、单倍型和KIR基因-人类白细胞抗原配基对在临床上明确的高加索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。我们将使用我们最新开发的Roche 454 GS Flx测序系统来解析等位基因HLA，并将完成我们KIR(16基因)454分析的开发和验证，以对我们队列中的两个基因复合体进行测序。将检查高加索人(1300名患者/550名对照和100个家庭三人组)和波多黎各(300名患者/200名对照)CD队列，以及高加索人(300名患有难治性疾病的患者/550名对照)和波多黎各(200名患者/200名对照)UC队列。我们还将开发生物信息学工具来处理高度多态的人类白细胞抗原和KIR基因的复杂分析，并通过NIAID的ImmPort与BISC合作提供这些数据管理和分析工具。

项目成果

16(th) IHIW: population global distribution of killer immunoglobulin-like receptor (KIR) and ligands.

• DOI: 10.1111/iji.12028
• 发表时间: 2013-02
• 期刊: International journal of immunogenetics
• 影响因子: 2.2
• 作者: Hollenbach JA;Augusto DG;Alaez C;Bubnova L;Fae I;Fischer G;Gonzalez-Galarza FF;Gorodezky C;Karabon L;Kusnierczyk P;Noble J;Rickards O;Roberts C;Schaffer M;Shi L;Tavoularis S;Trachtenberg E;Yao Y;Middleton D
• 通讯作者: Middleton D

Human leukocyte antigen-A, -B, -C, -DRB1 allele and haplotype frequencies in Americans originating from southern Europe: contrasting patterns of population differentiation between Italian and Spanish Americans.

• DOI: 10.1016/j.humimm.2010.10.017
• 发表时间: 2011-02
• 期刊: HUMAN IMMUNOLOGY
• 影响因子: 2.7
• 作者: Mack, Steven J.;Tu, Bin;Yang, Ruyan;Masaberg, Carly;Ng, Jennifer;Hurley, Carolyn Katovich
• 通讯作者: Hurley, Carolyn Katovich

A multi-site study using high-resolution HLA genotyping by next generation sequencing.

• DOI: 10.1111/j.1399-0039.2010.01606.x
• 发表时间: 2011-03
• 期刊: Tissue antigens
• 作者: Holcomb CL;Höglund B;Anderson MW;Blake LA;Böhme I;Egholm M;Ferriola D;Gabriel C;Gelber SE;Goodridge D;Hawbecker S;Klein R;Ladner M;Lind C;Monos D;Pando MJ;Pröll J;Sayer DC;Schmitz-Agheguian G;Simen BB;Thiele B;Trachtenberg EA;Tyan DB;Wassmuth R;White S;Erlich HA
• 通讯作者: Erlich HA

High-resolution, high-throughput HLA genotyping by next-generation sequencing.

• DOI: 10.1111/j.1399-0039.2009.01345.x
• 发表时间: 2009-11
• 期刊: Tissue antigens
• 作者: Bentley G;Higuchi R;Hoglund B;Goodridge D;Sayer D;Trachtenberg EA;Erlich HA
• 通讯作者: Erlich HA

Common and well-documented HLA alleles: 2012 update to the CWD catalogue.

• DOI: 10.1111/tan.12093
• 发表时间: 2013-04
• 期刊: Tissue antigens
• 作者: Mack SJ;Cano P;Hollenbach JA;He J;Hurley CK;Middleton D;Moraes ME;Pereira SE;Kempenich JH;Reed EF;Setterholm M;Smith AG;Tilanus MG;Torres M;Varney MD;Voorter CE;Fischer GF;Fleischhauer K;Goodridge D;Klitz W;Little AM;Maiers M;Marsh SG;Müller CR;Noreen H;Rozemuller EH;Sanchez-Mazas A;Senitzer D;Trachtenberg E;Fernandez-Vina M
• 通讯作者: Fernandez-Vina M