Genetic effects of the MHC /KIR locus on autoimmune dis

MHC/KIR 位点对自身免疫性疾病的遗传效应

• 批准号: 6951000
• 负责人: Mary N. Carrington
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6951000
• 关键词: MHC class I antigen; antibody receptor; autoimmune disorder; cancer risk; colorectal neoplasms; cytotoxic T lymphocyte; disease /disorder proneness /risk; family genetics; genetic polymorphism; histocompatibility typing; human genetic material tag; human tissue; immune response genes; immunogenetics; inflammatory bowel diseases; leukocyte activation /transformation; linkage mapping; nasopharyngeal neoplasms; natural killer cells; neoplasm /cancer genetics; pathologic process; receptor expression; rheumatoid arthritis; spondylitis

Limited genetic data have been reported regarding effects of HLA on cancer, and no studies have been published that address the influence of the killer immunoglobulin-like receptors (KIR) repertoire on predisposition to cancer. We have established a collaboration with Dr. Metka Ravnik-Glavac in Slovenia to study a large group of individuals with primary colorectal cancer (CRC) and ethnically matched controls. The prevalence of CRC in Slovenia, which has a population size of 2,000,000, is approximately 850 new cases each year. Samples were obtained from clinics throughout the country, so the CRC sample being tested is representative of the entire Slovenian population. We have typed HLA class I and KIR (presence/absence) loci in 484 individuals with colorectal cancer and 212 controls, the latter of which are being supplemented with an additional group of 180 individuals. Nasopharyngeal carcinoma (NPC), which arises in the epithelial cells of the nasopharynx, exhibits a strong association with Epstein Barr virus (EBV). Although it is a relatively rare malignancy in most populations, it is a substantial source of cancer morbidity in Southern China. NPC occurs among family members of patients and disease risk has been linked with HLA, although the HLA associations differ by ethnic group. We are studying the effects of these genes in a case-control study of NPC involving 618 individuals from Taiwan. These individuals have been typed previously for the HLA-A and HLA-B loci. We have now completed typing HLA-C and the KIR locus in these individuals and the data are now being analysed. We propose that the presence of activating KIR expressed on natural killer (NK) cells may aggravate autoimmune and inflammatory pathogenesis by inducing NK cell-mediated cytokine secretion and cytolysis. Data supporting this hypothesis was observed in a group of patients with psoriatic arthritis (PsA) attending the University of Toronto Psoriatic Arthritis Clinic in collaboration with Dr. Dafna Gladman. In a related study, we have begun to genotype KIR/HLA in patients with ankylosing spondylitis (AS), a chronic, systemic, inflammatory rheumatic autoimmune disease of the axial skeleton. Although multiple genes are probably involved in susceptibility to AS, HLA-B*27 exhibits the strongest association identified to date, with more than 95% of patients being B*27 positive. The AS samples have been obtained from Addenbrooke's Hospital at Cambridge University, and the Royal National Hospital of Rheumatic Disease, through our collaborators Drs. Rachel Allen and John Trowsdale (Cambridge University). To date, we have received 199 samples from AS patients and are scheduled to receive at minimum 100 additional samples over the next few months. The chronic inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis, are idiopathic, inflammatory disorders of the gastrointestinal tract that are thought to result from inappropriate and ongoing activation of the mucosal immune system. Recently, our collaborators combined linkage results of genome-wide scans from five independent studies using an algorithm called genome search meta-analysis. A locus at 6p, which contains the major histocompatibility complex (MHC), showed the strongest evidence for linkage to disease across the five studies. In collaboration with Dr. John Rioux (Massachusetts Institute of Technology), we have planned a pilot study in which 200 individuals with Crohn's disease and 200 matched (age, gender, geographic location, ancestry) controls, as well as 200 sets of mother-father-IBD affected child trios will be typed for the HLA class I and KIR genes to determine whether previously identified HLA associations with IBD can be attributed in part to KIR genetic variation. If associations are identified, then we will confirm these effects with additional samples from the Genetics Core of the Quebec IBD Genetics Consortium, which is directed by Dr. Rioux. Genetic analysis of HLA/KIR in these diseases may provide information regarding a general

关于HLA对癌症影响的遗传学数据有限，并且没有发表关于杀伤免疫球蛋白样受体（KIR）库对癌症易感性影响的研究。我们与斯洛文尼亚的Metka Ravnik-Glavac博士建立了合作关系，研究了一大批原发性结直肠癌（CRC）患者和种族匹配的对照组。斯洛文尼亚人口为2，000，000人，每年约有850例新病例。样本从全国各地的诊所获得，因此正在测试的CRC样本代表了整个斯洛文尼亚人口。我们分型HLA I类和KIR（存在/不存在）基因座在484个人与结直肠癌和212个控制，后者正在补充一组额外的180个人。 鼻咽癌（NPC）发生于鼻咽上皮细胞，与爱泼斯坦巴尔病毒（EB病毒）密切相关。虽然它在大多数人群中是一种相对罕见的恶性肿瘤，但它是中国南方癌症发病率的重要来源。NPC发生在患者的家庭成员中，疾病风险与HLA有关，尽管HLA相关性因种族而异。我们正在研究这些基因的影响，在一个病例对照研究的鼻咽癌涉及618人来自台湾。这些个体先前已被分型为HLA-A和HLA-B基因座。我们现在已经完成了对这些人的HLA-C和KIR位点的分型，目前正在分析数据。 我们认为，激活KIR表达的自然杀伤（NK）细胞的存在下，可能会加剧自身免疫和炎症的发病机制，诱导NK细胞介导的细胞因子分泌和细胞溶解。与Dafna Gladman博士合作，在多伦多大学银屑病关节炎诊所的一组银屑病关节炎（PsA）患者中观察到支持这一假设的数据。在一项相关的研究中，我们已经开始对强直性脊柱炎（AS）患者进行KIR/HLA基因分型，AS是一种中轴骨骼的慢性、全身性、炎症性风湿性自身免疫性疾病。虽然可能有多个基因参与AS的易感性，但迄今为止，HLA-B*27表现出最强的相关性，超过95%的患者为B*27阳性。AS样本通过我们的合作者Rachel艾伦和John Trowsdale博士（剑桥大学）从剑桥大学Addenbrooke医院和皇家国立风湿病医院获得。到目前为止，我们已经收到了199份来自AS患者的样本，并计划在未来几个月内再收到至少100份样本。慢性炎症性肠病（IBD）克罗恩病和溃疡性结肠炎是胃肠道的特发性炎性疾病，被认为是由粘膜免疫系统的不适当和持续激活引起的。最近，我们的合作者使用一种称为基因组搜索荟萃分析的算法，将来自五项独立研究的全基因组扫描的连锁结果结合起来。一个位于6p的位点，包含主要组织相容性复合体（MHC），在五项研究中显示出与疾病联系的最强有力的证据。与John Rioux博士合作（马萨诸塞州理工学院），我们已经计划了一项试点研究，其中200名克罗恩病患者和200名匹配的（年龄、性别、地理位置、血统）对照，以及200套父母-将对受IBD影响的儿童三人组进行HLA I类和KIR基因分型，以确定之前确定的HLA与IBD的相关性是否可以部分归因于KIR基因变异。如果确定了相关性，那么我们将使用来自魁北克IBD遗传学联盟遗传学核心的额外样本来证实这些影响，该联盟由Rioux博士指导。这些疾病中HLA/KIR的遗传学分析可能提供关于一般性免疫缺陷的信息。