Genetic effects of the MHC /KIR locus on autoimmune dis

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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