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 killer immunoglobulin-like receptor (KIR) locus in these individuals and the analysis is ongoing. We have proposed 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 from our lab that supports this hypothesis was observed in a group of patients with psoriatic arthritis (PsA) attending the University of Toronto Psoriatic Arthritis Clinic under the care of Dr. Dafna Gladman. In a related study, we have genotyped 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-B27 exhibits the strongest association identified to date, with more than 95% of patients being B27 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). 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 begun a pilot study in which 200 individuals with Crohn's disease and 200 matched (age, gender, geographic location, and 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. Thus far, we have received approximately 500 samples and are in the process of genotyping them. In addition, we are also collaborating with Dr. Kathy Siminovitch at the University of Toronto and have received approximately 1200 samples from her IBD cohort. Genotyping of these samples will begin once the first set of IBD samples is typed. Genetic analysis of HLA/KIR in these diseases may provide information regarding a general tendency of predisposition to autoimmune disease among individuals with specific activating KIR.
