Activating Killer-cell Immunoglobulin-like Receptor genes confer risk for Crohn’s disease in children and adults of the Western European descent: Findings based on case-control studies

BACKGROUND: Killer-cell Immunoglobulin-like Receptor (KIR) genes encode receptors, which are mainly expressed on, and control functional activities of, Natural Killer (NK) cells. There exist six distinct activating KIR genes in humans, who differ from one another with respect to the repertoire of these genes. Because activated NK cells can potentially cause tissue destruction, we hypothesized that variation in the inherited activating KIR genes in humans is associated with their innate susceptibility/resistance to developing Crohn disease (CD). METHODS: We performed case control studies on three independent Canadian CD patient cohorts (all of the Western European descent): two comprising children (Montreal having 193 cases and 245 controls, and Ottawa having 93 cases and 120 controls) and the third one comprising predominantly adults (Winnipeg having 164 cases and 200 controls). We genotyped cases and controls for activating KIR genes by PCR with gene-specific primers and investigated associations between the genes and cases using unconditional logistic regression. RESULTS: We observed strong associations between all the six KIR genes and CD in Ottawa children, with the strongest risk observed for the KIR2DS1 (p = 1.7 x10(-10)). Associations between all but the KIR2DS2 were replicated in the Montreal cohort with the strongest association evident for the KIR2DS5 (8.0 x 10(−10)). Similarly associations between five genes were observed in the adult Winnipeg cohort. In this cohort, strongest associations were evident with the KIR2DS5 (8.75 x 10(−8)). An overall analysis for all cohorts showed strong associations with four of the genes, with the strongest association evident for the KIR2DS5 (p = 1.35 x 10−(17)). In the combined analysis for four KIR genes, individuals carrying one or more of the KIR genes were at significantly higher risks for acquiring CD (p = 3.5 x 10(−34)). CONCLUSIONS: Activating KIR genes are associated with risk for developing CD in both children and adults.