Susceptibility to IBD is associated with with specific KIR and HLA ligand genotypes

Abstract Adaptive and innate host immune responses to intestinal microbes have been implicated in the pathogenesis of Ulcerative Colitis and Crohn’s Disease, the subtypes of Inflammatory Bowel Disease (IBD). Polymorphisms of the Killer Ig-like Receptors (KIR) genes, which encode receptors on natural killer cells, influence immune mediated diseases. Here we study the genetic contribution of KIR and their HLA ligands in UC and CD. HLA genotyping was performed by next generation sequencing and KIR genotyping with our MALDI-TOF assay. The KIR HLA ligands, Bw4/6 and C1/C2 were assigned using HLA-B and HLA-C residue positions 77-83. The case-control analysis consisted of 1232 Caucasian IBD patients (461 with UC, 771 with CD) and 203 Caucasian controls. The homozygous genotypic combination of KIR2DL3, KIR3DL1 (homozygous KIR A/A haplotype) and Bw6 (absence of Bw4) with a heterozygous C1/C2 genotype was protective (cf, C1/C1 and C2/C2) against ulcerative colitis (OR = 0.29, p < 0.001). No significant association was found with KIR loci and their HLA-ligands with CD. In a C1/C2 heterozygote, signaling would be expected via both the KIR2DL3 receptor and the KIR2DL1 receptor. These data reveal a central role for a specific combination of KIRs and HLA ligands (i.e., homozygous KIR A haplotype, absence of Bw4 and C1/C2 heterozygosity) in protecting against UC disease and underscore the importance of analyzing KIR genotypes in the context of their HLA ligands in disease association studies.