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CUTTING EDGE |
* Basic Research Program, Science Applications International Corporation-Frederick, National Cancer Institute, Frederick, MD 21702;
Toronto Western Research Institute and Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, and
Regional HLA Laboratory, University Health Network, Toronto, Ontario, Canada; and
Immunology Division, Department of Pathology, University of Cambridge, Cambridge, United Kingdom
Functionally relevant combinations of HLA and killer Ig-like receptor (KIR) genotypes influence resistance to several diseases in humans. Analysis of genetic data from such studies is challenging because it involves multiple linked and unlinked loci that exert their influence in an epistatic manner. We previously reported that subjects with certain activating receptors were susceptible to developing psoriatic arthritis (PsA), an effect that was strongest when HLA ligands for corresponding homologous inhibitory receptors were missing. In this study, we present a novel model in which susceptibility to PsA is determined by the overall balance of activating and inhibitory composite KIR-HLA genotypes. This model fits our knowledge of clonal NK cell expression of KIR and regulation of NK cell activity better than does the previous model, as reflected in a robust trend for increasing susceptibility to PsA with more activating genotypes. These data emphasize the remarkable influence of KIR/HLA combinations on this disease.
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