Cutting edge: heterozygote advantage in autoimmune disease: hierarchy of protection/susceptibility conferred by HLA and killer Ig-like receptor combinations in psoriatic arthritis.
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.
Nelson
George W
GW
Basic Research Program, Science Applications International Corporation-Frederick, National Cancer Institute, Frederick, MD 21702, USA.
Martin
Maureen P
MP
Gladman
Dafna
D
Wade
Judith
J
Trowsdale
John
J
Carrington
Mary
M
D015535:Arthritis, Psoriatic / Q000235:genetics* / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control*; D006580:Genetic Carrier Screening; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics* / Q000378:metabolism; D015796:HLA-B27 Antigen / Q000235:genetics / Q000378:metabolism; D015236:HLA-C Antigens / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D018448:Models, Immunological; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D054340:Receptors, KIR; D054342:Receptors, KIR2DL1
D006680:HLA Antigens; D015796:HLA-B27 Antigen; D015236:HLA-C Antigens; C093100:KIR2DL1 protein, human; C433932:KIR2DS2 protein, human; D008024:Ligands; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054342:Receptors, KIR2DL1