Objective To study the genetic contribution of major histocompatibility complex class I polypeptide-related sequence A (MICA), important in natural killer (NK) cell function, in patients with systemic lupus erythematosus (SLE). Methods Japanese patients with SLE (n = 716), those with rheumatoid arthritis (RA) (n = 327), and healthy control subjects (n = 351) were genotyped for the Val129Met polymorphism (rs1051792) and transmembrane (TM) alanine-encoding GCT repeats, termed A4, A5, A5.1, A6, and A9, in the MICA gene. Recombinant human MICA-GST fusion proteins were tested on the NK cell line NK92MI for the expression of NK group 2, member D (NKG2-D), NK cell-mediated cytotoxicity, and interferon-γ (IFNγ) production. Results The MICA 129Met allele, TMA9 allele, and 129Met/Met genotype were positively associated with SLE (corrected P [Pcorr] = 0.01 and odds ratio [OR] 1.3, Pcorr = 0.003 and OR 1.6, and Pcorr = 0.02 and OR 1.8, respectively), while the MICA 129Val allele was negatively associated with SLE (Pcorr = 0.01, OR 0.8). The MICA 129Met;A9 haplotype was also associated with SLE (Pcorr = 0.0006, OR 1.8), and there was an additive genetic effect between the MICA 129Met;A9 haplotype and HLA-DRB115:01. When NK92MI cells were incubated in vitro with recombinant human disease-associated 129Met;A9 (the combination of polymorphisms at 129Met and TMA9), expression of NKG2-D on NK92MI cells and cytotoxicity of the NK cells were inhibited, but production of IFNγ from NK92MI cells was enhanced. Conclusion The MICA polymorphism is genetically associated with SLE, and MICA appears to contribute to the pathogenesis of SLE by modulating NK cell function.
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