Presentation: Studies on the Genetic Association of MHC Class I Chain-related Gene A (MICA) with Japanese Patients with Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) (2007)

824 Studies on the Genetic Association of MHC Class I Chain-related Gene A (MICA) with Japanese Patients with Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE)

PURPOSE: MICA interacts with an activating receptor NKG2D, that is expressed on CD8 T cells, γd T cells and NK cells. MICA is normally expressed on gastrointestinal epithelium, but is also aberrantly expressed on tumor cells, cytomegalovirus infected cells or rheumatoid synoviocytes. Recent findings suggest that MICA is released from proliferating cells such as tumor cells, and soluble MICA (sMICA) downregulates surface NKG2D and reduces NK cytotoxicity. Importantly, substantial amounts of sMICA are also detectable in sera of patients with rheumatoid arthritis (RA), and NK cell function is defective in systemic lupus erythematosus (SLE). MICA is highly polymorphic, and previous studies have shown that the tandem repeat of GCT in the transmembrane (TM) region of MICA encodes for variable number of alanines (A), and the different alleles existed in the MICA gene are named A4, A5, A6, A5.1 or A9 and the polymorphism in the TM region are associated with autoimmunity. Further, substitution of methionine to valine at codon 129 of MICA gene (rs1051792) significantly influences the affinity with NKG2D. Therefore, we have studied the TM polymorphism and the SNP at codon 129 of MICA in Japanese patients with RA and SLE.
METHODS: Genomic DNA samples were obtained from peripheral blood from Japanese 335 patients with RA (60 males vs. 275 females) and 44 SLE (5 males vs. 39 females) and 211 healthy controls (96 males vs. 115 females). For analysis of the polymorphism in TM region of MICA gene, genotyping was performed by PCR using fluorescent labeled primers and length analysis. Second, the MICA-129val allele was identified by PCR-RFLP. Differences in allele or genotype frequencies between RA, SLE and controls were evaluated by using chi-square test.
RESULTS: MICA A4/A5.1 genotype was increased in RA as compared with controls: 7.7% vs. 2.7% (p<0.05, OR=3.01), whereas MICA A5/A5.1 genotype was decreased as compared with controls: 3.0% vs. 7.0% (p<0.05, OR=0.41). The polymorphism in MICA-129 allele was not associated with RA. In contrast, MICA A9 allele was significantly increased in SLE as compared with controls: 17.4% vs. 9.7% (p<0.05, OR=1.96). Accordingly, MICA A4/A9 and A5/A9 genotypes were significantly increased in SLE as compared with controls: 14.0% vs. 3.2% (p<0.01, OR=4.84) and 18.6% vs. 6.5% (p<0.05, OR=3.29), respectively. MICA-129met allele was also significantly increased in SLE as compared with controls: 39.8% vs. 28.7% (p<0.05, OR=1.64).
CONCLUSIONS: The polymorphism in the MICA gene was uniquely associated with Japanese patients with RA and SLE. In particular, since the MICA-129met allele associated with SLE in the present study has been shown to heighten MICA-NKG2D signaling, the present finding may have an important implication to pathogenesis of autoimmunity.

 K. Yoshida, None; K. Komai, None; A. Mashida, None; M. Murata, None; K. Shiozawa, None; S. Shiozawa, None.