Contribution of MHC class I chain-related A (MICA) gene polymorphism to genetic susceptibility for systemic lupus erythematosus

Objective. To evaluate the contribution of the MHC class I chain-related A (MICA) gene polymorphism to the genetic risk of systemic lupus erythematosus (SLE). Methods. HLA-DRB1-DQA1-DQB1 genotyping, MICA exon 5 microsatellite genotyping and HLA-B8 genotyping were performed in 48 Italian SLE patients and in 158 healthy control subjects. Results. Of HLA class II haplotypes, only DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) was significantly more frequent among SLE patients than among healthy control subjects [odds ratio (OR) = 6.5, corrected P<0.0026]. HLA-B8 was detected in 31% SLE patients and 13% healthy control subjects (OR = 3.0, P = 0.005). The allele-wise comparison between patients and controls showed that both MICA5 (OR = 2.5, corrected P<0.0005) and MICA5.1 (OR = 2.4, corrected P<0.0005) were positively and MICA9 (OR = 0.2, corrected P<0.0005) was negatively associated with the disease. The MICA5/5.1 genotype was positively associated with SLE (OR = 28.9, corrected P<0.0015) also in subjects negative for DR3-DQ2 (OR>22.6, corrected P<0.011). The simultaneous presence of DR3-DQ2 and MICA5.1 was detected in 15/48 (31%) SLE and in 10/158 (6%) healthy control subjects (OR = 6.7, corrected P<0.011). The simultaneous combination of DR3-DQ2 and MICA5 was found in 10/48 (21%) SLE patients and in only 1/158 healthy control subjects (OR = 41.3, corrected P<0.011). Logistic regression analysis showed the independent positive associations of MICA5 and MICA5.1 and negative association of MICA9 with the disease, and revealed that the interaction of the three major markers (DR3-DQ2, MICA5 and MICA5.1) was associated with increasing genetic risk, which was highest (OR>30.3) in DR3-DQ2-positive subjects carrying the MICA5-5.1 genotype. Conclusions. Our study provides the first demonstration of the independent association of the MICA gene polymorphism with genetic risk of SLE.