Association analysis between the MIC-A and HLA-B alleles in Japanese patients with Behçet's disease.

Abstract

Behçet's disease is known to be strongly associated with HLA-B51 in many different ethnic groups. Recently, by association analysis using refined microsatellite mapping, the critical region for Behçet's disease was identified as a 46-kb segment centromeric to the HLA-B gene. No expressed gene has been detected in this segment to date except the MIC-A (major histocompatibility complex class I chain-related gene A) and HLA-B genes. The present study was undertaken to analyze allelic distribution of the MIC-A gene among Japanese patients with Behçet's disease. Ninety-five Japanese patients with Behçet's disease and 116 ethnically matched healthy controls were enrolled in this study. MIC-A genotyping was performed by direct sequencing of polymerase chain reaction products from exons 2, 3, and 4 of the MIC-A gene, using an automated DNA sequencer. The MIC-A009 allele was significantly more frequent in the patient group (69.5%) compared with the healthy controls (31.0%) (relative risk 5.06, corrected P = 0.00000024). In stratification analysis on the confounding effect of MIC-A009 on HLA-B*51 association and vice versa, Behçet's disease was distinctively associated only with HLA-B*51. Further, MIC-A009 was found to be strongly associated not only with HLA-B51, but also with HLA-B52, which was not increased in the patient group to any degree. These results imply that the real disease susceptibility gene involved in the development of Behçet's disease is the HLA-B*51 allele itself and that the significant increase of the MIC-A009 allele in the patient group results secondarily from a strong linkage disequilibrium with HLA-B*51.