The effect of HLA-DRB1 disease susceptibility markers on the expression of RA

The study was designed to examine the effect on clinical expression of rheumatoid arthritis (RA) of HLA alleles, particularly DR4 and DR1 that contain susceptibility sequences for RA in the third hypervariable region (HVR3) of HLA-DRB1. We studied 114 consecutive Australian patients with RA attending a hospital outpatient clinic. The effects on indices of disease severity and activity of HLA DR4 and DR1, the DRB1*04 subtypes, and the polymorphism in the RA susceptibility sequence (QRRAA or QKRAA) were examined. The patients were initially divided into 6 groups, DR4,4; DR4,1; DR1,1; DR4/X; DR1,X, and DRX/X, and then further subdivided according to the actual HVR3 susceptibility sequence. The high risk conferred by the HVR3 susceptibility sequence, present in 76%, was confirmed, but 24% of the patients with long-standing seropositive erosive RA lacked this sequence. Among these those with DR2 had early-onset severe disease, and those with DR3 had late-onset milder disease. Differences in expression correlated with polymorphisms in the susceptibility sequence, in that active RA was associated more with QRRAA than QKRAA. There was no correlation of any HLA allele with disease severity. Our finding that the presence of the HVR3 sequence confers susceptibility and also influences the clinical expression and tempo of progression of RA suggests a role in pathogenesis for antigen presentation, whether of an autoantigenic molecule or a persisting infection.