HLA CLASS-II SEQUENCE POLYMORPHISMS AND SUSCEPTIBILITY TO RHEUMATOID-ARTHRITIS IN GREEKS - THE HLA-DR-BETA SHARED-EPITOPE HYPOTHESIS ACCOUNTS FOR THE DISEASE IN ONLY A MINORITY OF GREEK PATIENTS

Objective. In Northern Europeans, rheumatoid arthritis (RA) is strongly associated with a relatively conserved pentapeptide sequence of HLA-DR-beta found notably in the HLA-DR4 subtypes Dw4 and Dw14 and in DR1. A previous serologic study of HLA class II polymorphism in a Greek population with RA failed to show significant associations with any antigen. Methods. We characterized HLA-DRB polymorphisms in Greek patients with RA and in control subjects by restriction fragment length polymorphism analysis. Allelic DRB subtypes were examined by polymerase chain reaction amplification and oligonucleotide hybridization. Results. DNA analysis in the RA patients showed that although individual HLA-DR allelic associations were weak, a relatively conserved HLA-DR-beta motif was significantly associated with RA in this population of Greek patients. The third hypervariable region amino acid sequences QRRAA, QKRAA, or RRRAA were found in the HLA-DR-beta-1 of 43.5% of the RA patients versus 15.5% of the controls (uncorrected P = 0.00004). Conclusion. Sequences shown to influence susceptibility to RA in patients in the UK also play a role in patients in Greece. However, 57% of Greek patients lack the putative HLA-DR-beta motif, which suggests that considerable immunogenetic heterogeneity underlies disease susceptibility in this population.