INVESTIGATION OF THE HLA COMPONENT INVOLVED IN RHEUMATOID-ARTHRITIS (RA) BY USING THE MARKER ASSOCIATION-SEGREGATION GAMMA(2) (MASC) METHOD- REJECTION OF THE UNIFYING-SHARED-EPITOPE HYPOTHESIS

In order to investigate the HLA component involved in rheumatoid arthr itis (RA), we tested genetic models by the marker association-segregat ion chi2 (MASC) method, using the HLA genotypic distribution observed in a sample of 97 RA patients. First we tested models assuming the inv olvement of a susceptibility gene linked to the DR locus. We showed th at the present data are compatible with a simple model assuming the ef fect of a recessive allele of a biallelic locus linked to the DR locus and without any assumption of synergistic effect. Then we considered models assuming the direct involvement of the DR allele products, and we tested the unifying-shared-epitope hypothesis, which has been propo sed. Under this hypothesis the DR alleles are assumed to be directly i nvolved in the susceptibility to the disease because of the presence o f similar or identical amino acid sequences in position 70-74 of the t hird hypervariable region of the DRBI molecules, shared by the RA-asso ciated DR alleles DR4Dw4, DR4Dw14, and DR1. This hypothesis was strong ly rejected with the present data. In the case of the direct involveme nt of the DR alleles, hypotheses more complex than the unifying-shared -epitope hypothesis would have to be considered.