Paradoxical inheritance of HLA-linked susceptibility to rheumatoid arthritis

In order to clarify the discrepancy between population studies showing association of rheumatoid arthritis (RA) with HLA-DR4/-Dw4 and family studies failing to show linkage with HLA, we analysed 16 multicase families in which RA and DR4 status of both parents was known. 120 HLA-haplotypes of affected and unaffected children could be analysed for co-segregation with RA. In a combined analysis of both affected and unaffected children co-segregation of RA with the DR4 carrying haplotype was observed when both parents were unaffected (p=0.001). Co-segregation of RA with one of the two haplotypes of affected parents was observed (p=0.01), but in this case there was no preference for the DR4 carrying haplotype. In both cases preferential inheritance of the other (not associated with RA) haplotype was observed in unaffected siblings. These data indicate that susceptibility to RA is controlled by an HLA-linked gene. This gene is often but not always identical to the gene coding for a product carrying the DR4 epitope or in strong linkage disequilibrium with it. Combined with previous population data, the present data provide evidence for genetic heterogeneity of RA. Finally, they contain a paradox, based on which a new hypothesis for HLA-linked susceptibility to RA is formulated.