HLA and rheumatoid arthritis: an analysis of multicase families.

In a study of multicase RA families, significantly raised frequencies of the HLA antigens DR4, DR1, Bw62, Cw3, A2, A31 and significantly lower frequencies of DR2, DR3, and B8 were found in probands compared to normal controls. When haplotype frequencies were compared between probands and controls, two haplotypes A2-B44-DR4 and A2-Bw62-DR4 were at higher frequency in probands. These differences no longer reached significance when only DR4-containing haplotypes were compared between probands and controls. A significantly lower haplotype frequency of A1-B8-DR3 was observed in probands compared to controls. This difference did not remain significant when only non-DR4 haplotypes were compared. Using an affected sibling pair ratio method, significant linkage between HLA and RA was found (P less than 0.01). Significant linkage was also observed between HLA and seropositivity. Analysis of Hardy-Weinberg equilibrium for the DR locus did not support the suggestion that DR4-associated RA susceptibility was inherited as a dominant trait. In addition it did not support the notion of an additive effect of DR4 and DR1 in RA susceptibility as these antigens were not found together more frequently than predicted by their individual gene frequencies.