Rheumatoid arthritis (RA) is a chronic peripheral arthritis of unknown etiology affecting 1-2% of the world's population. Studies of identical twins and multiplex families strongly suggest a genetic component of RA susceptibility, but these same studies point to multiple genes and reduced penetrance. The purpose of this project is to identify the chromosomal location of these genes. Population studies have already shown that at least one susceptibility locus is probably associated with the HLA-DR4 and DR1 alleles of the major histocompatibility complex (MHC). Since HLA-DR molecules are known to present antigen to the T-cell receptor (TCR), we speculated that TCR genes might also contribute to RA susceptibility. In the collagen-induced arthritis mouse model of RA, disease susceptibility is jointly determined by MHC and TCR genes. We therefore decided to study the role of TCR genes in determining RA susceptibility in man. DNA specimens were obtained from multiplex RA families seen in rheumatology clinics in Cork (Ireland), Salt Lake City, and Toronto. A total of 259 individuals were studied (77 affected). Families were genotyped for markers associated with the TCR beta and gamma chains, both by Southern blotting and by the polymerase chain reaction. Data were analyzed by a linkage analysis method that allowed for more than one susceptibility locus, and by affected sib pair analysis. To date we have obtained suggestive, although not conclusive evidence that the TCR beta chain gene may encode RA susceptibility. Using the Vbeta6.7 PCR marker in affected sib pair analysis, there was more sharing of haplotypes than expected by chance. The p value or this comparison was 0.0., but the value required for significance is controversial (it may be as low as 0.001). We have found no evidence that the TCR gamma gene encodes RA susceptibility.
