Primary association of tumor necrosis factor-region genetic markers with susceptibility to rheumatoid arthritis

Objective. To determine whether tumor necrosis factor (TNF) polymorphisms a re associated with susceptibility to rheumatoid arthritis (RA) independentl y of the HLA-DR shared epitope. Methods. Fifty-two Spanish families with one or more affected members were typed for HLA-DRB1, TNF promoter polymorphisms, and TNFa and TNFb microsate llites. We performed an association analysis comparing transmitted versus n ot transmitted haplotypes, dth or without shared epitope, to determine whet her there is an independent effect of TNF genetic markers on RA susceptibil ity. Results. TNFa6,b5 was significantly associated with susceptibility to RA. T he haplotypes containing these markers were preferentially transmitted to t he affected offspring, even if these haplotypes lacked the HLA-DR shared ep itope, TNF promoter polymorphisms were not associated with susceptibility t o RA. Conclusion. The data suggest that TNFa/b is an independent marker of RA sus ceptibility, pointing to a genetic role of the TNF region in the pathogenes is of RA.