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

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Abstract
Objective To determine whether tumor necrosis factor (TNF) polymorphisms are associated with susceptibility to rheumatoid arthritis (RA) independently 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 microsatellites. We performed an association analysis comparing transmitted versus not transmitted haplotypes, with or without shared epitope, to determine whether there is an independent effect of TNF genetic markers on RA susceptibility. Results TNFa6,b5 was significantly associated with susceptibility to RA. The haplotypes containing these markers were preferentially transmitted to the affected offspring, even if these haplotypes lacked the HLA–DR shared epitope. TNF promoter polymorphisms were not associated with susceptibility to RA. Conclusion The data suggest that TNFa/b is an independent marker of RA susceptibility, pointing to a genetic role of the TNF region in the pathogenesis of RA.

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