Interaction between tumor necrosis factor microsatellite polymorphisms andthe HLA-DRB1 shared epitope in rheumatoid arthritis - Influence on diseaseoutcome

Objective. To investigate whether interactions between tumor necrosis facto r (TNF) microsatellite polymorphisms and the HLA-DRB1 shared epitope (SE) a re associated with disease severity in rheumatoid arthritis (RA), and to de termine if such associations are the same in male and female patients. Methods, Genotyping for the TNFa microsatellite and HLA-DRB1 was carried ou t on 157 RA patients with established disease (duration >5 years). Disease severity measures included radiographic damage (the Larsen method), functio nal assessment by the Health Assessment Questionnaire, history of joint sur gery, and global appraisal of outcome by means of a visual analog scale sco re. The association of severity measures with TNFa microsatellite polymorph isms stratified by SE status, and the interaction between TNFa and the SE, were investigated using stratified analyses and multiple or logistic regres sion analyses, Results. No significant associations were observed between any single TNFa microsatellite polymorphism and disease severity, although preliminary evid ence for an interaction between TNFa6 and TNFa11 was obtained. In the prese nce of the SE, a significantly worse outcome was associated with individual s carrying TNFa6, and a significant interaction (P = 0.04-0.006) was found between these alleles fur all the outcome measures examined except history of joint surgery. In the absence of the SE, the TNFa6 allele was associated with significantly better outcome scores. When examined by sex, significan t associations between the TNFa6/SE haplotype and disease outcome measures were found only in females, No statistically significant interactions were found in males, although the TNFa6/SE haplotype was still associated with t he worst outcome scores. Conclusion. The association of the SE with disease severity in RA is influe nced by an interaction with the TNFa6 microsatellite polymorphism. This int eraction appears to be acting predominantly in female patients, although th e trend is similar in the smaller percentage of males carrying the TNFa6/SE haplotype.