Objective: To investigate whether interactions between tumor necrosis factor (TNF) microsatellite polymorphisms and the HLA-DRB1 shared epitope (SE) are associated with disease severity in rheumatoid arthritis (RA), and to determine if such associations are the same in male and female patients.
Methods: Genotyping for the TNFa microsatellite and HLA-DRB1 was carried out on 157 RA patients with established disease (duration >5 years). Disease severity measures included radiographic damage (the Larsen method), functional assessment by the Health Assessment Questionnaire, history of joint surgery, and global appraisal of outcome by means of a visual analog scale score. The association of severity measures with TNFa microsatellite polymorphisms stratified by SE status, and the interaction between TNFa and the SE, were investigated using stratified analyses and multiple or logistic regression analyses.
Results: No significant associations were observed between any single TNFa microsatellite polymorphism and disease severity, although preliminary evidence for an interaction between TNFa6 and TNFa11 was obtained. In the presence of the SE, a significantly worse outcome was associated with individuals carrying TNFa6, and a significant interaction (P = 0.04-0.006) was found between these alleles for 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, significant 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 the worst outcome scores.
Conclusion: The association of the SE with disease severity in RA is influenced by an interaction with the TNFa6 microsatellite polymorphism. This interaction appears to be acting predominantly in female patients, although the trend is similar in the smaller percentage of males carrying the TNFa6/SE haplotype.