Association of tumor necrosis factor alpha polymorphism, but not the shared epitope, with increased radiographic progression in a seropositive rheumatoid arthritis inception cohort

Arthritis Rheum. 2006 Apr;54(4):1105-16. doi: 10.1002/art.21750.


Objective: To determine whether the tumor necrosis factor alpha (TNFA) -308 guanine-to-adenosine polymorphism and/or the shared epitope (SE) is associated with radiographic damage in patients with early rheumatoid arthritis (RA).

Methods: The cohort consisted of 189 patients with early seropositive RA (median 5.6 months since symptom onset) who had active disease, no previous disease-modifying antirheumatic drug treatment, and >or=2 sets of scored radiographs of the hands/wrists and forefeet. TNFA -308 polymorphism was analyzed by polymerase chain reaction pyrosequencing. The SE was defined as presence of any 1 of the following HLA-DRB1 alleles: *0101, *0102, *0401, *0404, *0405, *0408, *0410, *1001, *1402, or *1406. Radiographic progression was assessed by the total Sharp score.

Results: Using a weighted least-squares regression analysis, patients with the -308 TNFA AA plus AG genotypes (n=49) had significantly higher rates of progression in erosion scores (median 0.84 versus 0.48 units/year), joint space narrowing (JSN) scores (0.42 versus 0.04), and total Sharp scores (1.70 versus 0.61) compared with patients with the TNFA GG genotype (n=140). Presence of the SE (n=137) was associated with significantly lower progression rates (per year) for total Sharp scores (median 0.9 versus 1.25 units/year) and JSN scores (0.04 versus 0.41), but not for erosion scores (0.50 versus 0.61) compared with patients without the SE (n=52). In a least-squares multiple linear regression model, the presence of the AA plus AG genotypes was associated with a significantly higher progression rate after adjusting for the presence of the SE, interaction between the SE and the AA plus AG genotypes, baseline log C-reactive protein level, Health Assessment Questionnaire Disability Index, total Sharp score, swollen joint count, and presence of osteophytes (osteoarthritis). There was a strong linkage disequilibrium between DRB1*0301 and TNFA polymorphism (D'=0.84, r2=0.45, P<0.001).

Conclusion: This study showed an association between the TNFA -308 polymorphism and progression of radiographic damage in patients with early seropositive RA. This association appeared to be independent of the SE, but might be dependent on other genetic variants in linkage disequilibrium with the -308 TNFA A allele and DRB1*0301. Further studies should be conducted to validate these results in both longitudinal observational cohorts and randomized clinical trials.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / diagnostic imaging*
  • Arthritis, Rheumatoid / genetics*
  • Disease Progression
  • Epitopes / genetics*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Genetic*
  • Radiography
  • Regression Analysis
  • Tumor Necrosis Factor-alpha / genetics*


  • Epitopes
  • Tumor Necrosis Factor-alpha