Tumor necrosis factor a microsatellite polymorphism is associated with rheumatoid arthritis severity through an interaction with the HLA-DRB1 shared epitope

Arthritis Rheum. 1999 Mar;42(3):438-42. doi: 10.1002/1529-0131(199904)42:3<438::AID-ANR7>3.0.CO;2-F.


Objective: To determine whether tumor necrosis factor microsatellite a (TNFa) polymorphism is associated with severity of rheumatoid arthritis (RA), and to examine the evidence for interaction between TNFa and the HLA-DRB1 shared epitope (SE).

Methods: One hundred seventy-one community-based white female RA patients were genotyped for both TNFa and HLA-DRB1 alleles. We performed pairwise association analyses, stratified analyses, and multivariate logistic regressions to determine whether TNFa was associated with 4 measures of RA severity, and whether there was significant interaction between TNFa and the HLA-DRB1 SE.

Results: Simple pairwise analyses did not reveal significant association between TNFa polymorphism and RA severity. However, when the data were stratified by the presence versus absence of the SE, striking associations were observed between TNFa allele 11 (TNFa11) and RA severity. These analyses also demonstrated significant interaction between TNFa11 and the SE (P = 0.07-0.005), and this was confirmed in our multivariate regressions. Specifically, the most severe outcomes were observed among individuals who had inherited both TNFa11 and the SE (61-71% had severe RA based on 1 of the 4 outcomes). In contrast, individuals who had inherited TNFa11 in the absence of the SE had the best outcomes (8-21% with severe RA). The odds ratios comparing these 2 groups ranged from 8.8 to 22.7 for the 4 severity measures. The differential effect of TNFa11 according to the presence versus absence of the SE (and vice versa) illustrated their interaction with respect to RA severity.

Conclusion: The data suggest that TNFa is associated with RA severity through an interaction with the HLA-DRB1 SE.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Alleles
  • Arthritis, Rheumatoid / genetics*
  • Arthritis, Rheumatoid / immunology*
  • DNA, Satellite / analysis
  • DNA, Satellite / immunology*
  • Epitopes / analysis
  • Epitopes / immunology
  • Female
  • HLA-DR Antigens / analysis
  • HLA-DR Antigens / immunology*
  • HLA-DRB1 Chains
  • Histocompatibility Testing
  • Humans
  • Longitudinal Studies
  • Middle Aged
  • Multivariate Analysis
  • Polymorphism, Genetic
  • Tumor Necrosis Factor-alpha / genetics*


  • DNA, Satellite
  • Epitopes
  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • Tumor Necrosis Factor-alpha