ARTHRITIS & RHEUMATISM Vol. 42, No. 3, March 1999, pp 438–442 © 1999, American College of Rheumatology TUMOR NECROSIS FACTOR a MICROSATELLITE POLYMORPHISM IS ASSOCIATED WITH RHEUMATOID ARTHRITIS SEVERITY THROUGH AN INTERACTION WITH THE HLA–DRB1 SHARED EPITOPE HUA MU, JOHN J. CHEN, YEBIN JIANG, MARY-CLAIRE KING, GLENYS THOMSON, and LINDSEY A. CRISWELL Objective. To determine whether tumor necrosis factor microsatellite a (TNFa) polymorphism is associ- ated 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 multivar- iate 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 demon- strated 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, individ- uals 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 asso- ciated with RA severity through an interaction with the HLA–DRB1 SE. The most well-established genetic risk factor for RA susceptibility and disease expression is the HLA– DRB1 locus. The molecular basis for this association is widely understood in the framework of the “shared epitope” hypothesis, in which genetic susceptibility is associated with inheritance of particular alleles that share a conserved amino acid sequence (QKRAA, QRRAA, or RRRAA) in their third hypervariable re- gions (1). However, the HLA–DRB1 gene does not account for the total genetic contribution to the disease. Genetic epidemiologic studies indicate that an HLA- linked locus accounts for less than half of familial RA, and at least 25% of RA patients do not possess the HLA–DRB1 shared epitope (SE) (2–6). To date, how- ever, no additional genes have been definitively proven to be associated with RA susceptibility or severity. Several lines of evidence implicate an important role for tumor necrosis factor  (TNF) in RA. TNF appears to play a pivotal role in RA synovitis (7) and to mediate the bone erosions characteristic of the disease (8). Transgenic mice carrying a modified human TNF gene develop an erosive arthritis that closely resembles RA (9). Finally, treatment with agents designed to interfere with TNF action has demonstrated clinical efficacy in a growing number of RA clinical trials (10,11). Supported by Multipurpose Arthritis Center grant AR-20684 and NIH grants GM-28428 and GM-56688. This work was performed while Dr. Criswell was a Pfizer Scholar. Hua Mu, MD, PhD, Mary-Claire King, PhD: University of Washington School of Medicine, Seattle; John J. Chen, MS, MA, Glenys Thomson, PhD: University of California, Berkeley; Yebin Jiang, MD, PhD, Lindsey A. Criswell, MD, MPH: Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco. Drs. Mu and Chen contributed equally to this work. Address reprint requests to Lindsey A. Criswell, MD, MPH, Division of Rheumatology, 521 Parnassus Avenue, C405, Box 0633, San Francisco, CA 94143-0633. Submitted for publication April 20, 1998; accepted in revised form September 8, 1998. 438