Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.

GSTM1, HLA-DBR1, and Smoking Interactions Suggest a Role for Oxidative Stress in the Pathogenesis of APCA-Positive Rheumatoid Arthrtits

Mikuls1,  T. R., Gould2,  Karen A., Bynote2,  Kimberly K., Yu2,  Fang, LeVan2,  Tricia D., Thiele3,  Geoffrey M., Michaud4,  Kaleb D.

U Nebraska, Omaha, NE
Veterans Affairs Medical Ctr, Washington, DC
University of California, San Francisco
Feinstein Institute for Medical Research, Manhasset, NY
VA and University of Utah, Salt Lake City, UT
University of Nebraska Medical Center, Omaha, NE
Univ of NE Medical Ctr, Omaha, NE
University of Nebraska and NDB, Omaha, NE
VAMC, University of Texas Southwestern Medical Center, Dallas, TX
Department of Veterans Affairs, Dallas, TX
Univ of CO Denver School of Med, Aurora, CO
University of MS Med Ctr, Jackson, MS
VAMC, Georgetown University, Washington, DC


Approximately half of Caucasians are homozygous for a deletion allele in glutathione S-transferase Mu-1 (GSTM1-null), a genotype previously associated with rheumatoid arthritis (RA). The purpose of this study was to examine the associations of GSTM1 status with anti-cyclic citrullinated peptide antibody (ACPA) positivity and to assess interactions of this genotype with other known RA risk factors.


Associations of GSTM1-null, HLA-DRB1 shared epitope (SE), and smoking with autoantibody positivity were examined in U.S. veterans with RA (n = 595). Additive gene-gene and gene-smoking interactions were examined by calculating an attributable proportion (AP) due to interaction.


Patients were predominantly men (93%) with a history of ever smoking (79%). Most were positive for ACPA (77%), rheumatoid factor (RF) (81%), and SE (75%) while 53% were GSTM1-null. GSTM1-null (vs. GSTM1-present) was associated with a significantly higher odds of ACPA positivity (OR = 1.58; 95% CI 1.07 to 2.32) but not with RF positivity. There were significant additive interactions between SE-smoking (AP = 0.56; 95% CI 0.27 to 0.86) and SE-GSTM1 (AP = 0.49; 95% CI 0.21 to 0.77) in ACPA positivity, the latter most striking in ever smokers (Figure, right panel, O.R. 58.2 [95% CI 7.4 to 456.6] in SE+ 2 copy/GSTM1-null) vs. never smokers (left panel). Study results were not changed after the exclusion of women.

Figure. Odds ratios (ORs) of ACPA positivity based on SE copy number and GSTM1-null status among ever smokers (left panel) and never smokers (right panel)


The GSTM1-null genotype adds substantially to the risk of ACPA positivity already imposed by HLA-DRB1 SE in RA, a risk that is most pronounced in smokers. With an antioxidant function of GSTM1, these data suggest that oxidative stress may play an important pathogenic role in ACPA-positive RA.

To cite this abstract, please use the following information:
Mikuls, T. R., Gould, Karen A., Bynote, Kimberly K., Yu, Fang, LeVan, Tricia D., Thiele, Geoffrey M., et al; GSTM1, HLA-DBR1, and Smoking Interactions Suggest a Role for Oxidative Stress in the Pathogenesis of APCA-Positive Rheumatoid Arthrtits [abstract]. Arthritis Rheum 2009;60 Suppl 10 :376
DOI: 10.1002/art.25459

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