Glutathione S-Transferase M Null Homozygosity and Risk of Systemic Lupus Erythematosus Associated with Sun Exposure: A Possible Gene-Environment Interaction for Autoimmunity

PATRICIA A. FRASER, WEI-ZI DING, MEHRDAD MOHSENI, EDWARD L. TREADWELL, MARY ANNE DOOLEY, E. WILLIAM St. CLAIR, GARY S. GILKESON, and GLINDA S. COOPER

ABSTRACT.

Objective. Multiple genetic factors modulate predisposition to systemic lupus erythematosus (SLE). The glutathione S-transferase (GST) genes GSTM1, GSTT1, and GSTP1 catalyze metabolic pathways for the excretion of reactive oxygen species that may be generated by cellular oxidative stress induced by ultraviolet radiation in sunlight. We hypothesized that risk of SLE associated with occupational sun exposure is modulated by GSTM1, GSTT1, and GSTP1 genotypes.

Methods. DNA samples and occupational history were collected from 243 cases and 298 controls in the Carolina Lupus Study, a population based case-control study of patients with recently diagnosed SLE.

Results. There was no independent association between SLE and presence of the homozygous null GSTM1 or GSTT1 genotype, the homozygous Val/Val or heterozygous Val/Ile GSTP1 genotype, or occupational sunlight exposure. The prevalence of Ro autoantibodies was significantly increased among Caucasians with the GSTM1 null genotype (OR 2.6, 95% CI 1.0, 6.8), but was somewhat weaker among African-Americans (OR 1.5, 95% CI 0.7, 3.5). In the combined analysis of occupational sunlight exposure and GSTM1 genotype, the effect of sun exposure among Caucasians varied depending on GSTM1 genotype. There was a 3-fold increased risk (OR 3.1, 95% CI 0.9, 10.8) of SLE associated with 24 or more months' occupational sun exposure among Caucasians with the GSTM1 null genotype, but sun exposure was not associated with risk among GSTM1 positive Caucasians (OR 0.6, 95% CI 0.3, 1.5). The interaction was statistically significant (p = 0.028).

Conclusion. Our results suggest that GSTM1 homozygous null genotype may modify the effect of occupational sun exposure on the risk of SLE in caucasians. (J Rheumatol 2003;30:276-82)

Key Indexing Terms:

SYSTEMIC LUPUS ERYTHEMATOSUS
AUTOIMMUNE DISEASE
GLUTATHIONE S-TRANSFERASE
METABOLISM
ULTRAVIOLET RADIATION

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From the Center for Blood Research, Harvard Medical School, Boston, Massachusetts; Division of Rheumatology, East Carolina University School of Medicine, Greenville, North Carolina; Division of Rheumatology, University of North Carolina, Chapel Hill, North Carolina; Division of Rheumatology, Allergy, and Clinical Immunology, Duke University Medical Center, Durham, North Carolina; Medical Research Service, Ralph H. Johnson Veterans Administration Medical Center and Medical University of South Carolina, Charleston, South Carolina; and Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina, USA.

Supported by grant ES10295 from the National Institute of Environmental Health Sciences (NIEHS) to Dr. Fraser, and by the Intramural Research Program of the NIEHS and the National Center for Minority Health and Health Disparities of the National Institutes of Health.

P.A. Fraser, MD, MPH, Assistant Professor of Medicine; W-Z. Ding, BSc, Research Technologist; M. Mohseni, MD, Research Associate, Harvard Medical School; E.L. Treadwell, MD, Professor, East Carolina University School of Medicine; M.A. Dooley, MD, Associate Professor, University of North Carolina at Chapel Hill; E.W. St. Clair, MD, Associate Professor, Duke University Medical Center; G.S. Gilkeson, MD, Professor, Ralph H. Johnson Veterans Administration Medical Center and Medical University of South Carolina; G.S. Cooper, PhD, Investigator, National Institute of Environmental Health Sciences.

Address reprint requests to Dr. P.A. Fraser, Center for Blood Research, 800 Huntington Avenue, Boston, MA 02115. E-mail: fraser@cbr.med.harvard.edu

Submitted April 12, 2002; revision accepted August 12, 2002.

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