Association of Epstein‐Barr virus with systemic lupus erythematosus: Effect modification by race, age, and cytotoxic T lymphocyte–associated antigen 4 genotype

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Abstract
Objective Epstein-Barr virus (EBV) is hypothesized to play a role in the development of systemic lupus erythematosus (SLE). Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) is important in regulating T cell–mediated immunity, encompassing the first line of response to viral infections, and genetic variation in CTLA-4 has been associated with SLE. This study examined the seroprevalence of EBV in a population-based study of SLE patients from the southeastern United States, and potential interactions with CTLA-4 polymorphisms were assessed. Methods Cases comprised 230 subjects recently diagnosed as having SLE (144 African American and 86 white) from university and community-based clinics, and controls comprised 276 age-, sex-, and state-matched subjects (72 African American and 204 white) recruited from driver's license registries. Antibodies to EBV capsid antigen were determined by enzyme-linked immunosorbent assay, with results expressed as positive or negative using the international standardized ratio (ISR) (a ratio of the sample absorbance to a known standard). CTLA-4 genotypes were identified by polymerase chain reaction–based methods. Results In African Americans, EBV-IgA seroprevalence was strongly associated with SLE (odds ratio [OR] 5.6, 95% confidence interval [95% CI] 3.0–10.6). In whites, the modest association of SLE with EBV-IgA (OR 1.6) was modified by age, in that the strongest association was observed in those older than age 50 years (OR 4.1, 95% CI 1.6–10.4). The seroprevalence of EBV-IgM and that of EBV-IgG were not associated with SLE. Higher EBV-IgG absorbance ratios were observed in SLE patients, with a significant dose response across units of the ISR in African Americans (P < 0.0001). Allelic variation in the CTLA-4 gene promoter (−1661A/G) significantly modified the association between SLE and EBV-IgA (P = 0.03), with a stronger association among those with the −1661AA genotype. Conclusion These findings suggest that repeated or reactivated EBV infection, which results in increased EBV-IgA seroprevalence and higher IgG antibody titers, may be associated with SLE, and that the CTLA-4 genotype influences immune responsiveness to EBV in SLE patients. The observed patterns of effect modification by race, age, and CTLA-4 genotype should be examined in other studies and may help frame new hypotheses regarding the role of EBV in SLE etiology.