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Integrating risk factors

HLA-DRB1*1501 and Epstein–Barr virus in multiple sclerosis

From the Center for Neurologic Diseases, Department of Neurology (P.L.D.J., D.A.H.), and Channing Laboratory, Department of Medicine (A.A.), Brigham and Women's Hospital and Harvard Medical School, Boston; Harvard Medical School/Partners Healthcare Center for Genetics and Genomics (P.L.D.J., D.A.H.); Broad Institute (P.L.D.J., J.D.R., D.A.H.), Massachusetts Institute of Technology and Harvard University, Cambridge; Departments of Epidemiology (K.C.S., A.A.) and Nutrition (K.L.M., A.A.), Harvard School of Public Health, Cambridge, MA; and University of Montreal (J.D.R.), Montreal Heart Institute, Montreal, Quebec, Canada.

Address correspondence and reprint requests to Dr. Alberto Ascherio, 665 Huntington Avenue, Boston, MA 02115 aascheri{at}hsph.harvard.edu

Background: Individuals with high levels of antibodies to the Epstein–Barr virus nuclear antigen 1 (EBNA-1) have an increased risk of developing multiple sclerosis (MS), but this association could be confounded by genetic susceptibility.

Methods: We conducted a nested case-control study including 148 women with MS (18 with blood collected before disease onset) and 296 age-matched healthy women to determine whether the human leukocyte antigen (HLA) DRB1*1501 allele (DR15) and anti-Epstein–Barr virus (anti-EBV) antibody titers are independent risk factors for MS.

Results: The association between anti-EBNA-1 antibody titers and MS risk was not affected by adjustment for DR15 and was similar in DR15-positive and DR15-negative women. The relative risk of MS among DR15-positive women with elevated (>1:320) anti-EBNA-1 titers was ninefold higher than that of DR15-negative women with low (<1:80) anti-EBNA-1 titers.

Conclusions: Anti-Epstein–Barr virus nuclear antigen 1 (anti-EBNA-1) antibody titers are a risk factor for multiple sclerosis (MS), independently from the DR15 allele. Carriers of the DR15 allele with elevated anti-EBNA-1 antibody titers may have a markedly increased risk of MS.

GLOSSARY: CMV = cytomegalovirus; EBV = Epstein–Barr virus; HLA = human leukocyte antigen; MS = multiple sclerosis; NHS = Nurses' Health Study; RR = relative risk.

Editorial, page 1067

e-Pub ahead of print on February 13, 2008, at www.neurology.org.

Supported by NIH–National Institute of Neurological Disorders and Stroke Grant R01 NS47467 (A.A.). P.L.D.J. is the William C. Fowler scholar in Multiple Sclerosis and is supported by NIH–National Institute of Neurological Disorders and Stroke Grant K08. J.D.R. is supported by grants from the NIH–National Institute of Diabetes and Digestive and Kidney Diseases and NIH–National Institute of Allergy and Infectious Diseases.

Disclosure: The authors report no conflicts of interest.

Received July 18, 2007. Accepted in final form September 14, 2007.

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