title: Anti-Epstein-Barr virus antibodies as serological markers of multiple sclerosis: a prospective study among United States military personnel.
abstract: BACKGROUND
  Elevated Epstein-Barr virus (EBV) antibody titers are risk factors for multiple sclerosis (MS), but the strength and consistency of this association are not well characterized.
  
  
  OBJECTIVE
  The objectives of this study were to determine whether this association is confounded by vitamin D or modified by gender or race, and the usefulness of EBV nuclear antigen (EBNA) antibodies as a marker for MS.
  
  
  METHODS
  We conducted a prospective study among US military personnel. Antibody titers against EBV antigens were measured in serum samples from 222 individuals who developed MS and 444 age, sex, and race/ethnicity matched controls. Conditional logistic regression was used to estimate relative risks.
  
  
  RESULTS
  MS risk increased with increasing titers of anti-EBNA complex (p < 10(-9)) and anti-EBNA-1 (p = 5.8 × 10(-9)) titers. MS risk was 36-fold higher among individuals with anti-EBNA complex IgG titers ≥320 than among those with titers <20 (95% confidence interval [CI] 9.6-136), and 8-fold higher among those with anti-EBNA-1 ≥320 than among those with anti-EBNA-1 <20 (95% CI 2.6-23). These associations were consistent across gender and race/ethnicity groups and independent from 25-hydroxyvitamin D levels. Areas under the receiver operating characteristic (ROC) curves were 0.67 for EBNA complex and 0.65 for EBNA-1.
  
  
  CONCLUSIONS
  Serum titers of pre-onset anti-EBNA antibodies are strong, robust markers of MS risk and could be useful in an MS risk score.
authors.affiliation: Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA. kgorham@hsph.harvard.edu
authors.forename: K L
authors.initials: KL
authors.lastname: Munger
authors.forename: L I
authors.initials: LI
authors.lastname: Levin
authors.forename: E J
authors.initials: EJ
authors.lastname: O'Reilly
authors.forename: K I
authors.initials: KI
authors.lastname: Falk
authors.forename: A
authors.initials: A
authors.lastname: Ascherio
mesh_terms: D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000097:blood*; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood*; D016022:Case-Control Studies; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000453:epidemiology / Q000276:immunology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D008889:Military Personnel; D009103:Multiple Sclerosis / Q000097:blood* / Q000821:virology*; D011446:Prospective Studies; D012372:ROC Curve; D011863:Radioimmunoassay; D012307:Risk Factors; D014481:United States; D014807:Vitamin D / Q000097:blood; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D015415:Biomarkers; D019309:Epstein-Barr Virus Nuclear Antigens; D014807:Vitamin D