title: Current and past Epstein-Barr virus infection in risk of initial CNS demyelination.
abstract: OBJECTIVE
  To assess risk of a first clinical diagnosis of CNS demyelination (FCD) in relation to measures of Epstein-Barr virus (EBV) infection within the context of other known risk factors.
  
  
  METHODS
  This was a multicenter incident case-control study. FCD cases (n = 282) aged 18-59 years and controls (n = 558, matched on age, sex, and region) were recruited from 4 Australian centers between November 1, 2003, and December 31, 2006. A nested study (n = 215 cases, n = 216 controls) included measurement of whole blood quantitative EBV DNA load and serum EBV-specific antibodies. Conditional logistic regression was used to analyze case-control differences.
  
  
  RESULTS
  There were no significant case-control differences in the proportion with detectable EBV DNA (55.8% vs 50.5%, respectively, p = 0.28), or in quantitative EBV DNA load (p = 0.33). Consistent with previous work, higher anti-EBV-specific immunoglobulin G (IgG) titers and a history of infectious mononucleosis were associated with increased FCD risk and there was an additive interaction with HLA-DRB1*1501 status. We found additional interactions between high anti-EBNA IgG titer and SNPs in HLA-A (adjusted odds ratios [AOR] = 19.84 [95% confidence interval (CI) 5.95 to 66.21] for both factors compared to neither) and CTLA-4 genes (AOR = 0.31 [95% CI 0.13 to 0.76] for neither factor compared to both). EBV DNA load was lower at higher serum 25-hydroxyvitamin D concentrations in controls (r = -0.17, p = 0.01). An adverse effect of higher EBV DNA load on FCD risk was increased with higher 25-hydroxyvitamin D concentration (p[interaction] = 0.02).
  
  
  CONCLUSIONS
  Past infection with EBV, but not current EBV DNA load in whole blood, is significantly associated with increased FCD risk. These associations appear to be modified by immune-related gene variants.
authors.affiliation: National Centre for Epidemiology and Population Health, The Australian National University, Canberra 0200, Australia.
authors.forename: R M
authors.initials: RM
authors.lastname: Lucas
authors.forename: A-L
authors.initials: AL
authors.lastname: Ponsonby
authors.forename: K
authors.initials: K
authors.lastname: Dear
authors.forename: P
authors.initials: P
authors.lastname: Valery
authors.forename: M P
authors.initials: MP
authors.lastname: Pender
authors.forename: J M
authors.initials: JM
authors.lastname: Burrows
authors.forename: S R
authors.initials: SR
authors.lastname: Burrows
authors.forename: C
authors.initials: C
authors.lastname: Chapman
authors.forename: A
authors.initials: A
authors.lastname: Coulthard
authors.forename: D E
authors.initials: DE
authors.lastname: Dwyer
authors.forename: T
authors.initials: T
authors.lastname: Dwyer
authors.forename: T
authors.initials: T
authors.lastname: Kilpatrick
authors.forename: M-L J
authors.initials: ML
authors.lastname: Lay
authors.forename: A J
authors.initials: AJ
authors.lastname: McMichael
authors.forename: B V
authors.initials: BV
authors.lastname: Taylor
authors.forename: I A F
authors.initials: IA
authors.lastname: van der Mei
authors.forename: D
authors.initials: D
authors.lastname: Williams
mesh_terms: D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000378:metabolism*; D001315:Australia / Q000453:epidemiology; D016022:Case-Control Studies; D020278:Demyelinating Autoimmune Diseases, CNS / Q000097:blood / Q000150:complications / Q000453:epidemiology* / Q000821:virology*; D020031:Epstein-Barr Virus Infections / Q000097:blood / Q000150:complications / Q000453:epidemiology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology / Q000378:metabolism; D005260:Female; D015234:HLA-A Antigens / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D059811:HLA-DRB1 Chains; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D015994:Incidence; D007244:Infectious Mononucleosis / Q000150:complications / Q000821:virology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000150:complications / Q000821:virology; D012307:Risk Factors; D019562:Viral Load / Q000706:statistics & numerical data*; D014807:Vitamin D / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000914:Antibodies, Viral; D019309:Epstein-Barr Virus Nuclear Antigens; D015234:HLA-A Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D007074:Immunoglobulin G; D014807:Vitamin D; C104450:25-hydroxyvitamin D