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Abstract
Objectives: 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).
Conclusion: 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.
Footnotes
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Study funding: Supported by the National Multiple Sclerosis Society of the United States of America, the National Health and Medical Research Council of Australia, the ANZ William Buckland Foundation, and Multiple Sclerosis Research Australia.
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Supplemental data at www.neurology.org
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- AOR=
- adjusted odds ratio;
- CI=
- confidence interval;
- EBNA=
- Epstein-Barr virus nuclear antigen;
- EBV=
- Epstein-Barr virus;
- FCD=
- first clinical diagnosis of CNS demyelination;
- FDE=
- first demyelinating event;
- HLA=
- human leukocyte antigen;
- IgG=
- immunoglobulin G;
- IM=
- infectious mononucleosis;
- IQR=
- interquartile range;
- MS=
- multiple sclerosis;
- OR=
- odds ratio;
- PBMC=
- peripheral blood mononuclear cell;
- PPMS=
- primary progressive multiple sclerosis;
- SNP=
- single nucleotide polymorphism;
- VCA=
- viral capsid antigen
- Received January 15, 2011.
- Accepted April 5, 2011.
- Copyright © 2011 by AAN Enterprises, Inc.
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