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Abstract
Objective: We analyzed the Epstein-Barr nuclear antigen 2 (EBNA2) gene, which contains the most variable region of the viral genome, in persons with multiple sclerosis (MS) and control subjects to verify whether virus genetic variants are involved in disease development.
Methods: A seminested PCR approach and Sanger sequencing were used to analyze EBNA2 in 53 patients and 38 matched healthy donors (HDs). High-throughput sequencing by Illumina MiSeq was also applied in a subgroup of donors (17 patients and 17 HDs). Patients underwent gadolinium-enhanced MRI and human leucocyte antigen typing.
Results: MS risk significantly correlated with an excess of 1.2 allele (odds ratio [OR] = 5.13; 95% confidence interval [CI] 1.84–14.32; p = 0.016) and underrepresentation of 1.3B allele (OR = 0.23; 95% CI 0.08–0.51; p = 0.0006). We identified new genetic variants, mostly 1.2 allele- and MS-associated (especially amino acid variation at position 245; OR = 9.4; 95% CI 1.19–78.72; p = 0.0123). In all cases, the consensus sequence from deep sequencing confirmed Sanger sequencing (including the cosegregation of newly identified variants with known EBNA2 alleles) and showed that the extent of genotype intraindividual variability was higher than expected: rare EBNA2 variants were detected in all HDs and patients with MS (range 1–17 and 3–19, respectively). EBNA2 variants did not seem to correlate with human leucocyte antigen typing or clinical/MRI features.
Conclusions: Our study unveils a strong association between Epstein-Barr virus genomic variants and MS, reinforcing the idea that Epstein-Barr virus contributes to disease development.
GLOSSARY
- AUC=
- area under the curve;
- CI=
- confidence interval;
- EBNA=
- Epstein-Barr nuclear antigen;
- EBV=
- Epstein-Barr virus;
- HD=
- healthy donor;
- HLA=
- human leucocyte antigen;
- MS=
- multiple sclerosis;
- NCBI=
- National Center for Biotechnology Information;
- OR=
- odds ratio;
- PBMC=
- peripheral blood mononuclear cell;
- ROC=
- receiver operating characteristic
Footnotes
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Supplemental data at Neurology.org
- Received August 15, 2014.
- Accepted in final form December 15, 2014.
- © 2015 American Academy of Neurology
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