Epstein-Barr virus genetic variants are associated with multiple sclerosis.

Rosella Mechelli, Caterina Manzari, Claudia Policano, Anita Annese, Ernesto Picardi, Renato Umeton, Arianna Fornasiero, Anna Maria D'Erchia, Maria Chiara Buscarinu, Cristina Agliardi, Viviana Annibali, Barbara Serafini, Barbara Rosicarelli, Silvia Romano, Daniela F Angelini, Vito A G Ricigliano, Fabio Buttari, Luca Battistini, Diego Centonze, Franca R Guerini, Sandra D'Alfonso, Graziano Pesole, Marco Salvetti, Giovanni Ristori

Journal: Neurology 2015;84(13):1362-8

PMID: 25740864

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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.

Address: From the Centre for Experimental Neurological Therapies (R.M., C.P., R.U., V.A.G.R., A.F., V.A., M.C.B., S.R., M.S., G.R.), S. Andrea Hospital-site, Department of Neuroscience, Mental Health and Sensory Organs, Faculty of Medicine and Psychology, Sapienza University, Rome; Don C. Gnocchi Foundation IRCCS (F.R.G., C.A.), S. Maria Nascente, Milan; Department of Health Sciences (S.D.), Interdisciplinary Research Center of Autoimmune Diseases, Eastern Piedmont University, Novara; Clinica Neurologica (F.B., D.C.), Dipartimento di Medicina dei Sistemi, University of Tor Vergata, Rome; Department of Cell Biology and Neuroscience (B.S., B.R.), Istituto Superiore di Sanità, Rome; Department of Bioscience, Biotechnology and Biopharmaceutics (C.M., A.A., A.M.D., E.P., G.P.) University of Bari "Aldo Moro"; Institute of Biomembranes and Bioenergetics (G.P.), CNR, Bari; and Neuroimmunology Unit (D.F.A., L.B.), Fondazione Santa Lucia (I.R.C.C.S.), Rome, Italy.; From the Centre for Experimental Neurological Therapies (R.M., C.P., R.U., V.A.G.R., A.F., V.A., M.C.B., S.R., M.S., G.R.), S. Andrea Hospital-site, Department of Neuroscience, Mental Health and Sensory Organs, Faculty of Medicine and Psychology, Sapienza University, Rome; Don C. Gnocchi Foundation IRCCS (F.R.G., C.A.), S. Maria Nascente, Milan; Department of Health Sciences (S.D.), Interdisciplinary Research Center of Autoimmune Diseases, Eastern Piedmont University, Novara; Clinica Neurologica (F.B., D.C.), Dipartimento di Medicina dei Sistemi, University of Tor Vergata, Rome; Department of Cell Biology and Neuroscience (B.S., B.R.), Istituto Superiore di Sanità, Rome; Department of Bioscience, Biotechnology and Biopharmaceutics (C.M., A.A., A.M.D., E.P., G.P.) University of Bari "Aldo Moro"; Institute of Biomembranes and Bioenergetics (G.P.), CNR, Bari; and Neuroimmunology Unit (D.F.A., L.B.), Fondazione Santa Lucia (I.R.C.C.S.), Rome, Italy. [email protected].

DOI: 10.1212/WNL.0000000000001420

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MeSH Terms: Adult, Alleles, Case-Control Studies, Epstein-Barr Virus Nuclear Antigens, Genetic Variation, Genotype, HLA Antigens, Herpesvirus 4, Human, Histocompatibility Testing, Humans, Male, Multiple Sclerosis, Young Adult