Rosella Mechelli1, Caterina Manzari1, Claudia Policano1, Anita Annese1, Ernesto Picardi1, Renato Umeton1, Arianna Fornasiero1, Anna Maria D'Erchia1, Maria Chiara Buscarinu1, Cristina Agliardi1, Viviana Annibali1, Barbara Serafini1, Barbara Rosicarelli1, Silvia Romano1, Daniela F Angelini1, Vito A G Ricigliano1, Fabio Buttari1, Luca Battistini1, Diego Centonze1, Franca R Guerini1, Sandra D'Alfonso1, Graziano Pesole1, Marco Salvetti2, Giovanni Ristori1. 1. 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. 2. 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. marco.salvetti@uniroma1.it.
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.
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.
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