title: EBNA2 binds to genomic intervals associated with multiple sclerosis and overlaps with vitamin D receptor occupancy.
abstract: Epstein-Barr virus (EBV) is a non-heritable factor that associates with multiple sclerosis (MS). However its causal relationship with the disease is still unclear. The virus establishes a complex co-existence with the host that includes regulatory influences on gene expression. Hence, if EBV contributes to the pathogenesis of MS it may do so by interacting with disease predisposing genes. To verify this hypothesis we evaluated EBV nuclear antigen 2 (EBNA2, a protein that recent works by our and other groups have implicated in disease development) binding inside MS associated genomic intervals. We found that EBNA2 binding occurs within MS susceptibility sites more than expected by chance (factor of observed vs expected overlap [O/E] = 5.392-fold, p < 2.0e-05). This remains significant after controlling for multiple genomic confounders. We then asked whether this observation is significant per se or should also be viewed in the context of other disease relevant gene-environment interactions, such as those attributable to vitamin D. We therefore verified the overlap between EBNA2 genomic occupancy and vitamin D receptor (VDR) binding sites. EBNA2 shows a striking overlap with VDR binding sites (O/E = 96.16-fold, p < 2.0e-05), even after controlling for the chromatin accessibility state of shared regions (p <0.001). Furthermore, MS susceptibility regions are preferentially targeted by both EBNA2 and VDR than by EBNA2 alone (enrichment difference = 1.722-fold, p = 0.0267). Taken together, these findings demonstrate that EBV participates in the gene-environment interactions that predispose to MS.
authors: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom; Neuroimmunology Unit, Fondazione Santa Lucia (I.R.C.C.S.), Rome, Italy.
authors: Vito A G
authors: VA
authors: Ricigliano
authors: Medical Research Council Functional Genomics Unit and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom; Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom.
authors: Adam E
authors: AE
authors: Handel
authors: Department of Informatics, University of Oslo, Blindern, Norway.
authors: Geir K
authors: GK
authors: Sandve
authors: Centre for Experimental Neurological Therapies (CENTERS), Neurology and Department of Neuroscience, Mental Health and Sensory Organs, Faculty of Medicine and Psychology, "Sapienza" University of Rome, Rome, Italy.
authors: Viviana
authors: V
authors: Annibali
authors: Centre for Experimental Neurological Therapies (CENTERS), Neurology and Department of Neuroscience, Mental Health and Sensory Organs, Faculty of Medicine and Psychology, "Sapienza" University of Rome, Rome, Italy.
authors: Giovanni
authors: G
authors: Ristori
authors: Centre for Experimental Neurological Therapies (CENTERS), Neurology and Department of Neuroscience, Mental Health and Sensory Organs, Faculty of Medicine and Psychology, "Sapienza" University of Rome, Rome, Italy.
authors: Rosella
authors: R
authors: Mechelli
authors: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
authors: M Zameel
authors: MZ
authors: Cader
authors: Centre for Experimental Neurological Therapies (CENTERS), Neurology and Department of Neuroscience, Mental Health and Sensory Organs, Faculty of Medicine and Psychology, "Sapienza" University of Rome, Rome, Italy.
authors: Marco
authors: M
authors: Salvetti
mesh_terms: D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000821:virology*; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D021381:Protein Transport; D018167:Receptors, Calcitriol / Q000378:metabolism*
chemical_list: D019309:Epstein-Barr Virus Nuclear Antigens; D018167:Receptors, Calcitriol