Binding of Epstein Barr Virus EBNA2 Unifies Multiple Sclerosis Genetic Mechanisms

This study is focused on multiple sclerosis (MS). MS is likely caused by a combination of genetic and environmental factors; however, the mechanisms contributing to these factors remain poorly understood. Epstein-Barr virus (EBV) in particular is a well-established environmental risk factor for MS. We have created a computational algorithm that systematically searches for common molecular mechanisms that might be impacted at multiple MS-associated loci. Using this algorithm, we have discovered that over 40% of MS-associated loci contain MS genetic variants that fall within regions of the human genome occupied by the EBV-encoded EBNA2 protein. The same MS-associated variants also impact gene expression levels of MS-associated genes in EBV-infected B cell lines. Our hypothesis is that allele-dependent binding of EBNA2 and its co-factors explains the allele-dependent risk at many MS genetic loci. Importantly, this hypothesis links the genetic associations of MS to the known molecular roles played by EBV and Notch signaling in disease processes.Subjects with and without MS were recruited into an Institutional Review Board (IRB)-approved protocol through the Cincinnati Autoimmune Registry and Repository. From each subject, DNA from peripheral blood was isolated for whole genome sequencing (WGS). These data will be used to identify genotype-dependent transcriptional regulation in cells assessed from patients and controls. This WGS data was deposited before the full integration of sequence data with other functional genomic data types.From each subject, 90 mL of blood is drawn for isolation of peripheral blood mononuclear cells from which primary B and T cells will be isolated. For each B cell isolation, an EBV-transformed B cell line will be derived.]]>
This study includes cells isolated from the peripheral blood of subjects with and without Multiple Sclerosis (MS) who were recruited into our Institutional Review Board (IRB)-approved protocol through the Cincinnati Autoimmune Registry and Repository. Cases (with MS)Inclusion criteria:Diagnosis of Multiple Sclerosis under the updated 2017 McDonald criteria by a clinicianExclusion criteria:Related to another subject in the studyNot consented to participation in this studyHave been treated with or are currently taking corticosteroids or adrenocorticotropic hormones (ACTH) within 1 month prior to phlebotomyHave been treated with or are currently taking IFN-b or glatiramer acetate within 3 months prior to phlebotomyHave been treated with or are currently taking immunosuppressive medications such as azathioprine or methotrexate within 6 months phlebotomyHave been treated with or are currently taking immunoglobulins and/or monoclonal antibodies (including natalizumab) within 6 months prior to phlebotomyHave been treated with or are currently taking cladribine, cyclophosphamide or mitoxantrone at any time Controls (without MS)Inclusion criteria:Volunteers in response to IRB-approved advertisementAvailable to come to Cincinnati Children's Hospital Medical Center, meet with study staff, and provide peripheral blood Exclusion criteria:A history of chronic disease of the immune system including MS, rheumatic disease, autoimmune disease, autoinflammatory disease, or a known immunodeficiency syndrome Have been treated with or are currently taking corticosteroids or adrenocorticotropic hormones (ACTH) within 1 month prior to phlebotomyHave been treated with or are currently taking IFN-b or glatiramer acetate within 3 months prior to phlebotomyHave been treated with or are currently taking immunosuppressive medications such as azathioprine or methotrexate within 6 months phlebotomyHave been treated with or are currently taking immunoglobulins and/or monoclonal antibodies (including natalizumab) within 6 months prior to phlebotomyHave been treated with or are currently taking cladribine, cyclophosphamide or mitoxantrone Related to another subject in the studyNot consented to participation in this study]]>