Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis

2016 ◽  
Vol 22 (13) ◽  
pp. 1655-1664 ◽  
Author(s):  
Yuan Zhou ◽  
Gu Zhu ◽  
Jac C Charlesworth ◽  
Steve Simpson ◽  
Rohina Rubicz ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Genetic Risk ◽  
Epstein Barr Virus ◽  
Meta Analysis ◽  
Nuclear Antigen ◽  
Genetic Loci ◽  
Polygenic Risk ◽  
Barr Virus ◽  
Genome Wide ◽  
Epstein Barr

Background: Infection with the Epstein-Barr virus (EBV) is associated with an increased risk of multiple sclerosis (MS). Objective: We sought genetic loci influencing EBV nuclear antigen-1 (EBNA-1) IgG titers and hypothesized that they may play a role in MS risk. Methods: We performed a genome-wide association study (GWAS) of anti-EBNA-1 IgG titers in 3599 individuals from an unselected twin family cohort, followed by a meta-analysis with data from an independent EBNA-1 GWAS. We then examined the shared polygenic risk between the EBNA-1 GWAS (effective sample size ( Neff) = 5555) and a large MS GWAS ( Neff = 15,231). Results: We identified one locus of strong association within the human leukocyte antigen (HLA) region, of which the most significantly associated genotyped single nucleotide polymorphism (SNP) was rs2516049 ( p = 4.11 × 10−9). A meta-analysis including data from another EBNA-1 GWAS in a cohort of Mexican-American families confirmed that rs2516049 remained the most significantly associated SNP ( p = 3.32 × 10−20). By examining the shared polygenic risk, we show that the genetic risk for elevated anti-EBNA-1 titers is positively correlated with the development of MS, and that elevated EBNA-1 titers are not an epiphenomena secondary to MS. In the joint meta-analysis of EBNA-1 titers and MS, loci at 1p22.1, 3p24.1, 3q13.33, and 10p15.1 reached genome-wide significance ( p < 5 × 10−8). Conclusions: Our results suggest that apart from the confirmed HLA region, the association of anti-EBNA-1 IgG titer with MS risk is also mediated through non-HLA genes, and that studies aimed at identifying genetic loci influencing EBNA immune response provides a novel opportunity to identify new and characterize existing genetic risk factors for MS.

scholarly journals Systematic review and meta-analysis of the association between Epstein-Barr virus, Multiple Sclerosis, and other risk factors

2019 ◽  
Author(s):  
Benjamin M Jacobs ◽  
Gavin Giovannoni ◽  
Jack Cuzick ◽  
Ruth Dobson
Keyword(s):  
Risk Factors ◽  
Multiple Sclerosis ◽  
Epstein Barr Virus ◽  
Meta Analysis ◽  
Clinically Isolated Syndrome ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Hla Genotype ◽  
Additive Scale

AbstractBackgroundEBV infection is thought to play a central role in the development of Multiple Sclerosis (MS). If causal, it represents a target for interventions to reduce MS risk.ObjectiveTo examine the evidence for interaction between EBV and other risk factors, and explore mechanisms via which EBV infection may influence MS risk.MethodsPubmed was searched using the terms “multiple sclerosis” AND “Epstein Barr virus”, “multiple sclerosis” AND EBV, “clinically isolated syndrome” AND “Epstein Barr virus” and “clinically isolated syndrome” AND EBV. All abstracts were reviewed for possible inclusion.Results262 full-text papers were reviewed. There was evidence of interaction on the additive scale between anti-EBV antibody titre and HLA genotype (AP 0.48, p<1×10−4; RERI 3.84, p<5×10−3; S 1.68, p=0.06). Previous IM was associated with increased OR of MS in HLA-DRB1*1501 positive but not HLA-DRB1*1501 negative persons. Smoking was associated with a greater risk of MS in those with high anti-EBV antibodies (OR 2.76) but not low anti-EBV antibodies (OR 1.16). No interaction between EBV and risk factors was found on a multiplicative scale.ConclusionsEBV appears to interact with at least some established MS risk factors. The mechanism via which EBV influences MS risk remains unknown.

scholarly journals An Absence of Epstein–Barr Virus Reactivation and Associations with Disease Activity in People with Multiple Sclerosis Undergoing Therapeutic Hookworm Vaccination

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 487
Author(s):  
Peter A. C. Maple ◽  
Bruno Gran ◽  
Radu Tanasescu ◽  
David I. Pritchard ◽  
Cris S. Constantinescu
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Epstein Barr Virus ◽  
Nuclear Antigen ◽  
Virus Reactivation ◽  
Serum Samples ◽  
Barr Virus ◽  
Ebv Infection ◽  
Ebv Reactivation ◽  
Epstein Barr

Background: Epstein–Barr virus (EBV) infection is strongly associated with multiple sclerosis (MS). Helminth infection can downregulate antiviral immune responses, potentially protecting against MS, but with a theoretical risk for reactivating latent EBV infection. Objective: To investigate parameters of EBV infection and their relationship with disease activity in people with MS (PwMS) therapeutically vaccinated with Necator americanus (hookworm). Methods: Sequential serum samples from 51 PwMS; 26 therapeutically infected (25 larvae) with N. americanus and 25 controls were tested for EBV virus capsid antigen (VCA) IgG and IgM, EBV nuclear antigen-1 (EBNA-1) IgG, and EBV early antigen (EA) IgG. Disease activity was assessed by periodic MRI. Significance was set at p < 0.05. Results: All PwMS were EBV VCA IgG and EBNA-1 IgG positive, and 35.2% were EBV EA IgG positive. EBV antibody levels were generally stable, and EBV reactivation in PwMS was not demonstrated by significant increases in IgG titre over 12 months. Disease activity was most frequent in PwMS possessing high levels of EBV VCA IgG (>600 units/mL) or EBNA-1 IgG (>150 units/mL); however, there was no association with hookworm treatment. Interpretation: Therapeutic hookworm vaccination was not associated with EBV reactivation. Multiple sclerosis disease activity was associated with high levels of EBV VCA IgG or EBNA-1 IgG.

scholarly journals Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk

2019 ◽  
Vol 116 (34) ◽  
pp. 16955-16960 ◽  
Author(s):  
Katarina Tengvall ◽  
Jesse Huang ◽  
Cecilia Hellström ◽  
Patrick Kammer ◽  
Martin Biström ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Sclerosis ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Molecular Mimicry ◽  
Nuclear Antigen ◽  
Immune Reactivity ◽  
Barr Virus ◽  
Epstein Barr ◽  
Antibody Levels

Multiple sclerosis (MS) is a chronic inflammatory, likely autoimmune disease of the central nervous system with a combination of genetic and environmental risk factors, among which Epstein-Barr virus (EBV) infection is a strong suspect. We have previously identified increased autoantibody levels toward the chloride-channel protein Anoctamin 2 (ANO2) in MS. Here, IgG antibody reactivity toward ANO2 and EBV nuclear antigen 1 (EBNA1) was measured using bead-based multiplex serology in plasma samples from 8,746 MS cases and 7,228 controls. We detected increased anti-ANO2 antibody levels in MS (P = 3.5 × 10−36) with 14.6% of cases and 7.8% of controls being ANO2 seropositive (odds ratio [OR] = 1.6; 95% confidence intervals [95%CI]: 1.5 to 1.8). The MS risk increase in ANO2-seropositive individuals was dramatic when also exposed to 3 known risk factors for MS: HLA-DRB1*15:01 carriage, absence of HLA-A*02:01, and high anti-EBNA1 antibody levels (OR = 24.9; 95%CI: 17.9 to 34.8). Reciprocal blocking experiments with ANO2 and EBNA1 peptides demonstrated antibody cross-reactivity, mapping to ANO2 [aa 140 to 149] and EBNA1 [aa 431 to 440]. HLA gene region was associated with anti-ANO2 antibody levels and HLA-DRB1*04:01 haplotype was negatively associated with ANO2 seropositivity (OR = 0.6; 95%CI: 0.5 to 0.7). Anti-ANO2 antibody levels were not increased in patients from 3 other inflammatory disease cohorts. The HLA influence and the fact that specific IgG production usually needs T cell help provides indirect evidence for a T cell ANO2 autoreactivity in MS. We propose a hypothesis where immune reactivity toward EBNA1 through molecular mimicry with ANO2 contributes to the etiopathogenesis of MS.

Epstein-Barr virus-specific antibody response in cerebrospinal fluid and serum of patients with multiple sclerosis

2010 ◽  
Vol 16 (7) ◽  
pp. 883-887 ◽  
Author(s):  
Massimiliano Castellazzi ◽  
Carmine Tamborino ◽  
Alice Cani ◽  
Elena Negri ◽  
Eleonora Baldi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Neurological Disorders ◽  
Epstein Barr Virus ◽  
Serum Levels ◽  
Nuclear Antigen ◽  
Enzyme Linked Immunosorbent Assay ◽  
Barr Virus ◽  
Epstein Barr ◽  
Multiple Sclerosis Patients

Cerebrospinal fluid and serum levels and intrathecal synthesis of anti-Epstein—Barr virus (EBV) IgG were measured by enzyme-linked immunosorbent assay in 80 relapsing—remitting multiple sclerosis patients grouped according to clinical and magnetic resonance imaging (MRI) evidence of disease activity. Eighty patients with other inflammatory neurological disorders (OIND) and 80 patients with non-inflammatory neurological disorders (NIND) served as neurological controls. Cerebrospinal fluid concentrations were higher in OIND than in multiple sclerosis ( p < 0.0001) and NIND ( p < 0.01) for anti-viral-capsid-antigen (anti-VCA) IgG, in multiple sclerosis than in NIND ( p < 0.01) and in OIND than in NIND ( p < 0.05) for anti-EBV nuclear antigen-1 (EBNA-1) IgG. Serum levels were more elevated in OIND than in multiple sclerosis ( p < 0.05) and in MRI inactive than in MRI active multiple sclerosis ( p < 0.0001) for anti-VCA IgG, and in multiple sclerosis than in OIND and NIND ( p < 0.01) for anti-EBNA-1 IgG. Serum titres of anti-VCA and anti-EBNA-1 IgG were also positively ( p < 0.05) and inversely ( p < 0.001) correlated, respectively, with the Expanded Disability Status Scale. An intrathecal IgG production of anti-VCA and anti-EBNA-1 IgG, as indicated by Antibody Index, was present only in a limited number of multiple sclerosis patients and controls (range from 1.3 to 6.3%). These findings do not support a direct pathogenetic role of EBV-targeted humoral immune response in multiple sclerosis.

The interaction between smoking and Epstein-Barr virus as multiple sclerosis risk factors may depend on age

2013 ◽  
Vol 20 (6) ◽  
pp. 747-750 ◽  
Author(s):  
Jonatan Salzer ◽  
Hans Stenlund ◽  
Peter Sundström
Keyword(s):  
Risk Factors ◽  
Multiple Sclerosis ◽  
Epstein Barr Virus ◽  
Nuclear Antigen ◽  
Positive Interaction ◽  
Barr Virus ◽  
Older Subjects ◽  
Epstein Barr ◽  
A Prospective Study ◽  
Epstein Barr Nuclear Antigen

The multiple sclerosis (MS) risk factors smoking and remote Epstein-Barr virus (EBV) infection have been suggested to interact statistically, but the results are conflicting. In a prospective study on 192 MS cases and 384 matched controls, we analysed levels of cotinine as a marker of smoke exposure, and Epstein-Barr Nuclear Antigen-1 antibody reactivity. We assessed interaction on the additive and multiplicative scales, and estimated the effects of the risk factors across strata of each other. The results suggest that a negative interaction may be present in samples drawn at a young age, and a positive interaction among older subjects.

scholarly journals Epstein-Barr virus, cytomegalovirus, and multiple sclerosis susceptibility

Neurology ◽  
2017 ◽  
Vol 89 (13) ◽  
pp. 1330-1337 ◽  
Author(s):  
Annette Langer-Gould ◽  
Jun Wu ◽  
Robyn Lucas ◽  
Jessica Smith ◽  
Edlin Gonzales ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Ethnic Groups ◽  
Lower Risk ◽  
Epstein Barr Virus ◽  
Hygiene Hypothesis ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Epstein Barr ◽  
Incident Cases ◽  
Racial Ethnic

Objective:To determine whether Epstein-Barr virus (EBV) or cytomegalovirus (CMV) seropositivity is associated with multiple sclerosis (MS) in blacks and Hispanics and to what extent measures of the hygiene hypothesis or breastfeeding could explain these findings. EBV and CMV have been associated with MS risk in whites, and the timing and frequency of both viruses vary by factors implicated in the hygiene hypothesis.Methods:Incident cases of MS or its precursor, clinically isolated syndrome (CIS), and matched controls (blacks, 111 cases/128 controls; Hispanics, 173/187; whites, 235/256) were recruited from the membership of Kaiser Permanente Southern California. Logistic regression models accounted for HLA-DRB1*1501 status, smoking, socioeconomic status, age, sex, genetic ancestry, and country of birth.Results:Epstein-Barr nuclear antigen-1 (EBNA-1) seropositivity was independently associated with an increased odds of MS/CIS in all 3 racial/ethnic groups (p < 0.001 for blacks and whites, p = 0.02 for Hispanics). In contrast, CMV seropositivity was associated with a lower risk of MS/CIS in Hispanics (p = 0.004) but not in blacks (p = 0.95) or whites (p = 0.96). Being born in a low/middle-income country was associated with a lower risk of MS in Hispanics (p = 0.02) but not after accounting for EBNA-1 seropositivity. Accounting for breastfeeding did not diminish the association between CMV and MS in Hispanics.Conclusions:The consistency of EBNA-1 seropositivity with MS across racial/ethnic groups and between studies points to a strong biological link between EBV infection and MS risk. The association between past CMV infection and MS risk supports the broader hygiene hypothesis, but the inconsistency of this association across racial/ethnic groups implies noncausal associations.

scholarly journals Epstein–Barr virus nuclear antigen 3A partially coincides with EBNA3C genome-wide and is tethered to DNA through BATF complexes

2014 ◽  
Vol 112 (2) ◽  
pp. 554-559 ◽  
Author(s):  
Stefanie C. S. Schmidt ◽  
Sizun Jiang ◽  
Hufeng Zhou ◽  
Bradford Willox ◽  
Amy M. Holthaus ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Latent Infection ◽  
Protein Complexes ◽  
Nuclear Antigen ◽  
Lymphoblastoid Cell Lines ◽  
Barr Virus ◽  
Genome Wide ◽  
Epstein Barr

Epstein–Barr Virus (EBV) conversion of B-lymphocytes to Lymphoblastoid Cell Lines (LCLs) requires four EBV nuclear antigen (EBNA) oncoproteins: EBNA2, EBNALP, EBNA3A, and EBNA3C. EBNA2 and EBNALP associate with EBV and cell enhancers, up-regulate the EBNA promoter, MYC, and EBV Latent infection Membrane Proteins (LMPs), which up-regulate BCL2 to protect EBV-infected B-cells from MYC proliferation-induced cell death. LCL proliferation induces p16INK4A and p14ARF-mediated cell senescence. EBNA3A and EBNA3C jointly suppress p16INK4A and p14ARF, enabling continuous cell proliferation. Analyses of the EBNA3A human genome-wide ChIP-seq landscape revealed 37% of 10,000 EBNA3A sites to be at strong enhancers; 28% to be at weak enhancers; 4.4% to be at active promoters; and 6.9% to be at weak and poised promoters. EBNA3A colocalized with BATF-IRF4, ETS-IRF4, RUNX3, and other B-cell Transcription Factors (TFs). EBNA3A sites clustered into seven unique groups, with differing B-cell TFs and epigenetic marks. EBNA3A coincidence with BATF-IRF4 or RUNX3 was associated with stronger EBNA3A ChIP-Seq signals. EBNA3A was at MYC, CDKN2A/B, CCND2, CXCL9/10, and BCL2, together with RUNX3, BATF, IRF4, and SPI1. ChIP-re-ChIP revealed complexes of EBNA3A on DNA with BATF. These data strongly support a model in which EBNA3A is tethered to DNA through a BATF-containing protein complexes to enable continuous cell proliferation.

scholarly journals Epstein-Barr virus nuclear antigen 2 (EBNA2) extensively rewires the human chromatin landscape at autoimmune risk loci

2020 ◽  
Author(s):  
Ted Hong ◽  
Omer Donmez ◽  
Daniel Miller ◽  
Carmy Forney ◽  
Michael Lape ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Human Genome ◽  
Genetic Risk ◽  
Epstein Barr Virus ◽  
Critical Role ◽  
Chromatin Accessibility ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Chromatin Looping ◽  
Epstein Barr

AbstractThe interplay between environmental and genetic factors plays a key role in the development of many autoimmune diseases. In particular, the Epstein-Barr virus (EBV) is an established contributor to multiple sclerosis, lupus, and other disorders. Previously, we demonstrated that the EBV nuclear antigen 2 (EBNA2) transactivating protein occupies up to half of the risk loci for a set of seven autoimmune disorders. To further examine the mechanistic roles played by EBNA2 at these loci on genome-wide scale, we globally examined gene expression, chromatin accessibility, chromatin looping, and EBNA2 binding, in a B cell line that was 1) uninfected, 2) infected with a strain of EBV lacking EBNA2, or 3) infected with a strain that expresses EBNA2. We identified >400 EBNA2-dependent differentially expressed human genes and >4,000 EBNA2 binding events in the human genome. ATAC-seq analysis revealed >3,000 regions in the human genome with EBNA2-dependent chromatin accessibility, and HiChIP-seq data revealed >2,000 regions where EBNA2 altered chromatin looping interactions. Importantly, autoimmune genetic risk loci were highly enriched at the sites of these EBNA2-dependent chromatin-altering events. We present examples of autoimmune risk genotype-dependent EBNA2 events, nominating genetic risk mechanisms for autoimmune risk loci such as ZMIZ1 and CD80. Taken together, our results reveal important interactions between host genetic variation and EBNA2-driven disease mechanisms. Further, our study highlights a critical role for EBNA2 in rewiring human gene regulatory programs through rearrangement of the chromatin landscape and nominates these interactions as components of genetic mechanisms that influence the risk of multiple autoimmune diseases.

scholarly journals Epstein–Barr virus nuclear antigen 2 extensively rewires the human chromatin landscape at autoimmune risk loci

2021 ◽  
Author(s):  
Ted Hong ◽  
Sreeja Parameswaran ◽  
Omer A. Donmez ◽  
Daniel Miller ◽  
Carmy Forney ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Human Genome ◽  
Genetic Risk ◽  
Epstein Barr Virus ◽  
Chromatin Accessibility ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Chromatin Looping ◽  
A Genome ◽  
Epstein Barr

The interplay between environmental and genetic factors plays a key role in the development of many autoimmune diseases. In particular, the Epstein–Barr virus (EBV) is an established contributor to multiple sclerosis, lupus, and other disorders. Previously, we showed that the EBV nuclear antigen 2 (EBNA2) transactivating protein occupies up to half of the risk loci for a set of seven autoimmune disorders. To further examine the mechanistic roles played by EBNA2 at these loci on a genome-wide scale, we globally examined gene expression, chromatin accessibility, chromatin looping, and EBNA2 binding in a B cell line that was (1) uninfected, (2) infected with a strain of EBV lacking EBNA2, or (3) infected with a strain that expresses EBNA2. We identified more than 400 EBNA2-dependent differentially expressed human genes and more than 5000 EBNA2 binding events in the human genome. ATAC-seq analysis revealed more than 2000 regions in the human genome with EBNA2-dependent chromatin accessibility, and HiChIP data revealed more than 1700 regions where EBNA2 altered chromatin looping interactions. Autoimmune genetic risk loci were highly enriched at the sites of these EBNA2-dependent chromatin-altering events. We present examples of autoimmune risk genotype–dependent EBNA2 events, nominating genetic risk mechanisms for autoimmune risk loci such as ZMIZ1. Taken together, our results reveal important interactions between host genetic variation and EBNA2-driven disease mechanisms. Further, our study highlights a critical role for EBNA2 in rewiring human gene regulatory programs through rearrangement of the chromatin landscape and nominates these interactions as components of genetic mechanisms that influence the risk of multiple autoimmune diseases.

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