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Evidence from genome wide association studies implicates reduced control of Epstein-Barr virus infection in multiple sclerosis susceptibility

Citation

Afrasiabi, A and Parnell, GP and Fewings, N and Schibeci, SD and Basuki, MA and Chandramohan, R and Zhou, Y and Taylor, B and Brown, DA and Swaminathan, S and McKay, FC and Stewart, GJ and Booth, DR, Evidence from genome wide association studies implicates reduced control of Epstein-Barr virus infection in multiple sclerosis susceptibility, Genome Medicine, 11, (1) Article 26. ISSN 1756-994X (2019) [Refereed Article]


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Copyright 2019 the authors. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

DOI: doi:10.1186/s13073-019-0640-z

Abstract

Background: Genome wide association studies have identified > 200 susceptibility loci accounting for much of the heritability of multiple sclerosis (MS). Epstein-Barr virus (EBV), a memory B cell tropic virus, has been identified as necessary but not sufficient for development of MS. The molecular and immunological basis for this has not been established. Infected B cell proliferation is driven by signalling through the EBV produced cell surface protein LMP1, a homologue of the MS risk gene CD40.

Methods: We have investigated transcriptomes of B cells and EBV-infected B cells at Latency III (LCLs) and identified MS risk genes with altered expression on infection and with expression levels associated with the MS risk genotype (LCLeQTLs). The association of LCLeQTL genomic burden with EBV phenotypes in vitro and in vivo was examined. The risk genotype effect on LCL proliferation with CD40 stimulation was assessed.

Results: These LCLeQTL MS risk SNP:gene pairs (47 identified) were over-represented in genes dysregulated between B and LCLs (p < 1.53 × 10-4), and as target loci of the EBV transcription factor EBNA2 (p < 3.17 × 10-16). Overall genetic burden of LCLeQTLs was associated with some EBV phenotypes but not others. Stimulation of the CD40 pathway by CD40L reduced LCL proliferation (p < 0.001), dependent on CD40 and TRAF3 MS risk genotypes. Both CD40 and TRAF3 risk SNPs are in binding sites for the EBV transcription factor EBNA2, with expression of each correlated with EBNA2 expression dependent on genotype.

Conclusions: These data indicate targeting EBV may be of therapeutic benefit in MS.

Item Details

Item Type:Refereed Article
Keywords:Epstein-Barr virus, expression quantitative trait loci, genetics, multiple sclerosis, risk genes, transcription factors, miRNA
Research Division:Medical and Health Sciences
Research Group:Neurosciences
Research Field:Central Nervous System
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Nervous System and Disorders
UTAS Author:Zhou, Y (Mr Yuan Zhou)
UTAS Author:Taylor, B (Professor Bruce Taylor)
ID Code:133988
Year Published:2019
Deposited By:Menzies Institute for Medical Research
Deposited On:2019-07-18
Last Modified:2019-08-05
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