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

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Afrasiabi, A, Parnell, GP, Fewings, N, Schibeci, SD, Basuki, MA, Chandramohan, R, Zhou, Y ORCID: 0000-0003-1962-2574, Taylor, B, Brown, DA, Swaminathan, S, McKay, FC, Stewart, GJ and Booth, DR 2019 , 'Evidence from genome wide association studies implicates reduced control of Epstein-Barr virus infection in multiple sclerosis susceptibility' , Genome Medicine, vol. 11, no. 1 , pp. 1-13 , doi: 10.1186/s13073-019-0640-z.

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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 -4), and as target loci of the EBV transcription factor EBNA2 (p -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 Conclusions: These data indicate targeting EBV may be of therapeutic benefit in MS.

Item Type: Article
Authors/Creators: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
Keywords: Epstein-Barr virus, expression quantitative trait loci, genetics, multiple sclerosis, risk genes, transcription factors, miRNA
Journal or Publication Title: Genome Medicine
Publisher: BioMed Central Ltd.
ISSN: 1756-994X
DOI / ID Number: 10.1186/s13073-019-0640-z
Copyright Information:

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

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