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]
Copyright 2019 the authors. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/
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 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 Field:||Central Nervous System|
|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)|
|Deposited By:||Menzies Institute for Medical Research|
|Downloads:||1 View Download Statistics|
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