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

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. Electronic supplementary material The online version of this article (10.1186/s13073-019-0640-z) contains supplementary material, which is available to authorized users.

Epstein–Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies

“…Other viral targets could be obtained from a series of genome-wide association studies (GWAS) which have identified 250 variants that contribute to MS disease susceptibility [3][4][5]. In addition, the growing wealth of human genetic data grouped as viral interactomes or transcriptomes of B cells and EBV-infected B cells may be useful when selecting new targets, especially because EBV genetic variants are associated with MS [80,81]. Targeting B cell pathways (e.g., BAFF, BHRF1) or employing siRNAs targeting EBV genes (e.g., LMP1, LMP2a and EBNA1) to downregulate expression and induce apoptosis in EBV-infected cells might also be effective in reducing EBV reactivation.…”

Reworking GWAS Data to Understand the Role of Nongenetic Factors in MS Etiopathogenesis

“…This approach proved to be informative. In fact, two TRAF3 MS risk SNPs (rs12147246 and rs12588969; [11]) were then identified as being of genome-wide significance, while other studies have shown their involvement in a dysregulated response to EBV infection [42], i.e., one of the main environmental factors associated with MS [43,44].…”

Transcribed B lymphocyte genes and multiple sclerosis risk genes are underrepresented in Epstein–Barr Virus hypomethylated regions

“…We performed tiling analysis using 1-kb tiles centred upon MS risk loci identified previously by the International MS Genetics Consortium as being associated with increased disease risk [16] (MSGWAS). We also chose a subset of these risk loci which have been previously found to be associated with gene expression in LCLs [5] (LCLeQTL). We compared the number of differentially methylated regions (DMRs) with regions centred upon an unbiased list of single nucleotide polymorphisms from the NHGRI-EBI Catalog of published genome-wide association studies [17] (GWAS Catalog; downloaded 8 September 2018).…”

“…At present, over 200 singlenucleotide polymorphisms (SNPs) have been found to be associated with increased susceptibility to MS [3], and the vast proportion of the genes proximal to these SNPs are associated with immune cell pathways, and are associated with altered gene expression in immune cells of the blood [4]. Many of the MS risk SNPs have a stronger or different association with gene expression in EBV-infected B cells than blood [5]. The altered expression of risk genes appears in turn to affect infected B cell functions, including cell proliferation, and immune system evasion.…”