Latency III gene products of Epstein-Barr Virus (EBV) are associated with Systemic Lupus Erythematosus (SLE) genetic risk loci

Abstract

Abstract SLE affects millions with increasing diagnostic prevalence. Genetic studies have identified >600 mostly regulatory variant associations. EBV has been nominated as a causal factor for SLE from immunochemistry and epidemiologic studies. EBNA2 concentrates at SLE risk loci (Nat Genet 50:699 2018) suggesting mechanisms. Additional evidence supporting EBV as an SLE origin would advance this hypothesis of etiology. Previous simulation using our RELI algorithm revealed an astonishing association with Epstein-Barr virus nuclear antigen 2 (EBNA2) (OR=5.96, Pc=E-25) (Nat Genet 50:699, 2018). The >100 risk alleles associated at p<5E-8 for SLE were curated and reduced to 83 loci by linkage disequilibrium pruning. We evaluated the available 53 virally encoded and 13,051 human TF ChIP-seq (chromatin immunoprecipitation with DNA sequencing) datasets. In addition to EBNA2 (now OR=3.7, Pc=1.96E-18 after Bonferroni correction), two of the 53 viral TF data sets, EBNA3C and EBNALP, each of which are EBV Latency III gene products, were also strongly associated with the SLE risk loci (OR=6.0, Pc=4.19E-18; and OR=3.3, Pc=5.53E-18). Moreover, among the human TF datasets strongly associated with SLE risk loci (Pc<E-6), those from EBV infected and transformed B cells are highly concentrated (OR≈56, P<E-100) and, in addition, the human TFs that are known to form super-enhancers upon B cell transformation by EBV (e.g., NFκB subunits) also tend to be concentrated at the SLE risk loci (OR>30, p<E-25). Meanwhile, genetic associations for depression, anxiety, and schizophrenia show no such relationships. These new results further the possible validity of the hypothesis that SLE is originally caused by the Latency III expression program of EBV.