Background/Purpose: SLE affects millions worldwide. The etiology of this complex autoimmune disease is the consequence of both strong genetic and environmental components. Genome-wide association studies (GWAS) have identified many variants associated with SLE that mostly localize to incompletely understand regulatory regions. EBV has been nominated as potential triggering environmental factors in SLE from immunochemical, virologic, epidemiologic and genomic studies. Recent work reveals a possible mechanism via the concentration of the EBV-encoded transcription cofactor (co-TF), Epstein-Barr virus nuclear antigen 2 (EBNA2) at SLE risk loci (Nat Genet 50:699 2018).

Methods: In 124 GWAS and candidate-gene studies ~500 variants have been associated with SLE at p< 5E-08. By literature curation and linkage disequilibrium pruning, we identify 187 independent SLE loci when requiring r²< 0.2 or regression modeling to separate loci. Most loci (132, 71%) are ancestry specific. The most studied ancestries, European (100 loci) and East Asian (94 loci), share only 31 loci. 

The simulation algorithm, RELI, first presented in (Nat Genet 50:699, 2018), has been improved and applied to 53 viral and 11,781 human ChIP-seq (chromatin immunoprecipitation with DNA sequencing) datasets, a collection 8-times larger than previously available, to assess DNA binding of 1,467 regulatory proteins (TFs & co-TFs).

Results: We confirm association with EBNA2 DNA binding complexes (OR=2.4, Pc= 3.1×10^-12) and discover association with EBV Latency III genes EBNA3C (OR=2.7, Pc= 1.44×10^-23) and EBNA-LP (OR=2.0, Pc= 3.18×10^-15) that bind 33% to 51% of the 187 SLE loci. Among human TFs & co-TFs 193 significantly associated (Pc< 10^-6) with SLE risk loci. In GO Enrichment Analysis these 193 human TFs & co-TFs show involvement in JAK/STAT, Toll receptor, interleukin, apoptosis signaling pathways, oxidative stress response and transcription regulation pathways and enriched in such biological processes as T and B cell regulation and differentiation, dendritic cell, megakaryocyte and erythrocyte differentiation, cellular response to interleukin-6, -7, -9, 15, type I interferon, positive regulation of interleukin-10 and -12 biosynthetic processes, chromatin modification, mitosis, and viral transcription.

The EBV co-TFs EBNA2, EBNA3C, and EBNA-LP and human regulatory proteins, tend to cluster together at the same subset of the SLE risk loci (p< 10^-300). The associated human TFs have a powerful tendency to be from EBV transformed B cells (OR≈56, P< E-100) and to be known components of the super-enhancer complexes that form upon EBV infection and transformation of B cells (OR >30, p< 10^-25). Meanwhile, genetic associations for many other diseases, such as depression, anxiety, and schizophrenia and other complex genetic phenotypes (n >400) show no such relationships.

Conclusion: These new results confirm previous results and extend evidence supporting an etiologic role for EBV in SLE. At this moment, the most attractive hypothesis of mechanism is that the EBV alters a substantial proportion of SLE genetic risk through gene expression changes that occur in EBV transformed B cells as a consequence of the action of the Latency III EBV gene expression program.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/epstein-barr-virus-ebv-an-etiologic-factor-for-systemic-lupus-erythematosus-sle-interacts-with-sle-risk-loci-through-ebv-encoded-transcription-co-factors-co-tfs/