Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity

Abstract

Explaining the genetics of many diseases is challenging because most associations localize to incompletely characterized regulatory regions. We show that transcription factors (TFs) occupy multiple loci of individual complex genetic disorders using novel computational methods. Application to 213 phenotypes and 1,544 TF binding datasets identifies 2,264 relationships between hundreds of TFs and 94 phenotypes, including AR in prostate cancer and GATA3 in breast cancer. Strikingly, nearly half of the systemic lupus erythematosus risk loci are occupied by the Epstein-Barr virus EBNA2 protein and many co-clustering human TFs, revealing gene-environment interaction. Similar EBNA2-anchored associations exist in multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis, and celiac disease. Instances of allele-dependent DNA binding and downstream effects on gene expression at plausibly causal variants support genetic mechanisms dependent upon EBNA2. Our results nominate mechanisms that operate across risk loci within disease phenotypes, suggesting new paradigms for disease origins.

Epstein - Barr virus Infection in a Patient with Neuromyelitis Optica Spectrum Disorder and Sjögren’s Syndrome: A Case Report and Review of Literature

“…EBV resides in B lymphocytes of the infected individual in a latent form [25]. In the B lymphocytes, EBV Nuclear Antigen 2 (EBNA2) regulates latent viral transcription which allows immortalization of the virus and recruitment of transcription factors that bind to regions of both the EBV genome and the host’s own genome [9,26]. …”

“…Another hypothesis is the production of anti-apoptotic signals by EBV, which lead to development of ectopic lymphoid structures rich in infected B cells [29]. The elevated number of infected B cells constitutes a reservoir of antigenic and viral particles contributing to the autoimmune process [9]. In a recent study comparing genetic and protein sampling from healthy individuals and patients with autoimmune diseases, Harley et al identified regulatory gene regions associated with the risk of developing systemic erythematous lupus (SLE) and other autoimmune diseases.…”

“…On the other hand, Epstein Barr virus (EBV) infections can also present with neurological manifestations in up to 7.3% of the cases, with long extensive myelitis and acute demyelinating encephalomyelitis being rare [7,8]. Research unveiled that the long observed autoimmunity driven by EBV, is likely explained by an EBV gene product that appears to be central to the interaction between human transcription factors and gene expression patterns triggering autoimmunity [9]. Herein we present the case of middle age woman who had suffered Guillain-Barre Syndrome (GBS) two years prior and presented with progressive weakness.…”

Role of Epstein-Barr virus infection in SLE: gene-environment interactions at the molecular level

“…A paper by Harley et al in Nature Genetics provides an important new perspective on the mechanisms by which infection with Epstein-Barr virus (EBV) can promote autoimmunity and, in particular, systemic lupus erythematosus (SLE) 1. An interest in the role of EBV in lupus pathogenesis has a long history beginning in the 1970s with observations that patients with SLE have increased titres of anti-EBV antibodies 2.…”

“…Using data from a number of experimental sources, RELI can assess ‘the significance of the interactions of the genomic coordinators of plausibly causal genetic variation and DNA sequences bound by a particular TF, as determined through chromatin immunoprecipitation and sequencing (ChIP-seq)’ 1. The authors first validated this approach with prostate and breast cancer cell lines and then went on to study SLE and other autoimmune diseases, focusing on the interaction of EBNA2 with European ancestry risk alleles.…”