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Epstein-Barr Virus Protein, Human Transcription Factors Implicated in Autoimmune Diseases

NEW YORK (GenomeWeb) – A team led by Cincinnati Children's Hospital Medical Center has found links between the binding sites of an Epstein-Barr Virus (EBV) protein and genomic risk loci for systemic lupus erythematosus (SLE) and other autoimmune diseases.

As the researchers reported in Nature Genetics today, they also found associations between hundreds of other transcription factors and risk loci for various diseases, including prostate cancer and breast cancer.

EBV infection is common — more than 90 percent of people in the US become infected by age 20. While resulting in mild disease or no symptoms in children, EBV causes mononucleosis in adolescents and young adults, with symptoms that include fever and extreme fatigue.

EBV had already been implicated in SLE, increasing the risk for the disease by up to 50-fold in children, but the molecular mechanism by which the virus contributes to SLE had been unknown.

In addition, genome-wide association studies had previously identified more than 50 SLE risk loci in cohorts with European ancestry.

The Cincinnati Children's scientists, led by co-corresponding authors John Harley, Leah Kottyan, and Matthew Weirauch, asked whether DNA-binding proteins encoded by EBV also bind SLE risk loci, thus explaining the link.

For their analysis, they developed the RELI (Regulatory Element Locus Intersection) algorithm, which looks for overlap between disease-associated genetic variants and transcription factor binding sites, as determined by ChIP-seq studies.

To start, they investigated whether RELI could recapitulate already known relationships between transcription factors and diseases and found that it correctly identified links between the androgen receptor and prostate cancer, between GATA3 and breast cancer, and between EBV-encoded EBNA2 and multiple sclerosis.

They then analyzed 53 SLE risk loci in European-ancestry individuals together with ChIP-seq data for several EBV-encoded transcription factors, gathered from EBV-infected B cells, and found that EBNA2 binding sites overlap significantly with SLE risk loci, whereas other EBV protein binding sites don't.

Next, they applied RELI to a large number of human transcription factor ChIP-seq datasets and found that 60 transcription factors also intersected with SLE loci. Further experiments showed that several of these transcription factors bound SLE risk loci only in the presence of EBV and suggested a role for EBV-infected B cells in the disease.

To widen the investigation, the team went on to run RELI on 213 other diseases and phenotypes from the National Human Genome Research Institute GWAS catalog and other sources, and they identified strong associations between EBNA2-binding and risk loci for nine additional conditions or phenotypes: rheumatoid arthritis, inflammatory bowel syndrome, type 1 diabetes, juvenile idiopathic arthritis, celiac disease, chronic lymphocytic leukemia, Kawasaki disease, ulcerative colitis, and immunoglobulin glycosylation. Similar to SLE, the same human transcription factors also clustered with these loci.

To see whether the associations they discovered are allele-dependent, the researchers reanalyzed the ChIP-seq data using the MARIO (Measurement of Allelic Ratios Informatics Operator) pipeline. The results, they wrote, suggest that many autoimmune-associated variants may modify host gene regulatory programs through altered binding of EBNA2 and other proteins, leading to altered gene expression.

Applying RELI to GWAS data for 213 other phenotypes, they discovered additional associations between transcription factors and diseases that were independent of EBNA2, for example between hematopoietic phenotypes and blood cell regulators; between GATA3, FOXA1, and TCF7L2 and breast cancer; and between AR, NR3C1, and EZH2 and prostate cancer.

Several transcription factors that bind to the same disease risk loci as EBNA2 can be targeted with drugs, they noted, results that "offer promise for the development of future therapies for manipulating the action of these proteins in individuals harboring risk alleles at EBNA2-bound loci."