NEW YORK (Reuters Health) – The Epstein-Barr virus (EBV) transcription factor EBNA2 shows significant associations with genetic risk loci for at least seven autoimmune diseases, researchers report.
“Our work is based on the prediction that disease-specific regulatory elements will be concentrated in the risk loci of complex genetic diseases,” said Dr. John B. Harley of the University of Cincinnati, Ohio.
“That this appears to be true for so many diseases with so many results suggests that we have found a way to reveal unknown mechanisms of disease, some of which would then be amenable to efficacious therapeutic intervention,” he told Reuters Health by email.
Dr. Harley’s team developed the Regulatory Element Locus Intersection (RELI) algorithm and used it to identify associations between hundreds of transcription factors and numerous complex phenotypes.
They first demonstrated its ability to capture known relationships between transcription factors and diseases by using RELI analysis to identify androgen-receptor binding sites that significantly intersect with prostate-cancer-associated loci and to identify binding sites for GATA3 in a breast-cancer cell line (GATA3 has an established role in breast cancer).
RELI then showed that the EBV-encoded EBNA2 protein intersected significantly with multiple sclerosis (MS) risk loci and with European-ancestry systemic lupus erythematosus (SLE) risk loci, the team reports in Nature Genetics, online April 16.
Further analysis revealed especially strong associations between EBNA2 and five other diseases, including rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis and celiac disease.
Weaker associations were also identified between EBNA2 and chronic lymphocytic leukemia, Kawasaki disease, ulcerative colitis and immunoglobulin glycosylation.
Use of another computational method (Measurement of Allelic Ratios Informatics Operator, MARIO) identified numerous allele-dependent EBNA2 binding events within and across cell types, and further experiments identified 80 genes with significant EBV-dependent alterations in gene expression.
Further application of these methods suggested associations between other transcription factors and 94 different diseases or phenotypes.
“These results greatly contribute to the circumstantial evidence that Epstein-Barr virus contributes the cause (or causes) of lupus, multiple sclerosis, rheumatoid arthritis, and maybe other inflammatory diseases for many patients,” Dr. Harley said. “Perhaps our work will very much increase the public health interest in developing an effective vaccine that would prevent this virus infection.”
Co-author Dr. Leah C. Kottyan, also at the University of Cincinnati, told Reuters Health by email, “Diseases with genetic components to disease etiology have 10-150 regions of the genome that each affect disease risk. Over 90% of these genetic variations do not affect the composition of proteins, they change the regulation of gene expression.”
“Our study found that specific transcription factors (proteins inside of cells that bind DNA at specific sequences and regulate gene expression) bind disease risk loci more than would be expected by chance,” she explained.
Dr. Paul Farrell from Imperial College London, who has also researched EBV-related transcription factors, told Reuters Health by email, “The paper uses an impressive array of techniques to crunch a huge amount of data on a variety of diseases that have a genetic basis, including SLE. For SLE it identifies an important set of risk alleles and links them clearly to the B cell activation pathways. The answer to whether EBV is cause or consequence in SLE may have to wait for an EBV vaccine or trying out an EBV-targeted therapy and finding that it works.”
“Several autoimmune diseases are known to have aberrant control of the persistent EBV infection that the great majority of people carry,” he said. “Patients with MS or SLE can have higher EBV loads and distinct profiles of immune response to the virus. Because these are diseases of the immune system, it is currently not clear whether the altered EBV-related profiles are because the patient has a diseased immune system or because EBV is actually contributing to the disease.”
Dr. Marco Salvetti from Sapienza University in Rome recently identified EBNA2 genetic variants associated with multiple sclerosis. He told Reuters Health by email, “This work represents one of the most relevant advancements in our understanding of how gene-environment interactions cause multifactorial diseases.”
“To some extent it is surprising that similar mechanisms – EBV impact on the regulation of gene expression – operate across disease loci within disease phenotypes,” Dr. Salvetti said. “As for recent genetic studies, these findings may in the near future reshape phenotype-based disease classification.”
SOURCE: https://bit.ly/2JbgXCO
Nature Genet 2018.
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