Diabetes Risk Increases with Exposure to Epstein-Barr Virus

Researchers uncover genetic link involving b cells that suggest an increased risk of developing at least seven identified autoimmune disorders, including type 1 diabetes, following a person's infection with the Epstein-Barr virus.

With John Harley, MD, PhD, and Georgia Davis, MD

Investigators confirmed that the presence of the Epstein-Barr virus (EBV) increases a person’s risk for seven autoimmune diseases, including inflammatory bowel disease (IBD), celiac disease, and type 1 diabetes (T1D).1 The study, published in Nature Genetics, elucidated how environmental factors interact with the human genome, leading to the development of these diseases.

The research team at Cincinnati Children’s Center for Autoimmune Genomics and Etiology (CAGE), led by John Harley, MD, PhD, professor of pediatrics, and director of the Center for Autoimmune Genomics and Etiology at Cincinnati Children’s Hospital Medical Center, in Ohio, developed an algorithm called, Regulatory Element Locus Intersection (RELI), which allowed them to determine that a protein produced by the EBV, called EBNA2, binds to multiple locations along the human genome that are associated with these autoimmune disorders.1

Type 1 diabetes may arise after exposure to Epstein-Barr virus.Epstein-Barr virus has genetic link to type 1 diabetes.

“We found that the EBNA2 transcription factor was helping to change how infected B cells operated as well as how the body responded to the infected cells,” Dr. Harley told EndocrineWeb. Dr. Harley, and his research team, including Matthew Weirauch, PhD, and Leah Kottyan, PhD, et al, used this new computation method to locate these genetic connections.1

EPV Linked to Selective Autoimmune Diseases

The Epstein Barr virus—known for causing mononucleosis—infects an estimated 95% of the world’s population, although it is typically asymptomatic or presents with mild symptoms in younger children.2 And, gene-environment interactions have been suspected in the etiology of many autoimmune disorders. For example, prior research has linked EBV infection with SLE and has been shown to significantly increase the risk of SLE in children.3,4 EBV has also been linked with other diseases,5 although the underlying molecular mechanisms were unclear.

Until recently, researchers have been unable to identify the mechanisms for the genetic associations of most diseases. However, genome-wide association studies (GWAS) found most SLE loci occur in likely gene regulatory regions,6 leading the researchers to consider whether any DNA-interacting proteins preferentially bind SLE risk loci.

Genetics involved: The Role of Transcription Factors

Specifically, the researchers looked at transcription factors—the proteins that travel along DNA strands, turning specific genes on/off to ensure optimal cell functioning—and found that this process can alter the normal functions of a cell, leading to disease.1

A unique finding from this study is that the seven autoimmune disorders: SLE, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, celiac disease, and type 1 diabetes, share a common set of abnormal transcription factors – and each is affected by the EBNA2 protein,1 said Dr. Harley.

“Depending upon which portion of the genetic code the transcription factor becomes attached determines which autoimmune disorder manifests,” he said. Transcription factors that regulate human gene expression are typically thought to be human; this study found that when the virus infects cells, it makes its own transcription factors, which then connect to disease-specific risk loci on the human genome, thereby increasing the risk for that disease.1

What Is the Clinical Outlook from Exposure to EBV?

Together, the seven autoimmune diseases associated with EBNA2 affect nearly eight million people in the US.  One might wonder why, with the overwhelming prevalence of EBV in the population, there are not significantly higher rates of these disorders. Dr. Harley said, “a better question to ask is whether or not the virus is required for initiation of any of these diseases.”

Another surprising finding was that other autoimmune disorders—such as thyroid disease—were not affected by the same EBNA2 protein,1 according to the researchers.

There are approximately 1600 known transcription factors within the human genome, to which Dr. Harley and his team have applied these analytic methods to examine connections between them and the known gene variants associated with more than 200 diseases.1

So far, they have documented associations in 94 conditions, and have identified more than 2260 significant (Pc <10-6) TF-disease relationships.1 For example, Dr. Harley said, “I can tell you, for example, that we have found three of the 10 genes that intersect the transcription factor EZH2 and are concentrated almost 18-fold; the NZF143 transcription factor binds 6 of 17 genes to determine the age of onset of menopause, and the enrichment is 11-fold (p=8.511X10-11). We have similar information for metabolic syndrome, obesity, ovarian cancer, and on and on.”

Opportunities Ahead for Prevention and Avenues for Treatment

In an interview with EndocrineWeb, Georgia Davis, MD, an endocrinology fellow at Emory University School of Medicine in Atlanta, said, “although the relationship between EBV and SLE has been further characterized, it is likely only one of many complex genetic and environmental relationships contributing to the development of clinical autoimmune disease.

The diverse spectrum of clinical manifestations of autoimmune disease highlights the need for continued research in this area to 1) further define genetic characteristics of those developing autoimmune disease, 2) identify those who may respond best to targeted therapy, and 3) identify those without clinical disease who are at high risk for developing future autoimmunity.”

Dr. Harley acknowledged that this study was a massive undertaking and that it is impossible for him and his colleagues to be able to follow up on all the findings. Consequently, they are making their algorithms and genetic data available to other experts in the hopes of fostering a collaborative effort to further the research.

This ongoing research may eventually help “identify potential molecular targets for treatment, and considering research on prevention of potentially implicated viral infections such as EBV, in the fight against autoimmune diseases,” Dr. Davis said. 

The research was conducted with funding from the National Institutes of Health, and the researchers have submitted a patent application based on their findings. Dr. Davis has no financial conflicts.

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Increased Risk for Celiac Disease Found Early after Diagnosis of Type 1 Diabetes
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