Studying How Genes, Environment Contribute to Juvenile Arthritis

After asthma, juvenile idiopathic arthritis (JIA) is the most common chronic disease condition in children. While genetics play a small role in the disease, environmental factors are also known to be important.

The study, titled “Interplay Between Genetics and Epigenetics in Polyarticular JIA,” builds upon previous work by Jarvis and his fellow researchers.

The epigenome refers to the features of DNA and the proteins that DNA is wrapped around that do not control the genetic makeup of a person but do influence how cells respond to the environment, says Jarvis, principal investigator on the grant.

“Specifically, the epigenome determines what genes a cell will turn on or turn off in response to environmental cues,” he notes. 

Like most complex traits, genetic risk for JIA is principally located within non-coding regions of the genome.

“Our preliminary studies present the hope that we can finally understand the ‘gene-environment paradigm’ for JIA pathogenesis,” Jarvis says.

Rather than regarding JIA as an “autoimmune” disease, triggered by inappropriate recognition of a “self” protein by the adaptive immune system, Jarvis hypothesizes that JIA emerges because leukocytes suffer genetically and epigenetically mediated perturbations that blunt their capacity to regulate and coordinate transcriptions across the genome.

“This loss of coordinate regulation leads to inappropriate expression of inflammatory mediators in the absence of the normal external signals typically required to initiate or sustain an inflammatory response,” he says.

“Our field has been dominated by a single hypothesis for JIA pathogenesis for 30 years,” Jarvis notes. “However, as the field of functional genomics becomes increasingly wedded to the field of therapeutics, our work carries the promise of completely new approaches to therapy based on a completely different paradigm of pathogenesis.”

The researchers are recruiting 30 children with newly diagnosed polyarticular JIA for its study to survey the epigenome and CD4+ T cells in them and compare the results with findings in 30 healthy children.

“We plan to build a multidimensional genomic map that surveys the functional epigenome, examines underlying genetic variation and examines the effects of genetic and epigenetic variation on gene expression,” Jarvis says.

He notes the work will focus on CD4+ T cells because the researchers have already identified interesting interactions between their epigenome and transcriptome in the context of therapeutic response in JIA.

Because the epigenome is the medium through which the environment exerts its effects on cells, Jarvis believes that characterizing the epigenome in pathologically relevant cells, ascertaining where epigenetic change is linked to genetic variation and determining how genetic and epigenetic features of the genome regulate or alter transcription is the key to truly understanding this disease.

“This project addresses a question that parents always ask, which I never thought we’d begin to answer in my lifetime: ‘What causes JIA?’ This study won’t provide the whole answer, but it will go a long way toward taking us there,” he says.

The project has three specific aims:

• establishment of a cohort of children with newly diagnosed polyarticular JIA and examination of DNA methylation in peripheral blood CD4+ T cells and assessment of the significance of methylation changes (compared to healthy controls) by examining gene/transcript expression in CD4+ T cells using RNA sequencing
  
• assessment of the effects of DNA methylation on transcription by correlating methylation with chromatin accessibility using the assay for transposase-accessible chromatin-sequencing
  
• examination of the interplay between epigenetics and genetics by completing whole genome sequencing (WGS) on patients enrolled in the project and integration of the results from these patients with data previously obtained from children with polyarticular JIA

The two-year, $730,998 grant is part of the Arthritis Foundation’s 2016 Delivering on Discovery awards. It was one of only six projects out of 159 proposals chosen for funding. For the first time, arthritis patients helped the foundation select projects.

“Including patient input as part of the selection process was a new milestone in patient engagement for the Arthritis Foundation and allowed us to select projects that hold the most promise from an arthritis patient’s point of view,” says Guy Eakin, senior vice president, scientific strategy.

Collaborators from the Jacobs School of Medicine and Biomedical Sciences are:

• Tao Liu, PhD, assistant professor of biochemistry
• Michael Buck, PhD, associate professor of biochemistry
• Kaiyu Jiang, research scientist

Other collaborators include researchers from the Children’s Hospital of Philadelphia.