Studying How Genes, Environment Contribute to Juvenile Arthritis – UB School of Medicine and Biomedical Sciences News

James N. Jarvis, MD, is conducting a study of the gene-environment paradigm for juvenile idiopathic arthritis pathogenesis.

Published August 14, 2017

JamesN. Jarvis, MD, clinical professor of pediatrics, will usean Arthritis Foundationgrant to study how genes and environment work together to influencethe immune dysfunction in juvenile arthritis.

After asthma, juvenile idiopathic arthritis (JIA) is the mostcommon chronic disease condition in children. While genetics play asmall role in the disease, environmental factors are also known tobe important.

Study Focuses on Influence of Epigenome

The study, titled Interplay Between Genetics andEpigenetics in Polyarticular JIA, builds upon previous workby Jarvis and his fellow researchers.

The epigenome refers to the features of DNA and the proteinsthat DNA is wrapped around that do not control the genetic makeupof 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 cellwill turn on or turn off in response to environmental cues,he notes.

New Paradigm of Pathogenesis Informs Research

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

Our preliminary studies present the hope that we canfinally understand the gene-environment paradigm forJIA pathogenesis, Jarvis says.

Rather than regarding JIA as an autoimmunedisease, triggered by inappropriate recognition of aself protein by the adaptive immune system, Jarvishypothesizes that JIA emerges because leukocytes suffer geneticallyand epigenetically mediated perturbations that blunt their capacityto regulate and coordinate transcriptions across the genome.

This loss of coordinate regulation leads to inappropriateexpression of inflammatory mediators in the absence of the normalexternal signals typically required to initiate or sustain aninflammatory response, he says.

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

Newly Diagnosed Children Tested in Study

The researchers are recruiting 30 children with newly diagnosedpolyarticular JIA for its study to survey the epigenome and CD4+ Tcells in them and compare the results with findings in 30 healthychildren.

We plan to build a multidimensional genomic map thatsurveys the functional epigenome, examines underlying geneticvariation and examines the effects of genetic and epigeneticvariation on gene expression, Jarvis says.

He notes the work will focus on CD4+ T cells because theresearchers have already identified interesting interactionsbetween their epigenome and transcriptome in the context oftherapeutic response in JIA.

Taking Novel Approach to Understanding Disease

Because the epigenome is the medium through which theenvironment exerts its effects on cells, Jarvis believes thatcharacterizing the epigenome in pathologically relevant cells,ascertaining where epigenetic change is linked to genetic variationand determining how genetic and epigenetic features of the genomeregulate or alter transcription is the key to truly understandingthis disease.

This project addresses a question that parents alwaysask, which I never thought wed begin to answer in mylifetime: What causes JIA? This study wontprovide the whole answer, but it will go a long way toward takingus there, he says.

The project has three specific aims:

Arthritis Patients Help Determine Funded Projects

The two-year, $730,998 grant is part of the ArthritisFoundations 2016 Delivering on Discovery awards. It was oneof only six projects out of 159 proposals chosen for funding. Forthe first time, arthritis patients helped the foundation selectprojects.

Including patient input as part of the selection processwas a new milestone in patient engagement for the ArthritisFoundation and allowed us to select projects that hold the mostpromise from an arthritis patients point of view,says Guy Eakin, senior vice president, scientific strategy.

Partners from JSMBS, Philadelphia Hospital

Collaborators from the JacobsSchool of Medicine and Biomedical Sciences are:

Other collaborators include researchers from theChildrens Hospital of Philadelphia.

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Studying How Genes, Environment Contribute to Juvenile Arthritis - UB School of Medicine and Biomedical Sciences News