Using Genetics, Genomics, and Transcriptomics to Identify Therapeutic Targets in Juvenile Idiopathic Arthritis.

Abstract

Despite progress in improving outcomes for oligoarticular and polyarticular juvenile idiopathic arthritis (JIA), the field still faces considerable challenges. More than half of adults who had JIA continue to have active disease and have developed functional limitations. Medication side-effects are common and intrusive. Thus, the field continues to search for therapeutic agents that target specific aspects of disease pathobiology and will be accompanied by fewer and less intrusive side effects. We identified 28 candidate target genes that were associated with JIA according to Open Targets Genetics and were also differentially expressed in the CD4+ T cells of children with active JIA patients (when compared to healthy controls). Of the 28 candidates, the strongest new target to emerge was homeodomain interacting kinase (HIPK1), which suppresses T cell activation and is within the PTPN22 locus tagged by rs6679677. This locus includes an enhancer element that contacts the HIPK1 promoter, and HIPK1 shows decreased expression in JIA CD4+ T cells when compared to controls. Gene Ontology terms associated with HIPK1 were overrepresented among the differentially expressed genes between JIA and controls and PML, a known co-regulator of HIPK1, showed a similar suppressed gene expression profile. Two downstream transcription factors of HIPK1, TP53 and GATA4, showed enriched binding patterns near the promoters of JIA up-regulated genes. Taken together, these data suggest a pathogenic role for HIPK1 in JIA and make it a prime candidate for therapeutic modulation.