# Using genetics, genomics, and transcriptomics to identify therapeutic targets in juvenile idiopathic arthritis

## TL;DR

This study uses genetic and genomic data to find new treatment targets for juvenile idiopathic arthritis, focusing on a gene called HIPK1.

## Contribution

The study identifies HIPK1 as a novel therapeutic target for JIA, linking it to disease risk and T cell regulation.

## Key findings

- HIPK1 is a strong candidate target gene associated with JIA and is suppressed in CD4+ T cells of affected children.
- HIPK1 is located in the PTPN22 locus and is connected to an enhancer element that influences its expression.
- Downstream transcription factors of HIPK1 show enriched binding near promoters of JIA-related genes.

## 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 have 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 (when compared to healthy control subjects). Of the 28 candidates, the strongest new target to emerge was homeodomain-interacting protein kinase 1 (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 coregulator 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.

This study integrates genetic, genomic, and transcriptomic data to identify therapeutic targets in juvenile idiopathic arthritis (JIA). It highlights HIPK1 as a novel target, demonstrating its role in T cell regulation and its association with JIA risk variants. These findings offer insights into JIA pathobiology and potential drug development pathways.