Large-scale integrative analysis of juvenile idiopathic arthritis for new insight into its pathogenesis

• Published in: Arthritis research & therapy 2024-02, Vol.26 (1), p.47-47, Article 47
• Main Authors: Kim, Daeun, Song, Jaeseung, Mancuso, Nicholas, Mangul, Serghei, Jung, Junghyun, Jang, Wonhee
• Format: Article
• Language: English
• Subjects: Analysis; Antigens; Arthritis; Care and treatment; Diagnosis; Disease; Gene expression; Genomes; Juvenile arthritis; Juvenile idiopathic arthritis; Lymphocytes; Multi-ethnicity RNA typing; Pathogenesis; Peptides; Phenotype; Proteins; Risk factors; RNA sequencing; Single nucleotide polymorphisms; T cell receptor (TCR) repertoire; T cell receptors; Transcriptome-wide and proteome-wide association studies
• ISSN: 1478-6362; 1478-6354; 1478-6362
• DOI: 10.1186/s13075-024-03280-2

Juvenile idiopathic arthritis (JIA) is one of the most prevalent rheumatic disorders in children and is classified as an autoimmune disease (AID). While a robust genetic contribution to JIA etiology has been established, the exact pathogenesis remains unclear. To prioritize biologically interpretable susceptibility genes and proteins for JIA, we conducted transcriptome-wide and proteome-wide association studies (TWAS/PWAS). Then, to understand the genetic architecture of JIA, we systematically analyzed single-nucleotide polymorphism (SNP)-based heritability, a signature of natural selection, and polygenicity. Next, we conducted HLA typing using multi-ethnicity RNA sequencing data. Additionally, we examined the T cell receptor (TCR) repertoire at a single-cell level to explore the potential links between immunity and JIA risk. We have identified 19 TWAS genes and two PWAS proteins associated with JIA risks. Furthermore, we observe that the heritability and cell type enrichment analysis of JIA are enriched in T lymphocytes and HLA regions and that JIA shows higher polygenicity compared to other AIDs. In multi-ancestry HLA typing, B*45:01 is more prevalent in African JIA patients than in European JIA patients, whereas DQA1*01:01, DQA1*03:01, and DRB1*04:01 exhibit a higher frequency in European JIA patients. Using single-cell immune repertoire analysis, we identify clonally expanded T cell subpopulations in JIA patients, including CXCL13 BHLHE40 T cells which are significantly associated with JIA risks. Our findings shed new light on the pathogenesis of JIA and provide a strong foundation for future mechanistic studies aimed at uncovering the molecular drivers of JIA.