Network Analysis Uncovers Gene-Regulatory Intersections Linking Juvenile Idiopathic Arthritis to Blood Cancers and Other Autoimmune Diseases

Abstract

Background Juvenile idiopathic arthritis (JIA) is an inflammatory joint disease characterized by a complex genetic etiology. As JIA progresses, patients commonly develop additional comorbid conditions, including other autoimmune diseases and cancers. However, the specific gene-regulatory mechanism linking these conditions remains unknown. This study aims to elucidate the underlying gene-regulatory mechanisms that link JIA to its associated comorbidities. Methods A two-sample Mendelian Randomization (MR) analysis was conducted to identify blood-expressed genes causally linked to JIA. Integration of data from expression quantitative trait loci (eQTL), 3 dimensional (3D) genome organization, and protein-protein interaction network was performed to pinpoint sets of single-nucleotide polymorphisms (i.e., spatial eQTL SNPs) regulating the expression of these genes and their interaction partners. These SNPs were then cross-referenced against a public GWAS database to identify other traits that have been previously associated with these SNPs. Results MR analysis identified 54 blood-expressed genes causally linked to JIA. The spatial eQTLs regulating JIA causal genes and their interaction partners were enriched for the GWAS SNPs of 87 comorbid traits. Shared dysregulation of three HLA class II genes (HLA-DQB2, HLA-DRB1, and HLA-DQA2) underpins the association between JIA and most comorbid traits. We highlighted a set of genes on chromosome 6p22.1 (HLA-A, HCG4P5, HLA-T, MOG, TRIM26, HCG, IFITM4P) involved in the association between JIA and specific autoimmune diseases, such as Crohn’s disease, type 1 diabetes, asthma, and rheumatoid arthritis. Unique associations between JIA and Hodgkin lymphoma was identified through genes in 6p21.3 (FKBPL, PBX2, AGER) and chronic lymphocytic leukaemia through the BAK1 gene. Notably, genes like PBX2 and BAK1 have been implicated in the regulation of cell cycle and apoptosis. Conclusions The JIA phenotype is partially determined by an individual's genetic susceptibility to specific co-occurring conditions. Our research enhances the understanding of disease origins by identifying regulatory mechanisms linking JIA with its comorbidities. This offers avenues for pinpointing shared therapeutic targets, thereby improving outcomes for patients with multimorbidity.