Pediatric rheumatic diseases have unique genetic architecture compared to adults

Researchers from Children's Hospital of Philadelphia (CHOP) have found that pediatric-onset rheumatic and inflammatory diseases have distinct genetic architecture compared with adults. The findings, published today in the journal Annals of the Rheumatic Diseases, could pave the way for the discoveries that have benefitted adult patients with similar conditions, like better disease classification and the development of precision therapies.

Immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis, psoriasis and inflammatory bowel disease, comprise an array of disorders driven by overactive and dysregulated immune responses that lead to increased inflammation. Genome-wide association studies (GWAS) in adults have identified hundreds of genetic variations for IMIDs, particularly rheumatoid arthritis systemic lupus erythematosus, leading to the development of targeted therapeutic interventions. However, the genetic basis of pediatric-onset IMIDs like juvenile idiopathic arthritis and related rheumatic disease, remains far less characterized.

"The findings of this research challenge the assumption that pediatric-onset rheumatic and other immune disorders are simply early manifestations of adult diseases, underscoring the need for further research on the interaction between genetic factors and developmental context in disease pathogenesis," said senior study author Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at CHOP.

Using 24 different types of IMIDs, the researchers performed genome-wide association analyses of 18,086 cases and 131,019 controls. Single nucleotide polymorphism-based heritability – the concept that genetic variants lead to observed clinical symptoms – ranged from 28.9% for allergic IMIDs to 61.9% for autoimmune IMIDs, demonstrating that genetic variability was responsible for their diseases. A meta-analysis of the data identified 39 genome-wide significant variants in specific regions of the genome associated with immune responses, including 15 previously unreported variants. Of these variants, 18 were shared between different IMID categories.

While pediatric-onset IMIDs share many core genetic pathways with adult forms of the same diseases, they exhibit distinct genetic architecture shaped by age-specific immune and neurodevelopmental biology. These genes involved in these studies emphasize the contributions of developmental and growth-phase programs and their connections to pediatric IMID risk, since these processes are especially active or regulated in childhood but wane as children develop into adults. Pooling data from multiple diseases also revealed these connections in ways that single-disease studies might have missed, since the differences could be traced to individual genetic variants.

"The genomic framework generated here may inform precision approaches in pediatric rheumatology, including early risk stratification, mechanistic disease subclassification, and prioritization of therapeutic targets for childhood-onset immune disorders," Hakonarson said.

The study was supported by the Institutional Development Funds from CHOP, the fund of the CHOP Endowed Chair in Genomic Research, and the National Natural Science Foundation of China award 82572080.