Evaluating the causal effect of circulating proteome on the risk of Juvenile idiopathic arthritis: an omics pipeline study.

BACKGROUND

Genome-wide association studies (GWAS) have pinpointed a multitude of risk loci associated with Juvenile Idiopathic Arthritis (JIA), but it is challenging to decipher novel plasma proteins. To address this, we applied an integrative omics pipeline to uncover novel proteins associated with JIA risk.

METHODS

In this research, we utilized an integrative omics method to identify new plasma proteins associated with JIA. Complementary results from an independent cohort were analyzed through Whole Genome Sequencing (WGS), single-cell RNA sequencing (scRNA-seq), and bulk RNA sequencing (bulk RNA-seq) at the Children's Hospital of Chongqing Medical University to validate the reliability of the identified novel proteins. Additionally, to assess the therapeutic potential of novel proteins, we performed Phe-WAS and conducted an extensive review of existing literature using PubMed and Web of Science.

RESULTS

An integrative omics pipeline analysis identified ERAP2 as having putatively causal effects on JIA. In the fourth step of Summary-data-based Mendelian randomization analysis, we discovered that the SNP rs2927608 and rs2910686 can regulate the expression of the ERAP2 gene, thereby regulating the protein content of both ERAP2 and ERAP1. WGS analysis also detected two potentially pathogenic mutations on ERAP2 in sJIA patients. ScRNA-seq reveals that ERAP2 expression is significantly elevated in patients with sJIA compared to normal and other subtypes, particularly in monocytes. Bulk RNA-seq with ROC analysis demonstrating significant diagnostic power (AUC = 0.86, 95%CI: 0.71-1.00) in discriminating sJIA from healthy controls. Literature and Phe-WAS search revealed that ERAP2 is primarily studied in the context of genetic predisposition to disease and is closely related to autoimmune disorders.

CONCLUSIONS

ERAP2 was identified as a candidate associated with JIA, especially sJIA, through integrative omics analysis, indicating its potential role in protein-mediated disease mechanisms and therapeutic targeting.