Tissue Damage in Rheumatoid Arthritis Is Genetically Linked to Low Peptidylglycine Alpha‐Amidating Monooxygenase Activity in Synovial Fibroblasts

OBJECTIVE: Both susceptibility to, and severity of, rheumatoid arthritis (RA) is associated with the rs26232 C allele. Our primary aim was to identify the biologic mechanism underlying this association. METHODS: Expression of surrounding genes was compared among rs26232 genotypes. Publicly available databases were used to correlate expression with RA inflammation and single-cell synovial distribution. Inhibition of gene expression and activity was achieved using small interfering RNA and a pharmacology agent and effects on RA synovial fibroblasts (RASFs) characteristics in vitro were assayed. The amidated secretome of synovial fibroblasts were characterized by mass spectrometry and enzyme-linked immunosorbent assay. Effects of amidated peptides on macrophage polarity were determined using an RASF-macrophage coculture module. RESULTS: phenotypes. CONCLUSION: Genetically determined low PAM reduces the anti-inflammatory and tissue-damaging activities of ADM and PAMP mediated by macrophages and RASFs, explaining the association of rs26232 C with RA severity.