The Rare Variants and Transcriptomic Signatures of Peripheral Blood Mononuclear Cells in Axial Spondyloarthritis

Objectives: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that primarily affects the axial skeleton and imposes a substantial disability burden. It can be classified into radiographic axSpA (r-axSpA) and non-radiographic axSpA (nr-axSpA). AxSpA is highly heritable, with HLA-B27 accounting for about 20% and GWAS loci for <8% of r-axSpA heritability. In addition to genetic factors, transcriptional profiles of peripheral immune cells have provided important insights into axSpA molecular pathogenesis. This study aimed to uncover its unexplained heritability by identifying rare variants, map the axSpA transcriptome, and compare its molecular signatures with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and primary Sjögren’s syndrome (pSS). Methods: For genetic study, eight axSpA families comprising 30 individuals underwent whole exome sequencing (WES). Rare deleterious variants cosegregating with the disease phenotypes were identified. For transcriptomic profiling, bulk RNA sequencing (RNA-seq) was performed on 64 patients with r-axSpA, while RNA-seq data for 48 RA, 38 pSS, and 32 SLE patients were obtained from public datasets. Differentially expressed genes (DEGs), transcription factors (TFs), and immune cell compositions were analyzed. Results: In the genetic analysis of axSpA, we identified eight rare variants (P4HA3, ADAMTSL3, PAPLN, GOLGB1, ADAMTS12, IL15, LRBA, and COLGALT1) predominantly enriched in extracellular matrix and collagen fibril organization pathways. In the transcriptomic analysis, lineage-defining TFs and immune cell composition indicated a marked enrichment of monocytes in r-axSpA compared with healthy controls. Comparative transcriptomic analyses of r-axSpA against RA, SLE, and pSS revealed distinct immune cell signatures, characterized by T-cell enrichment in r-axSpA, platelet and megakaryocyte enrichment in RA, and B-cell enrichment in SLE and pSS. Conclusion: Genetic variants involved in extracellular matrix remodeling and monocyte-mediated inflammation characterize the pathogenesis of axSpA, although their mechanistic interplay remains to be clarified.