A multi-omic study of plasma proteins in ankylosing spondylitis: insights from single-cell RNA sequencing and Mendelian randomization

To investigate the causal relationships between circulating plasma proteins and ankylosing spondylitis (AS) risk using Mendelian randomization (MR) and to explore their roles in the AS immune microenvironment. A two-sample MR analysis used genetic instruments for 4,907 plasma proteins (35,559 participants) as exposures. AS genetic associations came from FinnGen (3,838 cases; 353,224 controls) for discovery, validated in two independent cohorts. Causal effects were estimated mainly via inverse-variance weighting. Functional analyses included protein-protein interaction, single-cell RNA sequencing of AS tissues, and immune cell correlations. Five proteins showed robust genetically predicted associations: UBE2M increased AS risk, while HLA, MAZ, TREML2, and EEF2K were protective. ScRNA-seq revealed cell-type-specific expression: MAZ was predominant in T cells, TREML2 was exclusive to monocytes, and UBE2M and EEF2K were co-expressed in CD8⁺T and NK cells. Transcript levels of UBE2M were elevated in AS patients, whereas EEF2K, MAZ, and TREML2 showed reduced expression, consistent with their protective MR associations. These expression changes correlated with specific immune cell infiltration. This study identifies five plasma proteins with genetically predicted effects on AS pathogenesis. The cell-type-specific expression patterns highlight distinct roles within the immune microenvironment, nominating MAZ, TREML2, EEF2K, and UBE2M as candidate molecules warranting further functional validation.