Dynamic immunogenetic profiling prioritizes ARL6IP4 in an immune-activated context of osteoarthritis

Osteoarthritis (OA) is biologically heterogeneous, and regulatory genetic effects may depend on cell type and activation state. The contribution of adaptive immune activation to OA is uncertain and is unlikely to be uniform across patients. We integrated a stimulation-time-resolved cis-eQTL atlas of human CD4 + T cells with OA genome-wide association study data. Mendelian randomization, Steiger directionality filtering, and Bayesian colocalization were used to prioritize state-dependent associations involving genetically predicted gene expression. Findings were compared with resting-state eQTL resources and evaluated for contextual concordance in single-cell RNA sequencing data from synovial membrane and matched articular cartilage samples from three patients with knee OA. Expression-stratified transcriptomic analysis, pathway enrichment, and structure-based virtual screening were used to generate mechanistic and ligand hypotheses. Genetically predicted higher ARL6IP4 expression in memory CD4 + T cells five days after stimulation was associated with higher OA odds (OR = 1.14, 95% CI: 1.09–1.20, nominal P < 0.001) and showed strong colocalization with the OA association signal (PPH4 = 0.99). Resting-state datasets showed weak or absent colocalization. Within the T-cell compartment of the OA joint single-cell dataset, ARL6IP4 expression increased along an inferred activation/differentiation trajectory. ARL6IP4 -high T cells had lower DUSP2 and FTH1 expression and enrichment of MAPK- and NF-κB-related programs. Docking nominated candidate ligands for ARL6IP4 and MPHOSPH9 , but target engagement and therapeutic activity were not tested. These convergent analyses nominate a state-dependent ARL6IP4 -centered hypothesis linked to a DUSP2 -low inflammatory expression state that may be relevant to an inflammatory or synovitis-enriched subgroup of OA. The data do not establish OA specificity, a dominant disease mechanism, or therapeutic efficacy, and independent OA-specific replication and experimental perturbation are required.