ARG1 is associated with reduced cardiometabolic risk in patients with rheumatoid arthritis: a cis-instrument Mendelian randomisation proteomic analysis

Background Epidemiological studies have shown that people with rheumatoid arthritis (RA) are at higher risk for coronary artery disease (CAD). Our previous work indicates that type 2 diabetes (T2D) could play a mediating role, as strong bidirectional Mendelian randomisation results connect both RA and CAD. Despite these findings, the shared disease mechanisms between these conditions are still unclear. Purpose The objective of this investigation was to identify protein-mediated molecular pathways that causally impact disease susceptibility across RA, T2D, and CAD. Methods We utilized a cis-instrument Mendelian randomisation approach employing genome-wide significant cis-acting pQTLs as genetic instruments for circulating plasma proteins, based on data from the UK Biobank Pharma Proteomics Project encompassing 54,306 individuals of European ancestry1. Proteins were selected according to prior evidence implicating them in T2D within proteome-wide MR analyses2. Outcome datasets included genetic instruments for RA sourced from 14,361 cases and 43,923 controls of European descent curated by Okada et al.3, DM II traits from the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium4 (34,840 cases and 114,981 controls), and CAD from the CARDIoGRAMplusC4D consortium5 (60,801 cases and 123,504 controls across 48 studies). Primary exposure-outcome analyses employed the inverse-variance weighted (IVW) method, with additional sensitivity assessments for pleiotropy and heterogeneity. Results Sixteen plasma proteins demonstrated significant causal effect sizes across all three outcomes; however, the majority exhibited discordant or negligible effects. Notably, ARG1 was the sole protein showing robust, directionally consistent associations, with genetically predicted higher levels correlating with reduced risk of RA, T2D, and CHD. For coronary heart disease, the IVW estimate was β = −0.224 (SE = 0.00955, p = 3.53 × 10⁻¹²²), utilizing 279 independent cis-acting instruments. The IVW estimate for RA was β = −0.285 (SE = 0.0107, p = 6.27 × 10⁻¹⁵⁷) using 392 SNPs, while for T2D, the IVW estimate was β = −0.258 (SE = 0.0122, p = 2.14 × 10⁻¹⁰⁰) based on 233 instruments. Conclusions Among the proteins analyzed, only ARG1 demonstrated strong, directionally consistent associations with all three diseases. Genetically elevated ARG1 levels were consistently linked to decreased risk of RA, T2D, and CHD, indicating a potential protective role in chronic inflammatory and cardiometabolic disorders. Integration of these genetic results with experimental evidence highlights the involvement of ARG1-related pathways in inflammation resolution and immunometabolic regulation.Forest plots