Plasma proteins and psoriatic arthritis: a proteome-wide Mendelian randomization study

Background: Previous epidemiological studies have identified a correlation between serum protein levels and Psoriatic Arthritis (PsA). However, the precise nature of this relationship remains uncertain. Therefore, our objective was to assess whether circulating levels of 2,923 plasma proteins are associated with the risk of PsA, utilizing the Mendelian randomization (MR) approach. Methods: Two-sample MR analysis was performed to assess the causal impact of proteins on PsA risk. Exposure data for plasma proteins were sourced from a genome-wide association study (GWAS) conducted within the UK Biobank Pharma Proteomics Project, which encompassed 2,923 unique plasma proteins. The outcome data for PsA were sourced from the FinnGen study, a large-scale genomics initiative, comprising 3,537 cases and 262,844 controls. Additionally, colocalization analysis, Phenome-wide MR analysis, and candidate drug prediction were employed to identify potential causal circulating proteins and novel drug targets. Results: We thoroughly assessed the association between 1,837 plasma proteins and PsA risk, identifying seven proteins associated with PsA risk. An inverse association of Interleukin-10 (IL-10) with PsA risk was observed [odds ratio (OR)=0.45, 95% confidence interval (CI), 0.28 to 0.70, P-FDR=0.072]. Additionally, Apolipoprotein F (APOF) has a positive effect on PsA risk (OR=2.08, 95% CI, 1.51 to 2.86, P FDR=0.005). Subsequently, we found strong evidence indicating that IL-10 and APOF were colocalized with PsA associations (PP.H4 = 0.834 for IL-10 and PP.H4 = 0.900 for APOF). Phenome-wide association analysis suggested that these two proteins may have dual effects on other clinical traits (P-FDR<0.1) Conclusion: This study identified 7 plasma proteins associated with PsA risk, particularly IL-10 and APOF, which offer new insights into its etiology. Further studies are needed to assess the utility and effectiveness of these candidate proteins.