Mendelian randomization study of serum uric acid levels and urate-lowering drugs on pulmonary arterial hypertension outcomes

This study aims to explore the causal relationships between serum uric acid level and pulmonary arterial hypertension (PAH) using the Mendelian randomization (MR) approach, and to assess the therapeutic impacts of urate-lowering drugs on PAH. Utilizing published genome-wide association study (GWAS) data, we applied MR and colocalization analysis to assess the link between serum uric acid levesl and PAH across four GWAS datasets from two distinct European populations. The validity and reliability of these findings were confirmed through multiple statistical methods, along with an MR analysis of urate-lowering drug targets to investigate their potential effects on PAH treatment. MR analysis revealed a significant positive correlation between serum uric acid levels and PAH (odds ratio (OR) 1.106, 95% confidence intervals (CI) 1.021-1.200, P = 0.014), corroborated by a replication MR analysis (OR 1.859, 95% CI 1.130-3.057, P = 0.015). No significant heterogeneity or horizontal pleiotropy was found in the sensitivity analyses. However, urate-lowering drugs did not demonstrate a significant direct therapeutic effect on PAH. This study establishes a genetic basis for a causal link between serum uric acid levels and PAH. However, urate-lowering drugs do not appear to have a direct causal effect on improving PAH. These findings provide a novel reference point for developing future therapeutic strategies for PAH.