Genetically predicted serum uric acid and pulmonary arterial hypertension: Mendelian randomization with an...

ObjectiveSerum uric acid (SUA) has been associated with cardiovascular and pulmonary vascular disease, but whether SUA has a causal role in pulmonary arterial hypertension (PAH) remains uncertain. This study aimed to evaluate the genetic association between SUA and PAH using Mendelian randomization (MR), with an exploratory population-based analysis in individuals with a higher PAH-related risk-factor burden.MethodsWe conducted two-sample MR using publicly available genome-wide association study (GWAS) summary statistics. The European-ancestry SUA dataset (GCST90014015) was used as the primary exposure dataset, and a cross-population SUA dataset (GCST90018977) was used as exploratory secondary evidence. PAH outcome data were obtained from the largest available PAH GWAS. Cross-sectional NHANES 2003-2018 data were used only as descriptive exploratory context based on a PAH-related risk-factor burden.ResultsGenetically predicted SUA was associated with higher PAH risk in the European primary analysis (GCST90014015: OR=1.31, 95% CI 1.03-1.68, P=0.028). The mixed-ancestry exploratory analysis showed a consistent direction of effect (GCST90018977: OR=1.52, 95% CI 1.16-2.00, P=0.003), but this estimate was not pooled with the European primary estimate and should not be interpreted as replication because of ancestry mismatch. Sensitivity analyses did not indicate substantial heterogeneity or horizontal pleiotropy. In NHANES, SUA was positively associated with a higher PAH-related risk-factor burden in exploratory logistic models (Model 2: OR=1.708, 95% CI 1.645-1.773, P<0.001).ConclusionOur study supports a positive genetic association between SUA and PAH risk. The NHANES analysis provides descriptive exploratory context in a high-risk population. Further research is needed to elucidate the underlying biological mechanisms and confirm these findings in diverse populations.