Serum uric acid levels as a causal factor in hypertension: Insights from Mendelian randomization analysis.

Background: Hyperuricemia and hypertension are prevalent chronic diseases that often co-occur. While numerous observational studies suggest an association between serum uric acid (SUA) levels and hypertension, the causal nature of this relationship remains unresolved due to confounding and reverse causation. This study systematically investigates the causal association between SUA levels and hypertension risk using Mendelian randomization (MR) methodologies.

Methods: We utilized single nucleotide polymorphisms (SNPs) identified in large-scale genome-wide association studies (GWAS) of European populations as genetic instruments for SUA levels. MR, a genetic epidemiology technique, uses genetic variations as proxies to mimic a randomized controlled trial and minimizing biases from confounding and reverse causation. Systolic and diastolic blood pressure (SBP and DBP) were the primary outcomes of interest. A two-sample MR analysis was conducted to assess the causal relationships, complemented by sensitivity analyses (weighted median, weighted mode, MR-Egger) to ensure result robustness. Findings are expressed as odds ratios (ORs) with 95% confidence intervals (Cis) per one standard deviation (SD) increase in SUA levels.

Results: Our MR analysis identified a significant causal effect of SUA levels on hypertension risk. Specifically, genetically predicted SUA levels were positively associated with SBP (β = 0.136 [0.035-0.238], p < .05) and DBP (β = 0.108 [0.007-0.209], p < .05).Conversely, reverse MR analysis revealed no significant causal effect of SBP (b = 0.058 [ - 9.52E-05-0.116],p = .0504] or DBP (β = 0.016 [ - 0.028-0.059], p > .05] on SUA levels, confirming the unidirectional nature of this association.

Conclusion: This study provides compelling evidence from MR supporting a unidirectional causal link between SUA levels and increased hypertension risk. Unlike prior observational studies, our genetic approach effectively mitigates confounding and reverse causation, offering novel insights into the etiology of hypertension. These findings highlight the clinical importance of managing SUA levels to mitigate hypertension risk. Further research, including randomized controlled trials, is needed to confirm these findings and explore potential therapeutic interventions targeting SUA.