Genetic susceptibility to uric acid and selected cardiovascular outcomes: a systematic review and meta-analysis of Mendelian randomization studies.

BACKGROUND

Serum urate has been associated with cardiovascular disease in observational studies, but whether genetically predicted higher serum urate levels contribute to specific cardiovascular outcomes remains uncertain. We conducted a systematic review and meta-analysis of Mendelian randomization (MR) studies evaluating serum urate-, hyperuricemia-, or gout-related genetic susceptibility in relation to selected cardiovascular outcomes.

METHODS

PubMed, Embase, and Web of Science were searched from inception to April 6, 2026. Eligible studies were one-sample or two-sample MR studies assessing relevant urate-related exposures and cardiovascular outcomes. Reporting completeness, overlapping or duplicate estimates, exposure-outcome GWAS sample overlap, and MR-specific risk of bias were assessed before quantitative synthesis. Effect estimates were harmonized and standardized to a 1.5 mg/dL increase in serum urate where applicable. Random-effects inverse-variance meta-analyses, Egger regression tests, leave-one-out analyses, Hartung-Knapp adjusted analyses, and stepwise GWAS-source-restricted sensitivity analyses were performed where applicable.

RESULTS

Thirty-two MR studies reporting 105 MR analyses were included. After estimate-level screening and MR-specific risk-of-bias assessment, 26 MR estimates were retained for quantitative synthesis. In primary analyses, genetically predicted higher serum urate was associated with increased risks of coronary heart disease (OR = 1.13, 95% CI: 1.10-1.15), myocardial infarction (OR = 1.13, 95% CI: 1.08-1.17), coronary artery disease (OR = 1.17, 95% CI: 1.08-1.26), atrial fibrillation (OR = 1.07, 95% CI: 1.02-1.12), and heart failure based on IVW estimates (OR = 1.08, 95% CI: 1.05-1.11). However, the atrial fibrillation association did not remain statistically significant after Hartung-Knapp adjustment and was reduced to a single estimate after GWAS-source restriction. In GWAS-source-restricted sensitivity analyses, only myocardial infarction and coronary artery disease retained at least three estimates and remained positively associated with serum urate.

CONCLUSION

Evidence was most consistent for myocardial infarction and coronary artery disease. Findings for coronary heart disease, atrial fibrillation, and heart failure were more limited after stricter source restriction. These results do not establish a broad causal effect on cardiovascular disease as a whole or direct cardiovascular benefit from urate-lowering therapy.

SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261380161.