Cardiology · Medical Literature
Genetic susceptibility to uric acid and selected cardiovascular outcomes: a systematic review and meta-analysis of Mendelian randomization studies.
Abstract
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. 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. 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. 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. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261380161.
Clinical relevance
Does genetically predicted elevation in serum urate — a proxy for lifetime exposure established via Mendelian randomization — causally increase the risk of specific cardiovascular outcomes, including coronary heart disease, myocardial infarction, coronary artery disease, atrial fibrillation, and heart failure? __SNAPSHOT__ {"studyDesign":"Systematic review and meta-analysis of Mendelian randomization (MR) studies (one-sample and two-sample designs); prespecified estimate-level screening and MR-specific risk-of-bias assessment performed prior to quantitative synthesis","setting":"International; included studies from multiple ancestries, though predominantly European-ancestry populations; institutional affiliation of corresponding authors: The Fourth People's Hospital of Shenyang, China Medical University, Shenyang, China","sampleSize":"32 primary 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","population":"General adult population participants from GWAS datasets whose genetic variants predict serum urate, hyperuricemia, or gout susceptibility; predominantly of European ancestry, with limited representation of Asian and other non-European populations","intervention":"Genetically predicted higher serum urate levels (exposure harmonized and standardized to a 1.5 mg/dL increment in serum urate where applicable); exposures included serum urate, hyperuricemia, and gout-related genetic susceptibility","comparator":"Genetically predicted lower serum urate levels (reference); inherent comparator within the MR framework using genetic instruments as instruments for lifetime urate exposure","primaryOutcome":"Selected cardiovascular outcomes including coronary heart disease (CHD), myocardial infarction (MI), coronary artery disease (CAD), atrial fibrillation (AF), and heart failure (HF); stroke subtypes and hypertension were evaluated but could not be retained for final quantitative synthesis due to insufficient eligible estimates","followUp":"Not applicable (cross-sectional GWAS-based MR design; no prospective follow-up in the meta-analysis itself)","fundingSource":"Not reported in the available abstract or full-text excerpt; no commercial or industry sponsorship disclosed"}
Key findings
Thirty-two MR studies reporting 105 MR analyses were screened; 26 MR estimates were retained for quantitative synthesis after rigorous estimate-level screening and MR-specific risk-of-bias assessment. In primary random-effects inverse-variance weighted (IVW) meta-analyses, genetically predicted higher serum urate (standardized to a 1.5 mg/dL increment) was associated with statistically significant increases in risk across five pre-specified cardiovascular outcomes: 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 (OR = 1.08, 95% CI: 1.05–1.11). P-values for individual outcomes are not reported in the available abstract. NNT and NNH are not calculable from the reported data, as absolute event rates in the underlying GWAS populations were not provided. Egger regression, leave-one-out analyses, Hartung-Knapp adjusted analyses, and stepwise GWAS-source-restricted sensitivity analyses were performed where applicable; specific sensitivity analysis results beyond the primary estimates are not reported in the available abstract or excerpt. Stroke subtypes and hypertension were evaluated but could not be retained for quantitative synthesis because fewer than three eligible estimates remained after screening; hypertension analyses were further hampered by heterogeneous case definitions and inconsistent reporting of antihypertensive medication use across source GWAS datasets. No safety or adverse event data are applicable given the MR design.
Practice implications
This meta-analysis of MR studies provides the most methodologically rigorous genetic-epidemiological synthesis to date suggesting that lifetime elevation in serum urate is causally associated — in the MR sense — with increased risks of CHD, MI, CAD, AF, and HF. The observed effect sizes are modest to moderate (OR range: 1.07–1.17 per 1.5 mg/dL genetically predicted increase), which, if causal, could translate into clinically meaningful population-attributable risk given the high prevalence of hyperuricemia globally. However, several critical caveats limit direct translation to practice: (1) MR estimates the lifelong effect of constitutively higher urate, not the effect of pharmacological urate lowering — these are not equivalent because urate-lowering therapies (e.g., allopurinol, febuxostat) act through mechanisms (e.g., xanthine oxidase inhibition) that extend beyond urate reduction alone; (2) existing large randomized trials of urate-lowering therapy (e.g., ALL-HEART for allopurinol in ischemic heart disease) have not demonstrated a consistent reduction in hard cardiovascular endpoints, creating an apparent paradox with the MR findings; (3) horizontal pleiotropy — whereby urate-associated genetic variants independently influence metabolic, renal, or inflammatory pathways — cannot be fully excluded even with sensitivity analyses; (4) results are predominantly from European-ancestry populations and may not generalize to Asian or other populations, which are epidemiologically important given differing baseline urate levels, genetic architecture, and dietary patterns; (5) stroke subtypes and hypertension could not be adequately synthesized due to insufficient eligible estimates after screening, leaving these clinically important endpoints unresolved; (6) the study was based only on the available abstract and selected full-text excerpts — the complete sensitivity analysis, funnel plot, and subgroup data are not fully evaluable in this summary, which is a limitation of this clinical teaching document. The findings do not establish whether urate-lowering therapy reduces cardiovascular events, and current evidence does not support routine urate-lowering therapy for cardiovascular prevention in asymptomatic hyperuricemia. __LIMITATIONS__ 1. Small number of retained MR estimates (26 of 105) limits statistical power for subgroup analyses, Egger tests, and Hartung-Knapp adjustments; 2. Stroke subtype and hypertension analyses were insufficiently powered and could not be retained for quantitative synthesis after estimate-level screening; 3. Hypertension outcome was further confounded by heterogeneous case definitions and inconsistent antihypertensive medication handling across source GWAS datasets; 4. Predominance of European-ancestry GWAS data severely limits generalizability to non-European populations; 5. Horizontal pleiotropy — whereby urate-raising genetic variants may influence cardiovascular risk via pathways independent of serum urate (e.g., renal function, metabolic syndrome, insulin resistance) — cannot be completely excluded despite use of Egger and other MR pleiotropy tests; 6. MR estimates reflect the effect of lifelong genetically determined urate elevation and do not model the pharmacological effect of therapeutic urate reduction, which operates differently; 7. Overlapping GWAS samples across included studies (exposure-outcome GWAS sample overlap) were assessed but may still introduce winner's curse and bias toward the null or away from it; 8. Only the abstract and selected full-text excerpts were fully available for this synthesis; individual study-level data, complete forest plots, funnel plots, and I² statistics for each outcome are not reported in the excerpt reviewed; 9. No assessment of dose-response relationship across the urate spectrum; 10. Funding source not reported, precluding conflict-of-interest appraisal. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ This systematic review and meta-analysis of 32 MR studies provides genetic-epidemiological evidence that lifelong elevation in serum urate is modestly but consistently associated with increased risks of CHD, MI, CAD, AF, and HF, with pooled ORs ranging from 1.07 to 1.17 per 1.5 mg/dL genetically predicted increase. These findings reinforce the biological plausibility of urate as a cardiovascular risk factor but do not establish that pharmacological urate lowering reduces cardiovascular events — a gap that existing RCT data have not bridged. Clinicians should not extrapolate these MR findings to support routine urate-lowering therapy for cardiovascular risk reduction outside of gout management pending confirmatory trial evidence.