Urate, Blood Pressure, and Cardiovascular Disease Evidence From Mendelian Randomization and Meta-Analysis of Clinical Trials

Serum urate has been implicated in hypertension and cardiovascular disease, but it is not known whether it is exerting a causal effect. To investigate this, we performed Mendelian randomization analysis using data from UK Biobank, Million Veterans Program and genome-wide association study consortia, and meta-analysis of randomized controlled trials. The main Mendelian randomization analyses showed that every 1-SD increase in genetically predicted serum urate was associated with an increased risk of coronary heart disease (odds ratio, 1.19 [95% CI, 1.10-1.30]; P=4x10(-5)), peripheral artery disease (1.12 [95% CI, 1.03-1.21]; P=9x10(-3)), and stroke (1.11 [95% CI, 1.05-1.18]; P=2x10(-4)). In Mendelian randomization mediation analyses, elevated blood pressure was estimated to mediate approximately one-third of the effect of urate on cardiovascular disease risk. Systematic review and meta-analysis of randomized controlled trials showed a favorable effect of urate-lowering treatment on systolic blood pressure (mean difference, -2.55 mm Hg [95% CI, -4.06 to -1.05]; P=1x10(-3)) and major adverse cardiovascular events in those with previous cardiovascular disease (odds ratio, 0.40 [95% CI, 0.22-0.73]; P=3x10(-3)) but no significant effect on major adverse cardiovascular events in all individuals (odds ratio, 0.67 [95% CI, 0.44-1.03]; P=0.07). In summary, these Mendelian randomization and clinical trial data support an effect of higher serum urate on increasing blood pressure, which may mediate a consequent effect on cardiovascular disease risk. High-quality trials are necessary to provide definitive evidence on the specific clinical contexts where urate lowering may be of cardiovascular benefit.

Automated summary

Mendelian randomization analysis suggests that genetically predicted serum urate levels are associated with increased risk of coronary heart disease, peripheral artery disease, and stroke. Elevated blood pressure may mediate a significant portion of the effect of urate on cardiovascular disease risk. High-quality trials are needed to determine the specific clinical contexts where lowering urate levels may benefit cardiovascular health.