Urate, Blood Pressure, and Cardiovascular Disease

Abstract

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 =4×10 −5 ), peripheral artery disease (1.12 [95% CI, 1.03–1.21]; P =9×10 −3 ), and stroke (1.11 [95% CI, 1.05–1.18]; P =2×10 −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 =1×10 −3 ) and major adverse cardiovascular events in those with previous cardiovascular disease (odds ratio, 0.40 [95% CI, 0.22–0.73]; P =3×10 −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.