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=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.
['Gill|Dipender|D|', 'Cameron|Alan C|AC|', 'Burgess|Stephen|S|', 'Li|Xue|X|', 'Doherty|Daniel J|DJ|', 'Karhunen|Ville|V|', 'Abdul-Rahim|Azmil H|AH|', 'Taylor-Rowan|Martin|M|', 'Zuber|Verena|V|', 'Tsao|Philip S|PS|', 'Klarin|Derek|D|', '|||', 'Evangelou|Evangelos|E|', 'Elliott|Paul|P|', 'Damrauer|Scott M|SM|', 'Quinn|Terence J|TJ|', 'Dehghan|Abbas|A|', 'Theodoratou|Evropi|E|', 'Dawson|Jesse|J|', 'Tzoulaki|Ioanna|I|']
D001794:Blood Pressure D002318:Cardiovascular Diseases D020022:Genetic Predisposition to Disease D006801:Humans D057182:Mendelian Randomization Analysis D020641:Polymorphism, Single Nucleotide D016032:Randomized Controlled Trials as Topic D014527:Uric Acid
blood pressure cardiovascular diseases odds ratio systematic review uric acid