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

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.

Keywords: blood pressure; cardiovascular diseases; odds ratio; systematic review; uric acid.

Figure 1.

Mendelian randomization estimates for the effect of 1-SD increase in genetically predicted serum urate levels on risk of coronary heart disease (CHD), peripheral artery disease (PAD), and stroke. Multivariable Mendelian randomization (MVMR) adjusting for genetic associations of the instrument variants with body mass index, estimated glomerular filtration rate, type 2 diabetes, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. The outlier-corrected pleiotropy residual sum and outlier (PRESSO) results are presented (5 outlier variants were identified for CHD, 8 for PAD, and 1 for stroke). The Egger intercept was 0.005 ([95% CI, 0.001–0.009] P=0.004) for CHD, 0.005 ([95% CI, 0.001–0.009] P=0.003) for PAD, and 0.001 ([95% CI, −0.001 to 0.003] P=0.24) for stroke. Con-Mix indicates contamination mixture; IVW, inverse-variance weighted; and OR, odds ratio.

Figure 2.

Mendelian randomization estimates for the effect of 1-SD increase in genetically predicted serum urate levels on systolic blood pressure. The outlier-corrected pleiotropy residual sum and outlier (PRESSO) results are presented (21 outlier variants were identified). The Egger intercept was 0.002 ([95% CI, 0.0004–0.003] P=0.02). Con-Mix indicates contamination mixture; IVW, inverse-variance weighted; and SBP, systolic blood pressure.

Figure 3.

Inverse-variance weighted (IVW) and multivariable Mendelian randomization (MVMR) estimates for the effect of 1-SD increase in genetically predicted serum urate levels on risk of coronary heart disease (CHD), peripheral artery disease (PAD), and stroke. The MVMR analysis adjusts for the associations of the genetic instruments with systolic blood pressure. The MVMR only adjusted for the associations of the genetic instruments with systolic blood pressure and not any other trait. OR indicates odds ratio.

Figure 4.

Forest plot of randomized controlled trial estimates for change in mean systolic blood pressure in patients receiving urate-lowering therapy or placebo/no treatment. I² heterogeneity statistic: 43%. A random-effects meta-analysis model was used.

Figure 5.

Forest plot of randomized controlled trial estimates for risk of major adverse cardiovascular events in all patients receiving urate-lowering therapy or placebo/no treatment. I² heterogeneity statistic: 0%. A random-effects meta-analysis model was used.

Figure 6.

Forest plot of randomized controlled trial estimates for risk of major adverse cardiovascular events in patients with existing cardiovascular disease receiving urate-lowering therapy or placebo/no treatment. I² heterogeneity statistic: 0%. A random-effects meta-analysis model was used.