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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.

SUBMITTER: Gill D

PROVIDER: S-EPMC7803439 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

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

Hypertension (Dallas, Tex. : 1979) 20201228 2

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 ...[more]

PMID: 33356394

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Project description:BACKGROUND:High blood pressure (BP) is a risk factor for cardiovascular morbidity and mortality. While BP is regulated by the function of kidney, vasculature, and sympathetic nervous system, recent experimental data suggest that immune cells may play a role in hypertension. METHODS:We studied the relationship between major white blood cell types and blood pressure in the UK Biobank population and used Mendelian randomization (MR) analyses using the ?750?000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies to examine which leukocyte populations may be causally linked to BP. RESULTS:A positive association between quintiles of lymphocyte, monocyte, and neutrophil counts, and increased systolic BP, diastolic BP, and pulse pressure was observed (eg, adjusted systolic BP mean±SE for 1st versus 5th quintile respectively: 140.13±0.08 versus 141.62±0.07 mm?Hg for lymphocyte, 139.51±0.08 versus 141.84±0.07 mm?Hg for monocyte, and 137.96±0.08 versus 142.71±0.07 mm?Hg for neutrophil counts; all P<10-50). Using 121 single nucleotide polymorphisms in MR, implemented through the inverse-variance weighted approach, we identified a potential causal relationship of lymphocyte count with systolic BP and diastolic BP (causal estimates: 0.69 [95% CI, 0.19-1.20] and 0.56 [95% CI, 0.23-0.90] of mm?Hg per 1 SD genetically elevated lymphocyte count, respectively), which was directionally concordant to the observational findings. These inverse-variance weighted estimates were consistent with other robust MR methods. The exclusion of rs3184504 SNP in the SH2B3 locus attenuated the magnitude of the signal in some of the MR analyses. MR in the reverse direction found evidence of positive effects of BP indices on counts of monocytes, neutrophils, and eosinophils but not lymphocytes or basophils. Subsequent MR testing of lymphocyte count in the context of genetic correlation with renal function or resting and postexercise heart rate demonstrated a positive association of lymphocyte count with urine albumin-to-creatinine ratio. CONCLUSIONS:Observational and genetic analyses demonstrate a concordant, positive and potentially causal relationship of lymphocyte count with systolic BP and diastolic BP.

Dataset Information

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

Publications

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

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