Urate, blood pressure and cardiovascular disease: evidence from Mendelian randomization and meta-analysis of clinical trials

Gill, D. et al. (2021) Urate, blood pressure and cardiovascular disease: evidence from Mendelian randomization and meta-analysis of clinical trials. Hypertension, 77(2), pp. 383-392. (doi: 10.1161/HYPERTENSIONAHA.120.16547) (PMID:33356394)

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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.

Item Type:Articles
Additional Information:This work was supported by funding from the US Department of Veterans Affairs Office of Research and Development, Million Veteran Program Grant MVP003 (I01-BX003362), and the UK National Institute for Health Research Cambridge Biomedical Research Centre. This publication does not represent the views of the Department of Veterans Affairs of the US Government. DG is funded by the Wellcome 4i Clinical PhD Program (203928/Z/16/Z) and the British Heart Foundation Centre of Research Excellence (RE/18/4/34215) at Imperial College London. SB is supported by Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 204623/Z/16/Z). VK is funded by the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant (721567). PE acknowledges support from the British Heart Foundation (RE/18/4/34215), the Medical Research Council (MR/S019669/1), the National Institute for Health Research Imperial Biomedical Research Centre, Imperial College London (RDF03), the UK Dementia Research Institute (DRI) at Imperial College London funded by UK DRI Ltd (funded by Medical Research Council, Alzheimer’s Society, Alzheimer’s Research UK), and Health Data Research (HDR) UK London funded by HDR UK Ltd (funded by a consortium led by the Medical Research Council 1004231). SMD was supported by the Department of Veterans Affairs Office of Research and Development (IK2-CX001780). ET is funded by a Cancer Research UK Career Development Fellowship (C31250/A22804). The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Abdul-Rahim, Dr Azmil and Doherty, Dr Daniel and Quinn, Dr Terry and Dawson, Professor Jesse and Taylor-Rowan, Mr Martin and Cameron, Dr Alan
Authors: Gill, D., Cameron, A. C., Burgess, S., Liu, X., Doherty, D. J., Karhunen, V., Abdul-Rahim, A., Taylor-Rowan, M., Zuber, V., Tsao, P. S., Klarin, D., VA Million Veteran Program, , Evangelou, E., Elliott, P., Damrauer, S. M., Quinn, T. J., Dehghan, A., Theodoratou, E., Dawson, J., and Tzoulaki, I.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Hypertension
Publisher:American Heart Association
ISSN:0194-911X
ISSN (Online):1524-4563
Published Online:28 December 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Hypertension 77(2):383-392
Publisher Policy:Reproduced under a Creative Commons License

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