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Genetically predicted serum urate, blood pressure and cardiovascular disease: an updated Mendelian randomization investigation

By Dipender Gill, Alan Cameron, Stephen Burgess, Xue Li, Daniel J Doherty, Ville Karhunen, Azmil H Abdul-Rahim, Martin Taylor-Rowan, Verena Zuber, Philip S. Tsao, Derek Klarin, Evangelos Evangelou, Paul Elliott, Scott M Damrauer, Terry Quinn, Abbas Dehghan, Evropi Theodoratou, Jesse Dawson, Ioanna Tzoulaki

Posted 15 Dec 2019
medRxiv DOI: 10.1101/2019.12.11.19014472

BackgroundElevated serum urate has been associated with an increased risk of cardiovascular disease (CVD), but it is not known whether this relationship is causal, non-linear or sex-specific. Basic science and clinical trial data have supported an effect of serum urate on systolic blood pressure (SBP), which may in turn mediate an effect on CVD risk. MethodsUsing recently available data from the Million Veterans Program and UK Biobank, we applied improved genetic instruments for serum urate in one and two-sample Mendelian randomization (MR) analyses to investigate for effects on risk of coronary heart disease (CHD), peripheral artery disease (PAD), and stroke. Potential mediation through SBP was explored, as well as evidence of non-linear and sex-specific effects. We performed a number of sensitivity analyses using different MR methodologies and populations to investigate consistency of our findings. ResultsHigher genetically predicted serum urate was associated with an increased risk of CHD (odds ratio [OR] per 1-standard deviation increase in genetically predicted urate 1.19, 95% confidence interval [CI] 1.10-1.30, P=4x10-5), PAD (OR 1.12, 95% CI 1.03-1.21, P=9x10-3), and stroke (OR 1.11, 95% CI 1.05-1.18, P=2x10-4). Similar estimates were produced when applying MR methods that make distinct assumptions, or when considering different populations. SBP was estimated to mediate 29%, 44% and 45% of the effect of urate on CHD, PAD and stroke respectively. There was no evidence of non-linear or sex-specific effects of genetically predicted urate on CVD risk. ConclusionsUsing contemporary data and MR methods, we provide support for an effect of serum urate on CVD risk that may partly be mediated through SBP. High-quality trials are necessary to provide definitive evidence on the cardiovascular benefit of urate lowering.

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