Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis

Jon White,Shah Ebrahim,Jorgen Engmann,Gibran Hemani,Andrew Wong,Tina Shah,Meena Kumari,Frank Dudbridge,Stela Mclachlan,Yoav Ben-Shlomo,Rebecca Hardy,Reecha Sofat,Caroline Dale,Claudia Giambartolomei,Alana Cavadino,Tom Palmer,Marcus Richards,Chris Finan,Delilah Zabaneh,Christine Power,Vincent Plagnol,Antoinette Amuzu,Claudia Langenberg,Sonia Shah,George Davey Smith,Fotios Drenos,Diana Kuh,Felix Krüger ,Peter H Whincup ,Philippa J Talmud ,Mika Kivimäki ,Ken K Ong ,Daniel I Swerdlow ,Nicholas J Wareham ,Ian N.m Day ,Helen R Warren ,Barbara J Jefferis ,Juan P Casas ,Tom R Gaunt ,Elina Hyppönen ,Richard W Morris ,Ruth C Lovering ,Jackie A Cooper ,Debbie A Lawlor ,Jacqueline F Price ,Michael V Holmes ,Mark W J Strachan ,Teri Louise Davies ,John C Whittaker ,Steve E Humphries ,Aroon D Hingorani

doi:10.1016/s2213-8587(15)00386-1

Abstract

SummaryBackgroundIncreased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis.MethodsWe first did a fixed-effects meta-analysis of the observational association of plasma urate and risk of coronary heart disease. We then used a conventional Mendelian randomisation approach to investigate the causal relevance using a genetic instrument based on 31 urate-associated single nucleotide polymorphisms (SNPs). To account for potential pleiotropic associations of certain SNPs with risk factors other than urate, we additionally did both a multivariable Mendelian randomisation analysis, in which the genetic associations of SNPs with systolic and diastolic blood pressure, HDL cholesterol, and triglycerides were included as covariates, and an Egger Mendelian randomisation (MR-Egger) analysis to estimate a causal effect accounting for unmeasured pleiotropy.FindingsIn the meta-analysis of 17 prospective observational studies (166 486 individuals; 9784 coronary heart disease events) a 1 SD higher urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07 (95% CI 1·04–1·10). The corresponding OR estimates from the conventional, multivariable adjusted, and Egger Mendelian randomisation analysis (58 studies; 198 598 individuals; 65 877 events) were 1·18 (95% CI 1·08–1·29), 1·10 (1·00–1·22), and 1·05 (0·92–1·20), respectively, per 1 SD increment in plasma urate.InterpretationConventional and multivariate Mendelian randomisation analysis implicates a causal role for urate in the development of coronary heart disease, but these estimates might be inflated by hidden pleiotropy. Egger Mendelian randomisation analysis, which accounts for pleiotropy but has less statistical power, suggests there might be no causal effect. These results might help investigators to determine the priority of trials of urate lowering for the prevention of coronary heart disease compared with other potential interventions.FundingUK National Institute for Health Research, British Heart Foundation, and UK Medical Research Council.

Highlights

Plasma urate is a circulating product of human purine metabolism synthesised from hypoxanthine and xanthine by the action of the enzyme xanthine oxidoreductase
The causal role of increased circulating urate concentrations in gout has been shown by Mendelian randomisation analysis[2], the role of urate in coronary heart disease has been under debate since the 19th century.[3]
In our fixed-effects meta-analysis of prospective observational studies in which urate was quantified before incident coronary heart disease, plasma urate concentration was associated with increased risk of coronary heart disease: a 1 SD increased urate concentration was associated with an odds ratio (OR) for coronary heart disease of 1·07, after adjustment for age, sex, and other variables

Summary

Introduction

Plasma urate is a circulating product of human purine metabolism synthesised from hypoxanthine and xanthine by the action of the enzyme xanthine oxidoreductase. With extreme increases in urate concentration, monosodium urate crystals are deposited in the joints, soft tissue, and renal parenchyma, causing acute inflammatory arthropathy (gout), gouty tophi, and nephropathy, respectively.[1] the causal role of increased circulating urate concentrations in gout has been shown by Mendelian randomisation analysis[2] (and urate lowering is the main treatment), the role of urate in coronary heart disease has been under debate since the 19th century.[3]. Patients with established coronary heart disease have increased concentrations of plasma urate compared with individuals free of the disease. Increased plasma urate concentration is associated with increased risk of incident coronary heart disease.[4]. Proatherogenic effects of urate have been described, including induction of cellular oxidative stress leading to attenuated nitric oxide bioavailability (linked to platelet and endothelial cell activation, and vascular smooth muscle proliferation).[6]

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