• Jon White, Reecha Sofat, Gibran Hemani, Tina Shah, Jorgen Engmann, Caroline Dale, Sonia Shah, Felix A Kruger, Claudia Giambartolomei, Daniel I Swerdlow, Tom Palmer, Stela McLachlan, Claudia Langenberg, Delilah Zabaneh, Ruth Lovering, Alana Cavadino, Barbara Jefferis, Chris Finan, Andrew Wong, Antoinette Amuzu, Ken Ong, Tom R Gaunt, Helen Warren, Teri-Louise Davies, Fotios Drenos, Jackie Cooper, Shah Ebrahim, Debbie A Lawlor, Philippa J Talmud, Steve E Humphries, Christine Power, Elina Hypponen, Marcus Richards, Rebecca Hardy, Diana Kuh, Nicholas Wareham, Yoav Ben-Shlomo, Ian N Day, Peter Whincup, Richard Morris, Mark W J Strachan, Jacqueline Price, Meena Kumari, Mika Kivimaki, Vincent Plagnol, John C Whittaker, International Consortium for Blood Pressure (ICBP), George Davey Smith, Frank Dudbridge, Juan P Casas, Michael V Holmes, Aroon D Hingorani, and UCLEB (University College London-London School of Hygiene & Tropical Medicine-Edinburgh-Bristol Consortium.
• UCL Genetics Institute, University College, London, UK. Electronic address: jon.white@ucl.ac.uk.
• Lancet Diabetes Endocrinol. 2016 Apr 1; 4 (4): 327-36.

BackgroundIncreased 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.Copyright © 2016 White et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

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