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

White, Jon and Sofat, Reecha and Hemani, Gibran and Shah, Tina and Engmann, Jorgen and Dale, Caroline and Shah, Sonia and Kruger, Felix A. and Giambartolomei, Claudia and Swerdlow, Daniel I. and Palmer, Tom and McLachlan, Stela and Langenberg, Claudia and Zabaneh, Delilah and Lovering, Ruth and Cavadino, Alana and Jefferis, Barbara and Finan, Chris and Wong, Andrew and Amuzu, Antoinette and Ong, Ken and Gaunt, Tom R. and Warren, Helen and Davies, Teri-Louise and Drenos, Fotios and Cooper, Jackie and Ebrahim, Shah and Lawlor, Debbie A. and Talmud, Philippa J. and Humphries, Steve E. and Power, Christine and Hypponen, Elina and Richards, Marcus and Hardy, Rebecca and Kuh, Diana and Wareham, Nicholas and Ben-Shlomo, Yoav and Day, Ian N. and Whincup, Peter and Morris, Richard and Strachan, Mark W. J. and Price, Jacqueline and Kumari, Meena and Kivimaki, Mika and Plagnol, Vincent and Whittaker, John C. and Smith, George Davey and Dudbridge, Frank and Casas, Juan P. and Holmes, Michael V. and Hingorani, Aroon D. (2016) Plasma urate concentration and risk of coronary heart disease:a Mendelian randomisation analysis. The Lancet Diabetes and Endocrinology, 4 (4). pp. 327-336. ISSN 2213-8587

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Abstract

Summary Background Increased 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. Methods We 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. Findings In 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. Interpretation Conventional 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.

Item Type:
Journal Article
Journal or Publication Title:
The Lancet Diabetes and Endocrinology
Additional Information:
© White et al. Open Access article distributed under the terms of CC BY.
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/2700/2724
Subjects:
ID Code:
78091
Deposited By:
Deposited On:
02 Feb 2016 11:48
Refereed?:
Yes
Published?:
Published
Last Modified:
26 Sep 2020 03:44