title: Plasma urate concentration and risk of coronary heart disease: a Mendelian randomisation analysis.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  UK National Institute for Health Research, British Heart Foundation, and UK Medical Research Council.
authors.affiliation: UCL Genetics Institute, University College, London, UK. Electronic address: jon.white@ucl.ac.uk.
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authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
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authors.affiliation: Institute of Cardiovascular Science and Farr Institute, University College London, London, UK.
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authors.affiliation: Institute of Cardiovascular Science and Farr Institute, University College London, London, UK.
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authors.affiliation: Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.
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authors.affiliation: Queensland Brain Institute, University of Queensland, QLD, Australia.
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authors.affiliation: Institute of Cardiovascular Science and Farr Institute, University College London, London, UK.
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authors.affiliation: UCL Genetics Institute, University College, London, UK.
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authors.affiliation: Institute of Cardiovascular Science and Farr Institute, University College London, London, UK.
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authors.affiliation: Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
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authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
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authors.affiliation: Institute of Cardiovascular Science and Farr Institute, University College London, London, UK; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
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authors.affiliation: UCL Genetics Institute, University College, London, UK.
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authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, University College London, London, UK.
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authors.affiliation: Population, Policy and Practice, UCL Institute of Child Health, University College London, London, UnK.
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authors.affiliation: Department of Primary Care & Population Health, University College London, Royal Free Campus, London, UK.
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authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK; MRC Unit for Lifelong Health and Ageing at UCL, London, UK.
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authors.affiliation: Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Denstistry, Queen Mary University of London, London, UK; NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK.
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authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
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authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, University College London, London, UK; MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Fotios
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authors.affiliation: Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.
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authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
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authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, University College London, London, UK.
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authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, University College London, London, UK.
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authors.affiliation: Population, Policy and Practice, UCL Institute of Child Health, University College London, London, UnK.
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authors.affiliation: Population, Policy and Practice, UCL Institute of Child Health, University College London, London, UnK; School of Population Health and Sansom Institute of Health Research, University of South Australia, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
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authors.affiliation: MRC Unit for Lifelong Health and Ageing at UCL, London, UK.
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authors.affiliation: MRC Unit for Lifelong Health and Ageing at UCL, London, UK.
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authors.affiliation: MRC Unit for Lifelong Health and Ageing at UCL, London, UK.
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authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
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authors.affiliation: Institute for Social and Economic Research, University of Essex, Colchester, UK.
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authors.affiliation: Department of Epidemiology & Public Health, UCL Institute of Epidemiology & Health Care, University College London, London, UK.
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authors.affiliation: UCL Genetics Institute, University College, London, UK.
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authors.affiliation: MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.affiliation: Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.
authors.forename: Frank
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authors.affiliation: Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK; Institute of Cardiovascular Science and Farr Institute, University College London, London, UK.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Casas
authors.affiliation: Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK; Department of Surgery and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: michael.holmes@ndph.ox.ac.uk.
authors.forename: Michael V
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mesh_terms: D003327:Coronary Disease / Q000097:blood* / Q000209:etiology*; D006801:Humans; D057182:Mendelian Randomization Analysis / Q000379:methods*; D015201:Meta-Analysis as Topic; D064887:Observational Studies as Topic; D012307:Risk Factors; D014527:Uric Acid / Q000009:adverse effects* / Q000097:blood*
chemical_list: D014527:Uric Acid