. 2016 Apr;4(4):327-36.

doi: 10.1016/S2213-8587(15)00386-1. Epub 2016 Jan 16.

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

Jon White¹, Reecha Sofat², Gibran Hemani³, Tina Shah⁴, Jorgen Engmann⁴, Caroline Dale⁵, Sonia Shah⁶, Felix A Kruger⁴, Claudia Giambartolomei⁷, Daniel I Swerdlow⁴, Tom Palmer⁸, Stela McLachlan⁹, Claudia Langenberg¹⁰, Delilah Zabaneh⁷, Ruth Lovering¹¹, Alana Cavadino¹², Barbara Jefferis¹³, Chris Finan¹⁴, Andrew Wong¹⁵, Antoinette Amuzu⁵, Ken Ong¹⁶, Tom R Gaunt¹⁷, Helen Warren¹⁸, Teri-Louise Davies¹⁹, Fotios Drenos²⁰, Jackie Cooper¹¹, Shah Ebrahim⁵, Debbie A Lawlor³, Philippa J Talmud¹¹, Steve E Humphries¹¹, Christine Power¹², Elina Hypponen²¹, Marcus Richards¹⁵, Rebecca Hardy¹⁵, Diana Kuh¹⁵, Nicholas Wareham²², Yoav Ben-Shlomo¹⁹, Ian N Day¹⁹, Peter Whincup²³, Richard Morris¹³, Mark W J Strachan²⁴, Jacqueline Price⁹, Meena Kumari²⁵, Mika Kivimaki²⁶, Vincent Plagnol⁷, John C Whittaker²⁷; International Consortium for Blood Pressure (ICBP); George Davey Smith³, Frank Dudbridge⁵, Juan P Casas²⁸, Michael V Holmes²⁹, Aroon D Hingorani⁴; UCLEB (University College London-London School of Hygiene & Tropical Medicine-Edinburgh-Bristol Consortium

Affiliations

¹ UCL Genetics Institute, University College, London, UK. Electronic address: jon.white@ucl.ac.uk.
² Centre for Clinical Pharmacology, University College London, London, UK.
³ MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
⁴ Institute of Cardiovascular Science and Farr Institute, University College London, London, UK.
⁵ Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.
⁶ Queensland Brain Institute, University of Queensland, QLD, Australia.
⁷ UCL Genetics Institute, University College, London, UK.
⁸ Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
⁹ Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
¹⁰ Institute of Cardiovascular Science and Farr Institute, University College London, London, UK; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
¹¹ Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, University College London, London, UK.
¹² Population, Policy and Practice, UCL Institute of Child Health, University College London, London, UnK.
¹³ Department of Primary Care & Population Health, University College London, Royal Free Campus, London, UK.
¹⁴ Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
¹⁵ MRC Unit for Lifelong Health and Ageing at UCL, London, UK.
¹⁶ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK; MRC Unit for Lifelong Health and Ageing at UCL, London, UK.
¹⁷ MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK; School of Social and Community Medicine, University of Bristol, Bristol, UK.
¹⁸ 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.
¹⁹ School of Social and Community Medicine, University of Bristol, Bristol, UK.
²⁰ 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.
²¹ 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.
²² MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
²³ Population Health Research Institute, St George's, University of London, London, UK.
²⁴ Metabolic Unit, Western General Hospital, Edinburgh, UK.
²⁵ Institute for Social and Economic Research, University of Essex, Colchester, UK.
²⁶ Department of Epidemiology & Public Health, UCL Institute of Epidemiology & Health Care, University College London, London, UK.
²⁷ Genetics Division, Research and Development, GlaxoSmithKline, Harlow, UK.
²⁸ 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.
²⁹ 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.

PMID: 26781229
PMCID: PMC4805857
DOI: 10.1016/S2213-8587(15)00386-1

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

Jon White et al. Lancet Diabetes Endocrinol. 2016 Apr.

. 2016 Apr;4(4):327-36.

doi: 10.1016/S2213-8587(15)00386-1. Epub 2016 Jan 16.

Authors

Affiliations

¹ UCL Genetics Institute, University College, London, UK. Electronic address: jon.white@ucl.ac.uk.
² Centre for Clinical Pharmacology, University College London, London, UK.
³ MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
⁴ Institute of Cardiovascular Science and Farr Institute, University College London, London, UK.
⁵ Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.
⁶ Queensland Brain Institute, University of Queensland, QLD, Australia.
⁷ UCL Genetics Institute, University College, London, UK.
⁸ Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
⁹ Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
¹⁰ Institute of Cardiovascular Science and Farr Institute, University College London, London, UK; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
¹¹ Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Science, University College London, London, UK.
¹² Population, Policy and Practice, UCL Institute of Child Health, University College London, London, UnK.
¹³ Department of Primary Care & Population Health, University College London, Royal Free Campus, London, UK.
¹⁴ Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
¹⁵ MRC Unit for Lifelong Health and Ageing at UCL, London, UK.
¹⁶ MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK; MRC Unit for Lifelong Health and Ageing at UCL, London, UK.
¹⁷ MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK; School of Social and Community Medicine, University of Bristol, Bristol, UK.
¹⁸ 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.
¹⁹ School of Social and Community Medicine, University of Bristol, Bristol, UK.
²⁰ 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.
²¹ 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.
²² MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
²³ Population Health Research Institute, St George's, University of London, London, UK.
²⁴ Metabolic Unit, Western General Hospital, Edinburgh, UK.
²⁵ Institute for Social and Economic Research, University of Essex, Colchester, UK.
²⁶ Department of Epidemiology & Public Health, UCL Institute of Epidemiology & Health Care, University College London, London, UK.
²⁷ Genetics Division, Research and Development, GlaxoSmithKline, Harlow, UK.
²⁸ 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.
²⁹ 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.

PMID: 26781229
PMCID: PMC4805857
DOI: 10.1016/S2213-8587(15)00386-1

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.

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.

Funding: UK National Institute for Health Research, British Heart Foundation, and UK Medical Research Council.

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Figures

**Figure 1**
Conceptual framework for the Mendelian randomisation analysis of urate concentration and risk of coronary heart disease G1–31 are genes containing urate variants that together form the multilocus instrument for urate concentration. Horizontal pleiotropy occurs when the instrument associates with traits other than urate that become confounders if also associated with coronary heart disease. Vertical pleiotropy occurs if their level is affected by urate, and does not invalidate Mendelian randomisation analysis. SNP=single nucleotide polymorphism. SBP=systolic blood pressure. DBP=diastolic blood pressure. *Multivariable Mendelian randomisation, including DBP, SBP, HDL cholesterol, and triglycerides as covariates was used to account for possible horizontal pleiotropy arising from association of the instrument with these variables. The effect of the adjustment is to block the paths indicated with red crosses. Egger Mendelian randomisation analysis was used to account for unknown or unmeasured pleiotropic confounders.

**Figure 2**
Association of individual SNPs with urate and coronary heart disease risk Estimates are derived from meta-analysis of data from several studies (appendix pp 2–3). Error bars represent 95% CIs. The numbers below the main figure correspond to the index column in the appendix (p 3) to allow cross-referencing. The slopes of the lines are instrumental variable regression estimates of the effect of urate on coronary heart disease risk with (blue) and without (red) SBP, DBP, HDL cholesterol, and triglycerides as covariates. OR=odds ratio. CHD=coronary heart disease. SNP=single nucleotide polymorphism. SBP=systolic blood pressure. DBP=diastolic blood pressure. HDL=high-density lipoprotein.

**Figure 3**
Observational and estimated causal association of plasma urate concentration risk of coronary heart disease Values represent a per 1 SD increase in urate concentration. Error bars represent 95% CIs. The vertical dotted line indicates the expectation under the null hypothesis (of no association between plasma urate and risk of coronary heart disease). SBP=systolic blood pressure. DBP=diastolic blood pressure. OR=odds ratio. UCLEB=University College London-London School of Hygiene & Tropical Medicine-Edinburgh-Bristol. HDL=high-density lipoprotein. CHD=coronary heart disease.

**Figure 4**
Comparison of observational and genetically instrumented associations between plasma urate concentration and several cardiovascular risk factors The genetically instrumented effect of urate without accounting for pleiotropic associations (A) and the genetically instrumented effect with DBP, SBP, HDL cholesterol, and triglycerides included as covariates in a multivariable Mendelian randomisation analysis (B). Error bars represent the 95% CIs. IV=instrumental variable. SBP=systolic blood pressure. DBP=diastolic blood pressure. HDL=high-density lipoprotein.

**Figure 5**
Observational association between binary traits and urate concentration against instrumental variable association for the 31 SNP instrument without covariates (A) and the 31 SNP instrument with DBP, SBP, HDL cholesterol, and triglycerides as covariates (B) Error bars represent 95% CI. OR=odds ratio. CHD=coronary heart disease. DBP=diastolic blood pressure. SBP=systolic blood pressure. HDL=high-density lipoprotein.

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Comment in

Plasma urate and coronary heart disease: fingerprint match, but no smoking gun.
Burgess S. Burgess S. Lancet Diabetes Endocrinol. 2016 Apr;4(4):292-4. doi: 10.1016/S2213-8587(15)00425-8. Epub 2016 Jan 16. Lancet Diabetes Endocrinol. 2016. PMID: 26781230 No abstract available.

References

1. Terkeltaub RA. Update on gout: new therapeutic strategies and options. Nat Rev Rheumatol. 2010;6:30–38. - PubMed
1. Yang Q, Köttgen A, Dehghan A. Multiple genetic loci influence serum urate and their relationship with gout and cardiovascular disease risk factors. Circ Cardiovasc Genet. 2010;3:523–530. - PMC - PubMed
1. Davis N. The cardiovascular and renal relations and manifestations of gout. JAMA. 1897;29:261–262.
1. Wheeler JG, Juzwishin DM, Eriksdottir G, Gudnason V, Danesh J. Serum uric acid and coronary heart disease in 9,458 incident cases and 155,084 controls: prospective study and meta-Analysis. PLoS Med. 2005;2:236–243. - PMC - PubMed
1. Waring WS, McKnight JA, Webb DJ, Maxwell SRJ. Uric acid restores endothelial function in patients with type 1 diabetes and regular smokers. Diabetes. 2006;55:3127–3132. - PubMed

Uncited Reference

1. Bento AP, Gaulton A, Hersey A. The ChEMBL bioactivity database: an update. Nucleic Acids Res. 2014;42:1083–1090. - PMC - PubMed

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

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

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