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

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 & 31 others 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, George Davey Smith, Frank Dudbridge, Juan P. Casas, Michael V. Holmes, Aroon D. Hingorani

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

LanguageEnglish
Pages327-336
Number of pages10
JournalThe Lancet Diabetes and Endocrinology
Volume4
Issue number4
DOIs
Publication statusPublished - 1 Apr 2016

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

White, Jon ; Sofat, Reecha ; Hemani, Gibran ; Shah, Tina ; Engmann, Jorgen ; Dale, Caroline ; Shah, Sonia ; Kruger, Felix A. ; Giambartolomei, Claudia ; Swerdlow, Daniel I. ; Palmer, Tom ; McLachlan, Stela ; Langenberg, Claudia ; Zabaneh, Delilah ; Lovering, Ruth ; Cavadino, Alana ; Jefferis, Barbara ; Finan, Chris ; Wong, Andrew ; Amuzu, Antoinette ; Ong, Ken ; Gaunt, Tom R. ; Warren, Helen ; Davies, Teri Louise ; Drenos, Fotios ; Cooper, Jackie ; Ebrahim, Shah ; Lawlor, Debbie A. ; Talmud, Philippa J. ; Humphries, Steve E. ; Power, Christine ; Hypponen, Elina ; Richards, Marcus ; Hardy, Rebecca ; Kuh, Diana ; Wareham, Nicholas ; Ben-Shlomo, Yoav ; Day, Ian N. ; Whincup, Peter ; Morris, Richard ; Strachan, Mark W.J. ; Price, Jacqueline ; Kumari, Meena ; Kivimaki, Mika ; Plagnol, Vincent ; Whittaker, John C. ; Smith, George Davey ; Dudbridge, Frank ; Casas, Juan P. ; Holmes, Michael V. ; Hingorani, Aroon D. / Plasma urate concentration and risk of coronary heart disease : A Mendelian randomisation analysis. In: The Lancet Diabetes and Endocrinology. 2016 ; Vol. 4, No. 4. pp. 327-336.
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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.",
author = "Jon White and Reecha Sofat and Gibran Hemani and Tina Shah and Jorgen Engmann and Caroline Dale and Sonia Shah and Kruger, {Felix A.} and Claudia Giambartolomei and Swerdlow, {Daniel I.} and Tom Palmer and Stela McLachlan and Claudia Langenberg and Delilah Zabaneh and Ruth Lovering and Alana Cavadino and Barbara Jefferis and Chris Finan and Andrew Wong and Antoinette Amuzu and Ken Ong and Gaunt, {Tom R.} and Helen Warren and Davies, {Teri Louise} and Fotios Drenos and Jackie Cooper and Shah Ebrahim and Lawlor, {Debbie A.} and Talmud, {Philippa J.} and Humphries, {Steve E.} and Christine Power and Elina Hypponen and Marcus Richards and Rebecca Hardy and Diana Kuh and Nicholas Wareham and Yoav Ben-Shlomo and Day, {Ian N.} and Peter Whincup and Richard Morris and Strachan, {Mark W.J.} and Jacqueline Price and Meena Kumari and Mika Kivimaki and Vincent Plagnol and Whittaker, {John C.} and Smith, {George Davey} and Frank Dudbridge and Casas, {Juan P.} and Holmes, {Michael V.} and Hingorani, {Aroon D.}",
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White, J, Sofat, R, Hemani, G, Shah, T, Engmann, J, Dale, C, Shah, S, Kruger, FA, Giambartolomei, C, Swerdlow, DI, Palmer, T, McLachlan, S, Langenberg, C, Zabaneh, D, Lovering, R, Cavadino, A, Jefferis, B, Finan, C, Wong, A, Amuzu, A, Ong, K, Gaunt, TR, Warren, H, Davies, TL, Drenos, F, Cooper, J, Ebrahim, S, Lawlor, DA, Talmud, PJ, Humphries, SE, Power, C, Hypponen, E, Richards, M, Hardy, R, Kuh, D, Wareham, N, Ben-Shlomo, Y, Day, IN, Whincup, P, Morris, R, Strachan, MWJ, Price, J, Kumari, M, Kivimaki, M, Plagnol, V, Whittaker, JC, Smith, GD, Dudbridge, F, Casas, JP, Holmes, MV & Hingorani, AD 2016, 'Plasma urate concentration and risk of coronary heart disease: A Mendelian randomisation analysis', The Lancet Diabetes and Endocrinology, vol. 4, no. 4, pp. 327-336. https://doi.org/10.1016/S2213-8587(15)00386-1

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

In: The Lancet Diabetes and Endocrinology, Vol. 4, No. 4, 01.04.2016, p. 327-336.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Plasma urate concentration and risk of coronary heart disease

T2 - The Lancet Diabetes and Endocrinology

AU - White, Jon

AU - Sofat, Reecha

AU - Hemani, Gibran

AU - Shah, Tina

AU - Engmann, Jorgen

AU - Dale, Caroline

AU - Shah, Sonia

AU - Kruger, Felix A.

AU - Giambartolomei, Claudia

AU - Swerdlow, Daniel I.

AU - Palmer, Tom

AU - McLachlan, Stela

AU - Langenberg, Claudia

AU - Zabaneh, Delilah

AU - Lovering, Ruth

AU - Cavadino, Alana

AU - Jefferis, Barbara

AU - Finan, Chris

AU - Wong, Andrew

AU - Amuzu, Antoinette

AU - Ong, Ken

AU - Gaunt, Tom R.

AU - Warren, Helen

AU - Davies, Teri Louise

AU - Drenos, Fotios

AU - Cooper, Jackie

AU - Ebrahim, Shah

AU - Lawlor, Debbie A.

AU - Talmud, Philippa J.

AU - Humphries, Steve E.

AU - Power, Christine

AU - Hypponen, Elina

AU - Richards, Marcus

AU - Hardy, Rebecca

AU - Kuh, Diana

AU - Wareham, Nicholas

AU - Ben-Shlomo, Yoav

AU - Day, Ian N.

AU - Whincup, Peter

AU - Morris, Richard

AU - Strachan, Mark W.J.

AU - Price, Jacqueline

AU - Kumari, Meena

AU - Kivimaki, Mika

AU - Plagnol, Vincent

AU - Whittaker, John C.

AU - Smith, George Davey

AU - Dudbridge, Frank

AU - Casas, Juan P.

AU - Holmes, Michael V.

AU - Hingorani, Aroon D.

PY - 2016/4/1

Y1 - 2016/4/1

N2 - 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.

AB - 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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U2 - 10.1016/S2213-8587(15)00386-1

DO - 10.1016/S2213-8587(15)00386-1

M3 - Article

VL - 4

SP - 327

EP - 336

JO - The Lancet Diabetes and Endocrinology

JF - The Lancet Diabetes and Endocrinology

SN - 2213-8587

IS - 4

ER -