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Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Plasma urate concentration and risk of coronary heart disease
T2 - a Mendelian randomisation analysis
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.
N1 - © White et al. Open Access article distributed under the terms of CC BY.
PY - 2016/4
Y1 - 2016/4
N2 - SummaryBackgroundIncreased 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.
AB - SummaryBackgroundIncreased 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.
U2 - 10.1016/S2213-8587(15)00386-1
DO - 10.1016/S2213-8587(15)00386-1
M3 - Journal 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 -