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

Abstract

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

Genetic analysis of atherosclerosis identifies a major susceptibility locus in the major histocompatibility complex of mice

“…Similar findings have been observed with other mouse crosses [15,23,30]. These findings are consistent with the observation made from Mendelian randomization studies of HDL for role in human coronary heart disease [31,32]. Although Mendelian randomization studies of blood lipids have suggested a role for triglyceride and LDL cholesterol in human coronary heart disease, no significant correlations with atherosclerotic lesions were observed in the present cross or previous crosses [13,33].…”

Interpreting findings from Mendelian randomization using the MR-Egger method

“…The method is being increasingly used in practice, with applications including analyses of the causal effects of plasma urate on coronary heart disease risk [10], of height on income [11], of sleep patterns on type 2 diabetes [12], and of pubertal development on prostate cancer risk [13]. However, critical assessment of the method is lacking.…”

Improving the accuracy of two-sample summary data Mendelian randomization: moving beyond the NOME assumption

“…it has a non-zero mean) then a random effects meta-analysis will be biased, but MR-Egger regression [11] can still yield reliable inferences. MR-Egger regression has been used extensively as a sensitivity analysis tool since its proposal for this reason (see [12,13,14,15,16] for some recent examples), although its estimate can often suffer from a lack of precision. In this paper we choose to focus solely on the IVW estimate.…”