Abstract
BackgroundThe role of urate in cardiovascular diseases (CVDs) has been extensively investigated in observational studies; however, the extent of any causal effect remains unclear, making it difficult to evaluate its clinical relevance.Methods and findingsA phenome-wide association study (PheWAS) together with a Bayesian analysis of tree-structured phenotypic model (TreeWAS) was performed to examine disease outcomes related to genetically determined serum urate levels in 339,256 unrelated White British individuals (54% female) in the UK Biobank who were aged 40–69 years (mean age, 56.87; SD, 7.99) when recruited from 2006 to 2010. Mendelian randomization (MR) analyses were performed to replicate significant findings using various genome-wide association study (GWAS) consortia data. Sensitivity analyses were conducted to examine possible pleiotropic effects on metabolic traits of the genetic variants used as instruments for urate. PheWAS analysis, examining the association with 1,431 disease outcomes, identified 13 distinct phecodes representing 4 disease groups (inflammatory polyarthropathies, hypertensive disease, circulatory disease, and metabolic disorders) and 9 disease outcomes (gout, gouty arthropathy, pyogenic arthritis, essential hypertension, coronary atherosclerosis, ischemic heart disease, chronic ischemic heart disease, myocardial infarction, and hypercholesterolemia) that were associated with genetically determined serum urate levels after multiple testing correction (p < 3.35 × 10−4). TreeWAS analysis, examining 10,750 ICD-10 diagnostic terms, identified more sub-phenotypes of cardiovascular and cerebrovascular diseases (e.g., angina pectoris, heart failure, cerebral infarction). MR analysis successfully replicated the association with gout, hypertension, heart diseases, and blood lipid levels but indicated the existence of genetic pleiotropy. Sensitivity analyses support an inference that pleiotropic effects of genetic variants on urate and metabolic traits contribute to the observational associations with CVDs. The main limitations of this study relate to possible bias from pleiotropic effects of the considered genetic variants and possible misclassification of cases for mild disease that did not require hospitalization.ConclusionIn this study, high serum urate levels were found to be associated with increased risk of different types of cardiac events. The finding of genetic pleiotropy indicates the existence of common upstream pathological elements influencing both urate and metabolic traits, and this may suggest new opportunities and challenges for developing drugs targeting a common mediator that would be beneficial for both the treatment of gout and the prevention of cardiovascular comorbidities.
Highlights
The role of urate has been explored in a large number of observational studies in relation to a multitude of health outcomes [1]
The genetic determinants of serum urate level have been explored in several genome-wide association studies (GWASs) [7,8,9,10] and the wealth of resultant data allows for the identification and application of genetic variants as instruments to help separate causal from noncausal associations, given that genotypes are generally independent of environmental exposures and the transmission of genetic information is usually unidirectional
To identify genetic variants showing pleiotropy, we examined their association with a set of metabolic traits (i.e., body mass index (BMI), waist-to-hip ratio [WHR], total cholesterol [TC], low-density lipoprotein cholesterol [LDL-c], high-density lipoprotein cholesterol [HDLc], fasting glucose, 2-hour glucose, glycoproteins, systolic blood pressure [SBP], and diastolic blood pressure [DBP]) through publicly available resources from various GWAS consortia
Summary
The role of urate has been explored in a large number of observational studies in relation to a multitude of health outcomes [1]. Apart from gout, compelling evidence exists for the associations between high serum urate level and an increased risk of non–crystal deposition disorders, including hypertension, cardiovascular diseases (CVDs), and metabolic syndrome [2,3]. Investigating the associations between genetic variants related to serum urate and disease outcomes might help provide causal evidence in support of the hypotheses that link urate to multiple clinical disorders. The role of urate in cardiovascular diseases (CVDs) has been extensively investigated in observational studies; the extent of any causal effect remains unclear, making it difficult to evaluate its clinical relevance
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