Genetically determined serum urate levels and cardiovascular and other diseases in UK Biobank cohort: A phenome-wide mendelian randomization study

Autor: Paul M. McKeigue, Athina Spiliopoulou, Tian Yang, Maria Timofeeva, Yazhou He, Harry Campbell, Xue Li, Wei-Qi Wei, Tim Varley, Joshua C. Denny, Xiangrui Meng, Aliya Gifford, Ioanna Tzoulaki, Evropi Theodoratou, Peter K. Joshi
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Male
Gout
Social Sciences
Blood Pressure
Genome-wide association study
Comorbidity
Disease
Cardiovascular Medicine
030204 cardiovascular system & hematology
Essential hypertension
Bioinformatics
Vascular Medicine
Cohort Studies
Angina
0302 clinical medicine
Sociology
Consortia
Medicine and Health Sciences
Coronary Heart Disease
Medicine
030212 general & internal medicine
Phenomics
11 Medical and Health Sciences
Biological Specimen Banks
Genetic Pleiotropy
Mendelian Randomization Analysis
Genomics
General Medicine
Middle Aged
3. Good health
Phenotype
Treatment Outcome
Cardiovascular Diseases
Hypertension
Female
Research Article
Adult
Inflammatory Diseases
Cardiology
Polymorphism
Single Nucleotide
Sensitivity and Specificity
03 medical and health sciences
Rheumatology
General & Internal Medicine
Mendelian randomization
Genetics
Genome-Wide Association Studies
Humans
Genetic Predisposition to Disease
Aged
business.industry
Biology and Life Sciences
Computational Biology
Genetic Variation
Reproducibility of Results
Human Genetics
Bayes Theorem
Genome Analysis
medicine.disease
United Kingdom
Uric Acid
Genetic Loci
Genetics of Disease
business
Genome-Wide Association Study
Zdroj: PLoS Medicine, Vol 16, Iss 10, p e1002937 (2019)
Li, X, Meng, X, He, Y, Spiliopoulou, A, Timofeeva, M, Wei, W-Q, Gifford, A, Yang, T, Varley, T, Tzoulaki, I, Joshi, P, Denny, J C, Mckeigue, P, Campbell, H & Theodoratou, E 2019, ' Genetically determined serum urate levels and cardiovascular and other diseases in UK Biobank cohort : A phenome-wide mendelian randomization study ', PLoS Medicine, vol. 16, no. 10, pp. e1002937 . https://doi.org/10.1371/journal.pmed.1002937
PLoS Medicine
ISSN: 1549-1676
1549-1277
DOI: 10.1371/journal.pmed.1002937
Popis: Background The 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 findings A 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. Conclusion In 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.
Evropi Theodoratou and colleagues investigate possible mechanisms linking urate with cardiovascular disease.
Author summary Why was this study done? Serum urate level has been extensively studied in epidemiological studies in relation to various diseases, but the extent of any causal effect is still unclear, making it difficult to evaluate the clinical importance of urate. Mendelian randomization (MR) uses naturally occurring genetic variants as instruments to infer the causal role of a risk factor in a disease or outcome of interest. Previous MR studies were typically hypothesis driven, and few studies have comprehensively investigated how serum urate level might influence overall health. What did the researchers do and find? We implemented a phenome-wide association study (PheWAS) followed by a Bayesian analysis of tree-structured phenotypic model (TreeWAS) and MR analyses to explore the association between urate and a broad range of disease outcomes in the UK Biobank. We identified gout, hypertension, hypercholesterolemia, and a multitude of cardiovascular and cerebrovascular diseases (e.g., coronary atherosclerosis, myocardial infarction, angina pectoris, ischemic heart disease, heart failure, and cerebral infarction) that were associated with serum urate levels. MR analysis using various GWAS consortia data successfully replicated these associations but indicated the existence of genetic pleiotropy. Sensitivity analyses examining the pleiotropic effects of urate genetic risk loci on a set of metabolic traits support an inference that genetic pleiotropy contributes to observational association between urate and different types of cardiac events. What do these findings mean? There was little evidence of causality; instead, the pleiotropy of genetic variants on urate and metabolic traits is indicated for the observed associations with cardiovascular/metabolic diseases. The linked biological pathways between urate and metabolic traits indicated that the frequent coexistence of gout with hypertension, cardiovascular diseases (CVDs), and hyperlipidemia is a range of interrelated disease outcomes due to linked pathogenic components, rather than isolated events. These findings support the European League against Rheumatism (EULAR) recommendation of systematic screening and assessment of cardiovascular/metabolic comorbidities in gout patients. These findings may suggest new opportunities and challenges for developing drugs targeting a more distal mediator that would be beneficial for both the treatment of gout and the prevention of cardiovascular/metabolic comorbidities.
Databáze: OpenAIRE
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