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Genetically determined serum urate levels and cardiovascular and other diseases in UK Biobank cohort: A phenome-wide mendelian randomization study.
PLoS Med 2019; 16(10):e1002937PM

Abstract

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.

Authors+Show Affiliations

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.Centre for Population Health Sciences, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Medical Research Council, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.Public Health and Intelligence, NHS National Services Scotland, Edinburgh, United Kingdom.Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom. Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.Centre for Population Health Sciences, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom. Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31626644

Citation

Li, Xue, et al. "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, 2019, pp. e1002937.
Li X, Meng X, He Y, et al. Genetically determined serum urate levels and cardiovascular and other diseases in UK Biobank cohort: A phenome-wide mendelian randomization study. PLoS Med. 2019;16(10):e1002937.
Li, X., Meng, X., He, Y., Spiliopoulou, A., Timofeeva, M., Wei, W. Q., ... 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, 16(10), pp. e1002937. doi:10.1371/journal.pmed.1002937.
Li X, et al. Genetically Determined Serum Urate Levels and Cardiovascular and Other Diseases in UK Biobank Cohort: a Phenome-wide Mendelian Randomization Study. PLoS Med. 2019;16(10):e1002937. PubMed PMID: 31626644.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genetically determined serum urate levels and cardiovascular and other diseases in UK Biobank cohort: A phenome-wide mendelian randomization study. AU - Li,Xue, AU - Meng,Xiangrui, AU - He,Yazhou, AU - Spiliopoulou,Athina, AU - Timofeeva,Maria, AU - Wei,Wei-Qi, AU - Gifford,Aliya, AU - Yang,Tian, AU - Varley,Tim, AU - Tzoulaki,Ioanna, AU - Joshi,Peter, AU - Denny,Joshua C, AU - Mckeigue,Paul, AU - Campbell,Harry, AU - Theodoratou,Evropi, Y1 - 2019/10/18/ PY - 2019/05/21/received PY - 2019/09/17/accepted PY - 2019/10/19/entrez PY - 2019/10/19/pubmed PY - 2019/10/19/medline SP - e1002937 EP - e1002937 JF - PLoS medicine JO - PLoS Med. VL - 16 IS - 10 N2 - 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. SN - 1549-1676 UR - https://www.unboundmedicine.com/medline/citation/31626644/Genetically_determined_serum_urate_levels_and_cardiovascular_and_other_diseases_in_UK_Biobank_cohort:_A_phenome_wide_mendelian_randomization_study_ L2 - http://dx.plos.org/10.1371/journal.pmed.1002937 DB - PRIME DP - Unbound Medicine ER -