ArticleJournal of the American College of Cardiology2016
Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study.
Abstract readMulticenter Study
In one paragraph
Article in Journal of the American College of Cardiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers, 7 of them syntheses that pooled it.
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91citing papers in PubMed, 7 pooled it
18.1field-weighted citation impact, top 1% of its field
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
91 citing papers in PubMed, 7 syntheses or guidelines pooled it, 181 citations in OpenAlex.
- Genetic susceptibility to uric acid and selected cardiovascular outcomes: a systematic review and meta-analysis of Mendelian randomization studies.Frontiers in endocrinology · 2026Pooled it
- Large-scale cross-ancestry genome-wide meta-analysis of serum urate.Nature communications · 2024Pooled it
- Serum uric acid is not associated with major depressive disorder in European and South American populations: a meta-analysis and two-sample bidirectional Mendelian Randomization study.European journal of clinical nutrition · 2022Pooled it
- Mendelian randomization analysis of 37 clinical factors and coronary artery disease in East Asian and European populations.Genome medicine · 2022Pooled it
- Urate, Blood Pressure, and Cardiovascular Disease: Evidence From Mendelian Randomization and Meta-Analysis of Clinical Trials.Hypertension (Dallas, Tex. : 1979) · 2021Pooled it
- The association between hyperuricemia and coronary artery calcification development: A systematic review and meta-analysis.Clinical cardiology · 2019Pooled it
- Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies.BMJ (Clinical research ed.) · 2017Pooled it
- Evaluation of the Relationship Between Serum Urate Levels, Clinical Manifestations of Gout, and Death From Cardiovascular Causes in Patients Receiving Febuxostat or Allopurinol in an Outcomes Trial.Arthritis & rheumatology (Hoboken, N.J.) · 2022Trial
- Sacubitril/valsartan reduces serum uric acid concentration, an independent predictor of adverse outcomes in PARADIGM-HF.European journal of heart failure · 2018Trial
- Serum urate at trial entry and ALS progression in EMPOWER.Amyotrophic lateral sclerosis & frontotemporal degeneration · 2017Trial
- Serum uric acid and the trajectory of cardiometabolic multimorbidity: a prospective study conducted with data from the UK Biobank.Nutrition journal · 2026Article
- Development of a risk assessment model for multimorbidity of diabetes, hypertension, and coronary heart disease with XGBoost in primary care in Shanghai, China: a retrospective study.BMC cardiovascular disorders · 2026Article
- Gout, Uric Acid, and Coronary Artery Disease.Journal of atherosclerosis and thrombosis · 2025Review
- Elevated serum uric acid as an independent risk factor for multiple stent placement in non-hypertensive, non-diabetic patients with coronary artery disease: a retrospective cohort analysis.Clinical rheumatology · 2025Article
- Causal association of modifiable factors with cardiometabolic multimorbidity: an exposome-wide Mendelian randomization investigation.Cardiovascular diabetology · 2025Observational
- Serum uric acid and coronary artery disease risk: a 10-year prospective cohort study in healthy adults.BMC cardiovascular disorders · 2025Observational
- Obesity, composite dietary antioxidant index, and their interactive association with the risk of cardiometabolic multimorbidity in the elderly from a large national survey.Lipids in health and disease · 2025Article
- Whole exome sequence reveals genetic profiles of primary cardiomyopathy and genotype-phenotype association in Chinese population.BMC genomics · 2025Article
- Serum uric acid trajectories and the risk of cardiovascular disease: a longitudinal association and pathway analysis.Endocrine · 2025Article
- Inflammation mediates the association between hyperuricemia and stroke mortality: a cohort study.Frontiers in neurology · 2025Article
31 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
57 authors at 20 institutions in 7 countries.
Tanya KeenanTranslational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Wei ZhaoTranslational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Asif RasheedCenter for Non-Communicable Diseases, Karachi, Pakistan.
Weang K HoDepartment of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Rainer MalikLudwig-Maximilians-University Munich, Medical Center, Institute for Stroke and Dementia Research (ISD), Munich, Germany.
Janine F FelixDepartment of Epidemiology, Erasmus MC University Medical Center Rotterdam, the Netherlands and The Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden, the Netherlands.
Robin YoungDepartment of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Nabi ShahCenter for Non-Communicable Diseases, Karachi, Pakistan.
Maria SamuelCenter for Non-Communicable Diseases, Karachi, Pakistan.
Nasir SheikhDepartment of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Megan L MucksavageTranslational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Omar ShahTranslational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Jin LiChildren's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Michael MorleyDepartment of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Annika LaserResearch Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
Nadeem Hayat MallickPunjab Institute of Cardiology, Lahore, Pakistan.
Khan Shah ZamanNational Institute of Cardiovascular Diseases, Karachi, Pakistan.
Mohammad IshaqKarachi Institute of Heart Diseases, Karachi, Pakistan.
Syed Zahed RasheedKarachi Institute of Heart Diseases, Karachi, Pakistan.
Fazal-Ur-Rehman MemonRed Crescent Institute of Cardiology, Hyderabad, Pakistan.
Faisal AhmedDepartment of Cardiology, Liaquat National Hospital, Karachi, Pakistan.
Bashir HanifDepartment of Cardiology, Tabba Heart Institute, Karachi, Pakistan.
Muhammad Shakir LakhaniDepartment of Cardiology, Tabba Heart Institute, Karachi, Pakistan.
Muhammad FahimCenter for Non-Communicable Diseases, Karachi, Pakistan.
Madiha IshaqCenter for Non-Communicable Diseases, Karachi, Pakistan.
Naresh Kumar ShardhaCenter for Non-Communicable Diseases, Karachi, Pakistan.
Naveeduddin AhmedDepartment of Neurology, Liaquat National Hospital, Karachi, Pakistan.
Khalid MahmoodDepartment of Medicine, Dow University of Health Sciences, Civil Hospital, Karachi, Pakistan.
Waseem IqbalDepartment of Medicine, Lahore General Hospital, Lahore, Pakistan.
Saba AkhtarCenter for Non-Communicable Diseases, Karachi, Pakistan.
Rabia RaheelCenter for Non-Communicable Diseases, Karachi, Pakistan.
Christopher J O'DonnellNational Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Christian HengstenbergInternal Medicine II - Cardiology, University Hospital of Regensburg, Regensburg, Germany.
Winifred MärzClinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria; Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany; Synlab Academy, Synlab Laboratory Services GmbH, Mannheim, Germany.
Sekar KathiresanCardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
Nilesh SamaniDepartment of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield General Hospital, Leicester, United Kingdom.
Anuj GoelWellcome Trust Center for Human Genetics, University of Oxford, Oxford, United Kingdom.
Jemma C HopewellDivision of Cardiovascular Science, Oxford University, Oxford, United Kingdom.
John ChambersSchool of Public Health, Imperial College, London, United Kingdom.
Yu-Ching ChengDepartment of Medicine, University of Maryland School of Medicine, Baltimore VA Medical Center, Baltimore, Maryland.
Pankaj SharmaImperial College London & Hammersmith Hospitals, London, United Kingdom.
Qiong YangSchool of Public Health, Boston University, Boston, Massachusetts.
Jonathan RosandDivision of Neurocritical Care, Massachusetts General Hospital, Boston, Massachusetts.
Giorgio B BoncoraglioDepartment of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico, Milan, Italy.
Shahana Urooj KazmiDepartment of Microbiology, University of Karachi, Karachi, Pakistan.
Hakon HakonarsonChildren's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Anna KöttgenRenal Division, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Andreas KalogeropoulosDivision of Cardiology, School of Medicine, Emory University, Atlanta, Georgia.
Philippe FrossardCenter for Non-Communicable Diseases, Karachi, Pakistan.
Ayeesha KamalDivision of Neurology, Department of Medicine, Aga Khan University, Karachi, Pakistan.
Martin DichgansLudwig-Maximilians-University Munich, Medical Center, Institute for Stroke and Dementia Research (ISD), Munich, Germany.
Thomas CappolaCardiovascular Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
Muredach P ReillyTranslational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Cardiovascular Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
John DaneshDepartment of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Daniel J RaderTranslational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Benjamin F VoightDepartment of Systems Pharmacology and Translational Therapeutics and Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: bvoight@upenn.edu.
Danish SaleheenTranslational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Non-Communicable Diseases, Karachi, Pakistan; Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: saleheen@mail.med.upenn.edu.
Center for Non-Communicable Diseases · PKUniversity of Pennsylvania · USUniversity of Cambridge · GBKarachi Institute of Heart Diseases · PKMassachusetts General Hospital · USChildren's Hospital of Philadelphia · USLiaquat National Hospital · PKLudwig-Maximilians-Universität München · DETabba Heart Institute · PKTranslational Therapeutics (United States) · USAga Khan University · PKBoston University · USCentre for Human Genetics · GBCivil Hospital Karachi · PKEmory University · USErasmus MC · NLFondazione Istituto Neurologico Nazionale Casimiro Mondino · ITFramingham Heart Study · USHammersmith Hospital · GBHelmholtz Zentrum München · DE
Funding
PRECURSORS OF STROKE INCIDENCE AND PROGNOSISR01NS017950 · NINDS · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI Hugo Javier Aparicio, Jose Rafael Romero · 1985 to 2026
$22.9MAN NCRR CENTER FOR HIGH THROUGHPUT SNP GENOTYPING AND ANALYSIS: GAIN NETWORKU54RR020278 · NCRR · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY · 2004 to 2008
$14.4MARIC Neurocognitive Study (ARIC-NCS) Renewal 2 of 5U01HL096917 · NHLBI · UNIVERSITY OF MISSISSIPPI MED CTR · PI MOSLEY, THOMAS H · 2010 to 2018
$11.9MThe NINDS International Stroke Genetics Consortium StudyU01NS069208 · NINDS · UNIVERSITY OF MARYLAND BALTIMORE · PI KITTNER, STEVEN J · 2010 to 2013
$9.4MComprehensive biomarker study to capitalize on existing GWAS in 10K South AsiansRC2HL101834 · NHLBI · UNIVERSITY OF PENNSYLVANIA · PI DANESH, JOHN NAVID, RADER, DANIEL JAMES · 2009 to 2010
$8.0MA Genome-wide Association Study for Early-Onset Myocardial InfarctionR01HL087676 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI ALTSHULER, DAVID · 2007 to 2009
$4.7MCollaborative GWAS of Dementia, AD and related MRI and Cognitive EndophenotypesR01AG033193 · NIA · BOSTON UNIVERSITY MEDICAL CAMPUS · PI SESHADRI, SUDHA · 2009 to 2016
$4.4MAlgorithms to identify non-coding mutational burden and disease-relevant pathwaysR01DK101478 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI VOIGHT, BENJAMIN FRANKLIN · 2014 to 2018
$2.9MA Genome-Wide Association Study of Ischemic Brain Vascular InjuryR01HL093029 · NHLBI · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI FORNAGE, MYRIAM · 2009 to 2010
$1.6MMarkers of the metabolic syndrome linking type 2 diabetes and MI in South AsiaRC1TW008485 · FIC · UNIVERSITY OF PENNSYLVANIA · PI DANESH, JOHN NAVID, RADER, DANIEL JAMES · 2009 to 2010
$1000kEstablishment of a bioresource for discovery and evaluation of genetic and otherR21NS064908 · NINDS · UNIVERSITY OF CAMBRIDGE · PI DANESH, JOHN NAVID, FROSSARD, PHILIPPE M. · 2009 to 2010
$215kTHE FRAMINGHAM HEART STUDY-N01HC25195-268025195-268025195N01HC025195 · HC · TRUSTEES OF BOSTON UNIVERSITY · PI WOLF, PHILIP A · 2002 to 2006
–British Heart Foundation FS/14/55/30806British Heart Foundation RG/08/014/24067British Heart Foundation RG/13/13/30194FIC NIH HHS RC1 TW008485Medical Research Council MR/L003120/1NCRR NIH HHS U54 RR020278NHLBI NIH HHS N01 HC025195NHLBI NIH HHS R01 HL087676NHLBI NIH HHS R01 HL093029NHLBI NIH HHS RC2 HL101834NHLBI NIH HHS U01 HL096917NIA NIH HHS R01 AG033193NIDDK NIH HHS R01 DK101478NINDS NIH HHS R01 NS017950NINDS NIH HHS R21 NS064908NINDS NIH HHS U01 NS069208Wellcome Trust
Abstract
backgroundAlthough epidemiological studies have reported positive associations between circulating urate levels and cardiometabolic diseases, causality remains uncertain.
objectivesThrough a Mendelian randomization approach, we assessed whether serum urate levels are causally relevant in type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), ischemic stroke, and heart failure (HF).
methodsThis study investigated 28 single nucleotide polymorphisms known to regulate serum urate levels in association with various vascular and nonvascular risk factors to assess pleiotropy. To limit genetic confounding, 14 single nucleotide polymorphisms exclusively associated with serum urate levels were used in a genetic risk score to assess associations with the following cardiometabolic diseases (cases/controls): T2DM (26,488/83,964), CHD (54,501/68,275), ischemic stroke (14,779/67,312), and HF (4,526/18,400). As a positive control, this study also investigated our genetic instrument in 3,151 gout cases and 68,350 controls.
resultsSerum urate levels, increased by 1 SD due to the genetic score, were not associated with T2DM, CHD, ischemic stroke, or HF. These results were in contrast with previous prospective studies that did observe increased risks of these 4 cardiometabolic diseases for an equivalent increase in circulating urate levels. However, a 1 SD increase in serum urate levels due to the genetic score was associated with increased risk of gout (odds ratio: 5.84; 95% confidence interval: 4.56 to 7.49), which was directionally consistent with previous observations.
conclusionsEvidence from this study does not support a causal role of circulating serum urate levels in T2DM, CHD, ischemic stroke, or HF. Decreasing serum urate levels may not translate into risk reductions for cardiometabolic conditions.
Indexed as
Polymorphism, Single NucleotideCoronary DiseaseDiabetes Mellitus, Type 2Global HealthHumansMendelian Randomization AnalysisMorbidityOdds RatioPrognosisRisk AssessmentRisk FactorsStrokeUric AcidUric Acidgeneticpleiotropysingle nucleotide polymorphism
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