title: Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study.
abstract: BACKGROUND
  Although epidemiological studies have reported positive associations between circulating urate levels and cardiometabolic diseases, causality remains uncertain.
  
  
  OBJECTIVE
  Through 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).
  
  
  METHODS
  This 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.
  
  
  RESULTS
  Serum 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.
  
  
  CONCLUSIONS
  Evidence 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.
authors.affiliation: Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
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authors.affiliation: Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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authors.affiliation: Center for Non-Communicable Diseases, Karachi, Pakistan.
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authors.forename: Naveeduddin
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authors.affiliation: Department of Microbiology, University of Karachi, Karachi, Pakistan.
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authors.lastname: Kazmi
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Renal Division, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Anna
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authors.affiliation: Division of Cardiology, School of Medicine, Emory University, Atlanta, Georgia.
authors.forename: Andreas
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authors.affiliation: Center for Non-Communicable Diseases, Karachi, Pakistan.
authors.forename: Philippe
authors.initials: P
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authors.affiliation: Division of Neurology, Department of Medicine, Aga Khan University, Karachi, Pakistan.
authors.forename: Ayeesha
authors.initials: A
authors.lastname: Kamal
authors.affiliation: Ludwig-Maximilians-University Munich, Medical Center, Institute for Stroke and Dementia Research (ISD), Munich, Germany.
authors.forename: Martin
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authors.lastname: Dichgans
authors.affiliation: Cardiovascular Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cappola
authors.affiliation: Translational 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.
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
authors.forename: John
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authors.lastname: Danesh
authors.affiliation: Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics and Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: bvoight@upenn.edu.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Voight
authors.affiliation: Translational 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.
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mesh_terms: D003327:Coronary Disease / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D014943:Global Health; D006801:Humans; D057182:Mendelian Randomization Analysis / Q000379:methods*; D009017:Morbidity / Q000639:trends; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D020521:Stroke / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D014527:Uric Acid / Q000097:blood*
chemical_list: D014527:Uric Acid
keywords: genetic; pleiotropy; single nucleotide polymorphism
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