PMID- 26821629
OWN - NLM
STAT- MEDLINE
DCOM- 20160531
LR  - 20220408
IS  - 1558-3597 (Electronic)
IS  - 0735-1097 (Print)
IS  - 0735-1097 (Linking)
VI  - 67
IP  - 4
DP  - 2016 Feb 2
TI  - Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a 
      Mendelian Randomization Study.
PG  - 407-416
LID - S0735-1097(15)07523-3 [pii]
LID - 10.1016/j.jacc.2015.10.086 [doi]
AB  - BACKGROUND: Although epidemiological studies have reported positive associations 
      between circulating urate levels and cardiometabolic diseases, causality remains 
      uncertain. OBJECTIVES: 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.
CI  - Copyright (c) 2016 American College of Cardiology Foundation. Published by Elsevier 
      Inc. All rights reserved.
FAU - Keenan, Tanya
AU  - Keenan T
AD  - Translational Medicine and Human Genetics, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, 
      Massachusetts General Hospital, Boston, Massachusetts.
FAU - Zhao, Wei
AU  - Zhao W
AD  - Translational Medicine and Human Genetics, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania.
FAU - Rasheed, Asif
AU  - Rasheed A
AD  - Center for Non-Communicable Diseases, Karachi, Pakistan.
FAU - Ho, Weang K
AU  - Ho WK
AD  - Department of Public Health and Primary Care, University of Cambridge, Cambridge, 
      United Kingdom.
FAU - Malik, Rainer
AU  - Malik R
AD  - Ludwig-Maximilians-University Munich, Medical Center, Institute for Stroke and 
      Dementia Research (ISD), Munich, Germany.
FAU - Felix, Janine F
AU  - Felix JF
AD  - Department 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.
FAU - Young, Robin
AU  - Young R
AD  - Department of Public Health and Primary Care, University of Cambridge, Cambridge, 
      United Kingdom.
FAU - Shah, Nabi
AU  - Shah N
AD  - Center for Non-Communicable Diseases, Karachi, Pakistan.
FAU - Samuel, Maria
AU  - Samuel M
AD  - Center for Non-Communicable Diseases, Karachi, Pakistan.
FAU - Sheikh, Nasir
AU  - Sheikh N
AD  - Department of Public Health and Primary Care, University of Cambridge, Cambridge, 
      United Kingdom.
FAU - Mucksavage, Megan L
AU  - Mucksavage ML
AD  - Translational Medicine and Human Genetics, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania.
FAU - Shah, Omar
AU  - Shah O
AD  - Translational Medicine and Human Genetics, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania.
FAU - Li, Jin
AU  - Li J
AD  - Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
FAU - Morley, Michael
AU  - Morley M
AD  - Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
FAU - Laser, Annika
AU  - Laser A
AD  - Research Unit of Molecular Epidemiology, Helmholtz Zentrum Munchen, Neuherberg, 
      Germany; Institute of Epidemiology II, Helmholtz Zentrum Munchen, Neuherberg, 
      Germany.
FAU - Mallick, Nadeem Hayat
AU  - Mallick NH
AD  - Punjab Institute of Cardiology, Lahore, Pakistan.
FAU - Zaman, Khan Shah
AU  - Zaman KS
AD  - National Institute of Cardiovascular Diseases, Karachi, Pakistan.
FAU - Ishaq, Mohammad
AU  - Ishaq M
AD  - Karachi Institute of Heart Diseases, Karachi, Pakistan.
FAU - Rasheed, Syed Zahed
AU  - Rasheed SZ
AD  - Karachi Institute of Heart Diseases, Karachi, Pakistan.
FAU - Memon, Fazal-Ur-Rehman
AU  - Memon FU
AD  - Red Crescent Institute of Cardiology, Hyderabad, Pakistan.
FAU - Ahmed, Faisal
AU  - Ahmed F
AD  - Department of Cardiology, Liaquat National Hospital, Karachi, Pakistan.
FAU - Hanif, Bashir
AU  - Hanif B
AD  - Department of Cardiology, Tabba Heart Institute, Karachi, Pakistan.
FAU - Lakhani, Muhammad Shakir
AU  - Lakhani MS
AD  - Department of Cardiology, Tabba Heart Institute, Karachi, Pakistan.
FAU - Fahim, Muhammad
AU  - Fahim M
AD  - Center for Non-Communicable Diseases, Karachi, Pakistan.
FAU - Ishaq, Madiha
AU  - Ishaq M
AD  - Center for Non-Communicable Diseases, Karachi, Pakistan.
FAU - Shardha, Naresh Kumar
AU  - Shardha NK
AD  - Center for Non-Communicable Diseases, Karachi, Pakistan.
FAU - Ahmed, Naveeduddin
AU  - Ahmed N
AD  - Department of Neurology, Liaquat National Hospital, Karachi, Pakistan.
FAU - Mahmood, Khalid
AU  - Mahmood K
AD  - Department of Medicine, Dow University of Health Sciences, Civil Hospital, 
      Karachi, Pakistan.
FAU - Iqbal, Waseem
AU  - Iqbal W
AD  - Department of Medicine, Lahore General Hospital, Lahore, Pakistan.
FAU - Akhtar, Saba
AU  - Akhtar S
AD  - Center for Non-Communicable Diseases, Karachi, Pakistan.
FAU - Raheel, Rabia
AU  - Raheel R
AD  - Center for Non-Communicable Diseases, Karachi, Pakistan.
FAU - O'Donnell, Christopher J
AU  - O'Donnell CJ
AD  - National 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.
FAU - Hengstenberg, Christian
AU  - Hengstenberg C
AD  - Internal Medicine II - Cardiology, University Hospital of Regensburg, Regensburg, 
      Germany.
FAU - Marz, Winifred
AU  - Marz W
AD  - Clinical 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.
FAU - Kathiresan, Sekar
AU  - Kathiresan S
AD  - Cardiovascular 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.
FAU - Samani, Nilesh
AU  - Samani N
AD  - Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences 
      Wing, Glenfield General Hospital, Leicester, United Kingdom.
FAU - Goel, Anuj
AU  - Goel A
AD  - Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, United 
      Kingdom.
FAU - Hopewell, Jemma C
AU  - Hopewell JC
AD  - Division of Cardiovascular Science, Oxford University, Oxford, United Kingdom.
FAU - Chambers, John
AU  - Chambers J
AD  - School of Public Health, Imperial College, London, United Kingdom.
FAU - Cheng, Yu-Ching
AU  - Cheng YC
AD  - Department of Medicine, University of Maryland School of Medicine, Baltimore VA 
      Medical Center, Baltimore, Maryland.
FAU - Sharma, Pankaj
AU  - Sharma P
AD  - Imperial College London & Hammersmith Hospitals, London, United Kingdom.
FAU - Yang, Qiong
AU  - Yang Q
AD  - School of Public Health, Boston University, Boston, Massachusetts.
FAU - Rosand, Jonathan
AU  - Rosand J
AD  - Division of Neurocritical Care, Massachusetts General Hospital, Boston, 
      Massachusetts.
FAU - Boncoraglio, Giorgio B
AU  - Boncoraglio GB
AD  - Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico, 
      Milan, Italy.
FAU - Kazmi, Shahana Urooj
AU  - Kazmi SU
AD  - Department of Microbiology, University of Karachi, Karachi, Pakistan.
FAU - Hakonarson, Hakon
AU  - Hakonarson H
AD  - Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
FAU - Kottgen, Anna
AU  - Kottgen A
AD  - Renal Division, University Medical Center Freiburg, University of Freiburg, 
      Freiburg, Germany; Department of Epidemiology, Johns Hopkins Bloomberg School of 
      Public Health, Baltimore, Maryland.
FAU - Kalogeropoulos, Andreas
AU  - Kalogeropoulos A
AD  - Division of Cardiology, School of Medicine, Emory University, Atlanta, Georgia.
FAU - Frossard, Philippe
AU  - Frossard P
AD  - Center for Non-Communicable Diseases, Karachi, Pakistan.
FAU - Kamal, Ayeesha
AU  - Kamal A
AD  - Division of Neurology, Department of Medicine, Aga Khan University, Karachi, 
      Pakistan.
FAU - Dichgans, Martin
AU  - Dichgans M
AD  - Ludwig-Maximilians-University Munich, Medical Center, Institute for Stroke and 
      Dementia Research (ISD), Munich, Germany.
FAU - Cappola, Thomas
AU  - Cappola T
AD  - Cardiovascular Division, Perelman School of Medicine at the University of 
      Pennsylvania, Philadelphia, Pennsylvania.
FAU - Reilly, Muredach P
AU  - Reilly MP
AD  - 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.
FAU - Danesh, John
AU  - Danesh J
AD  - Department of Public Health and Primary Care, University of Cambridge, Cambridge, 
      United Kingdom.
FAU - Rader, Daniel J
AU  - Rader DJ
AD  - Translational Medicine and Human Genetics, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, Pennsylvania.
FAU - Voight, Benjamin F
AU  - Voight BF
AD  - Department of Systems Pharmacology and Translational Therapeutics and Department 
      of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic 
      address: bvoight@upenn.edu.
FAU - Saleheen, Danish
AU  - Saleheen D
AD  - 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.
LA  - eng
GR  - R01 NS017950/NS/NINDS NIH HHS/United States
GR  - MR/L003120/1/MRC_/Medical Research Council/United Kingdom
GR  - RC2 HL101834/HL/NHLBI NIH HHS/United States
GR  - R01 HL093029/HL/NHLBI NIH HHS/United States
GR  - R01 DK101478/DK/NIDDK NIH HHS/United States
GR  - RG/08/014/24067/BHF_/British Heart Foundation/United Kingdom
GR  - N01HC25195/HL/NHLBI NIH HHS/United States
GR  - WT_/Wellcome Trust/United Kingdom
GR  - RC1 TW008485/TW/FIC NIH HHS/United States
GR  - R21 NS064908/NS/NINDS NIH HHS/United States
GR  - R01 HL087676/HL/NHLBI NIH HHS/United States
GR  - RG/13/13/30194/BHF_/British Heart Foundation/United Kingdom
GR  - U01 HL096917/HL/NHLBI NIH HHS/United States
GR  - R01 AG033193/AG/NIA NIH HHS/United States
GR  - U01 NS069208/NS/NINDS NIH HHS/United States
GR  - U54 RR020278/RR/NCRR NIH HHS/United States
GR  - FS/14/55/30806/BHF_/British Heart Foundation/United Kingdom
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Am Coll Cardiol
JT  - Journal of the American College of Cardiology
JID - 8301365
RN  - 268B43MJ25 (Uric Acid)
SB  - IM
CIN - J Am Coll Cardiol. 2016 Feb 2;67(4):417-9. PMID: 26821630
CIN - J Thorac Dis. 2016 Nov;8(11):E1462-E1466. PMID: 28066631
MH  - Coronary Disease/blood/epidemiology/*genetics
MH  - Diabetes Mellitus, Type 2/blood/epidemiology/*genetics
MH  - Global Health
MH  - Humans
MH  - Mendelian Randomization Analysis/*methods
MH  - Morbidity/trends
MH  - Odds Ratio
MH  - *Polymorphism, Single Nucleotide
MH  - Prognosis
MH  - Risk Assessment/*methods
MH  - Risk Factors
MH  - Stroke/blood/epidemiology/*genetics
MH  - Uric Acid/*blood
PMC - PMC5503188
MID - NIHMS874624
OTO - NOTNLM
OT  - genetic
OT  - pleiotropy
OT  - single nucleotide polymorphism
EDAT- 2016/01/30 06:00
MHDA- 2016/06/01 06:00
PMCR- 2017/07/10
CRDT- 2016/01/30 06:00
PHST- 2015/08/12 00:00 [received]
PHST- 2015/10/27 00:00 [accepted]
PHST- 2016/01/30 06:00 [entrez]
PHST- 2016/01/30 06:00 [pubmed]
PHST- 2016/06/01 06:00 [medline]
PHST- 2017/07/10 00:00 [pmc-release]
AID - S0735-1097(15)07523-3 [pii]
AID - 10.1016/j.jacc.2015.10.086 [doi]
PST - ppublish
SO  - J Am Coll Cardiol. 2016 Feb 2;67(4):407-416. doi: 10.1016/j.jacc.2015.10.086.