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J Am Coll Cardiol. 2016 Feb 2;67(4):407-416. doi: 10.1016/j.jacc.2015.10.086.

Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study.

Author information

1
Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
2
Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
3
Center for Non-Communicable Diseases, Karachi, Pakistan.
4
Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
5
Ludwig-Maximilians-University Munich, Medical Center, Institute for Stroke and Dementia Research (ISD), Munich, Germany.
6
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.
7
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
8
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
9
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany.
10
Punjab Institute of Cardiology, Lahore, Pakistan.
11
National Institute of Cardiovascular Diseases, Karachi, Pakistan.
12
Karachi Institute of Heart Diseases, Karachi, Pakistan.
13
Red Crescent Institute of Cardiology, Hyderabad, Pakistan.
14
Department of Cardiology, Liaquat National Hospital, Karachi, Pakistan.
15
Department of Cardiology, Tabba Heart Institute, Karachi, Pakistan.
16
Department of Neurology, Liaquat National Hospital, Karachi, Pakistan.
17
Department of Medicine, Dow University of Health Sciences, Civil Hospital, Karachi, Pakistan.
18
Department of Medicine, Lahore General Hospital, Lahore, Pakistan.
19
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.
20
Internal Medicine II - Cardiology, University Hospital of Regensburg, Regensburg, Germany.
21
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.
22
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.
23
Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield General Hospital, Leicester, United Kingdom.
24
Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, United Kingdom.
25
Division of Cardiovascular Science, Oxford University, Oxford, United Kingdom.
26
School of Public Health, Imperial College, London, United Kingdom.
27
Department of Medicine, University of Maryland School of Medicine, Baltimore VA Medical Center, Baltimore, Maryland.
28
Imperial College London & Hammersmith Hospitals, London, United Kingdom.
29
School of Public Health, Boston University, Boston, Massachusetts.
30
Division of Neurocritical Care, Massachusetts General Hospital, Boston, Massachusetts.
31
Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico, Milan, Italy.
32
Department of Microbiology, University of Karachi, Karachi, Pakistan.
33
Renal Division, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
34
Division of Cardiology, School of Medicine, Emory University, Atlanta, Georgia.
35
Division of Neurology, Department of Medicine, Aga Khan University, Karachi, Pakistan.
36
Cardiovascular Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
37
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.
38
Department of Systems Pharmacology and Translational Therapeutics and Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: bvoight@upenn.edu.
39
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.

Abstract

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.

KEYWORDS:

genetic; pleiotropy; single nucleotide polymorphism

PMID:
26821629
PMCID:
PMC5503188
DOI:
10.1016/j.jacc.2015.10.086
[Indexed for MEDLINE]
Free PMC Article

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