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

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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.

Key Words

genetic
pleiotropy
single nucleotide polymorphism

Abbreviations and Acronyms

CHD
coronary heart disease
GRS
genetic risk score
HF
heart failure
MR
Mendelian randomization
SNP
single nucleotide polymorphism
T2DM
type 2 diabetes mellitus

Cited by (0)

Dr. Saleheen has received funding from the National Institutes of Health, the Fogarty International, the Wellcome Trust, the British Heart Foundation and Pfizer. Dr. Voight was supported by a Fellowship from the Alfred P. Sloan Foundation (BR2012-087), and has received funding from the American Heart Association (13SDG14330006), and the W.W. Smith Charitable Trust (H1201). Acknowledgments by studies that contributed data to the analyses are as follows: PROMIS and RACE. Dr. Saleheen is the PI of the PROMIS and RACE studies. Genotyping in PROMIS was funded by the Wellcome Trust, UK and Pfizer. Biomarker assays in PROMIS have been funded through grants awarded by the NIH (RC2HL101834 and RC1TW008485) and the Fogarty International (RC1TW008485). The RACE study has been funded by the National Institute of Neurological Disorders (R21NS064908), the Fogarty International (R21NS064908), and the Center for Non-Communicable Diseases, Karachi, Pakistan. Dr. Kathiresian has received research grants from Regeneron, Bayer, and Aegerion; is a consultant with Novartis, Aegerion, Bristol-Myers Squibb, Sanofi, AstraZeneca, Alhylam, Lilly, Leerink Partners, Merck, and Noble Insights; has received SAB from Catabasis, Regeneron Genetics Center, Merck, and Celera; and has equity with San Therapeutics and Catabasis. Dr. Thomas is a DSMB member with Novartis; and has received lab assays from BG Medicine. Dr. Danesh is a consultant with Takeda; a member of the Novartis Cardiovascular & Metabolic Advisory Board; a member of the International Cardiovascular and Metabolism Research and Development portfolio committee at Novartis; a member of the Merck Sharp & Dohme UK Atherosclerosis Advisory Board; a member of Sanofi Advisory Board; and has received funding from the British Heart Foundation, BUPA Foundation, diaDexus, European Research Council, European Union, Evelyn Trust, Fogarty International Centre, GlaxoSmithKline, Merck, National Heart, Lung, and Blood Institute, National Health Service Blood and Transplant, National Institute for Health Research, National Institute of Neurological Disorders and Stroke, Novartis, Pfizer, Roche, Sanofi, Takeda, The Wellcome Trust, UK Biobank, University of British Columbia, and the UK Medical Research Council. Studies participating in the METASTROKE consortium: The MGH Genes Affecting Stroke Risk and Outcome Study (MGH-GASROS). GASROS was supported by the National Institute of Neurological Disorders and Stroke (U01 NS069208), the American Heart Association/Bugher Foundation Centers for Stroke Prevention Research 0775010N, the National Institutes of Health and National Heart, Lung, and Blood Institute's STAMPEED genomics research program (R01 HL087676), and a grant from the National Center for Research Resources. The Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research resources. CHARGE–Stroke data. This work was supported by the dedication of the Framingham Heart Study participants, the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195), and by grants from the National Institute of Neurological Disorders and Stroke (NS17950), the National Institute of Aging (AG033193), the and the National Heart, Lung, and Blood Association (HL93029, U01HL 096917). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke, the National Heart, Lung, and Blood Institute, the National Institute of Aging, or the National Institutes of Health. BRAINS. Pankaj Sharma is supported by a Department of Health (UK) Senior Fellowship. BRAINS is supported by grants from British Council (UK-India Education and Research Initiative), Henry Smith Charity, and Qatar National Research Fund. Funding support for GEOS was provided by NIH grants U01-HG004436 and U01-NS069208. CHARGE Heart Failure Consortium. At the time of preparation of the manuscript, Janine F Felix was working in Erasmus AGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA. These funding sources had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review or approval of the manuscript. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Dr. Keenan and Mr. Zhao are joint first authors. Dr. Voight and Dr. Saleheen are joint senior authors.

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