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Multicenter Study
. 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

Tanya Keenan  1 , Wei Zhao  2 , Asif Rasheed  3 , Weang K Ho  4 , Rainer Malik  5 , Janine F Felix  6 , Robin Young  4 , Nabi Shah  3 , Maria Samuel  3 , Nasir Sheikh  4 , Megan L Mucksavage  2 , Omar Shah  2 , Jin Li  7 , Michael Morley  8 , Annika Laser  9 , Nadeem Hayat Mallick  10 , Khan Shah Zaman  11 , Mohammad Ishaq  12 , Syed Zahed Rasheed  12 , Fazal-Ur-Rehman Memon  13 , Faisal Ahmed  14 , Bashir Hanif  15 , Muhammad Shakir Lakhani  15 , Muhammad Fahim  3 , Madiha Ishaq  3 , Naresh Kumar Shardha  3 , Naveeduddin Ahmed  16 , Khalid Mahmood  17 , Waseem Iqbal  18 , Saba Akhtar  3 , Rabia Raheel  3 , Christopher J O'Donnell  19 , Christian Hengstenberg  20 , Winifred März  21 , Sekar Kathiresan  22 , Nilesh Samani  23 , Anuj Goel  24 , Jemma C Hopewell  25 , John Chambers  26 , Yu-Ching Cheng  27 , Pankaj Sharma  28 , Qiong Yang  29 , Jonathan Rosand  30 , Giorgio B Boncoraglio  31 , Shahana Urooj Kazmi  32 , Hakon Hakonarson  7 , Anna Köttgen  33 , Andreas Kalogeropoulos  34 , Philippe Frossard  3 , Ayeesha Kamal  35 , Martin Dichgans  5 , Thomas Cappola  36 , Muredach P Reilly  37 , John Danesh  4 , Daniel J Rader  2 , Benjamin F Voight  38 , Danish Saleheen  39
Affiliations
Multicenter Study

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

Tanya Keenan et al. J Am Coll Cardiol. .

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.

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Figures

Figure 1
Figure 1
Association of Urate Genetic Score with Potential Confounders
Figure 2
Figure 2
Associations of Non-Pleiotropic Urate Variants with Serum Urate, Gout, and Type 2 Diabetes
Figure 3
Figure 3
Associations of Non-Pleiotropic Urate Variants with Coronary Artery Disease, Ischemic Stroke, and Heart Failure
Figure 4
Figure 4
Association of Genetically Raised Urate with Cardiometabolic Outcomes Using Multiple Genetic Variants
See this image and copyright information in PMC

Comment in

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