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

Tanya Keenan; Wei Zhao; Asif Rasheed; Weang K. Ho; Rainer Malik; Janine F. Felix; Robin Young; Nabi Shah; Maria Samuel; Nasir Sheikh; Megan L Mucksavage; Omar Shah; Michael Morley; Annika Laser; Nadeem Hayat Mallick; Khan Shah Zaman; Mohammad Ishaq; Syed Zahed Rasheed; Fazal-Ur-Rehman Memon; Faisal Ahmed; Bashir Hanif; Muhammad Shakir Lakhani; Muhammad Fahim; Madiha Ishaq; Naresh Kumar Shardha; Naveeduddin Ahmed; Khalid Mahmood; Waseem Iqbal; Saba Akhtar; Rabia Raheel; Christopher J. O'Donnell; Christian Hengstenberg; Winifred März; Sekar Kathiresan; Nilesh Samani; Anuj Goel; Jemma C. Hopewell; John Chambers; Yu-Ching Cheng; Pankaj Sharma; Qiong Yang; Jonathan Rosand; Giorgio B. Boncoraglio; Shahana Urooj Kazmi; Hakon Hakonarson; Anna Köttgen; Andreas Kalogeropoulos; Philippe Frossard; Ayeesha Kamal; Martin Dichgans; Thomas P. Cappola; Muredach P. Reilly; John Danesh; Daniel J. Rader; Benjamin F. Voight; Danish Saleheen

doi:10.1016/j.jacc.2015.10.086

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

Tanya Keenan, Wei Zhao, Asif Rasheed, Weang K. Ho, Rainer Malik, Janine F. Felix, Robin Young, Nabi Shah, Maria Samuel, Nasir Sheikh, Megan L Mucksavage, Omar Shah, Michael Morley, Annika Laser, Nadeem Hayat Mallick, Khan Shah Zaman, Mohammad Ishaq, Syed Zahed Rasheed, Fazal-Ur-Rehman Memon, Faisal AhmedBashir Hanif, Muhammad Shakir Lakhani, Muhammad Fahim, Madiha Ishaq, Naresh Kumar Shardha, Naveeduddin Ahmed, Khalid Mahmood, Waseem Iqbal, Saba Akhtar, Rabia Raheel, Christopher J. O'Donnell, Christian Hengstenberg, Winifred März, Sekar Kathiresan, Nilesh Samani, Anuj Goel, Jemma C. Hopewell, John Chambers, Yu-Ching Cheng, Pankaj Sharma, Qiong Yang, Jonathan Rosand, Giorgio B. Boncoraglio, Shahana Urooj Kazmi, Hakon Hakonarson, Anna Köttgen, Andreas Kalogeropoulos, Philippe Frossard, Ayeesha Kamal, Martin Dichgans, Thomas P. Cappola, Muredach P. Reilly, John Danesh, Daniel J. Rader, Benjamin F. Voight, Danish Saleheen (Lead / Corresponding author)

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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.

Original language	English
Pages (from-to)	407-416
Number of pages	10
Journal	Journal of the American College of Cardiology
Volume	67
Issue number	4
Early online date	25 Jan 2016
DOIs	https://doi.org/10.1016/j.jacc.2015.10.086
Publication status	Published - 2 Feb 2016

Keywords

Coronary Disease/blood
Diabetes Mellitus, Type 2/blood
Global Health
Humans
Mendelian Randomization Analysis/methods
Morbidity/trends
Odds Ratio
Polymorphism, Single Nucleotide
Prognosis
Risk Assessment/methods
Risk Factors
Stroke/blood
Uric Acid/blood

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jacc.2015.10.086

Cite this

Keenan, T., Zhao, W., Rasheed, A., Ho, W. K., Malik, R., Felix, J. F., Young, R., Shah, N., Samuel, M., Sheikh, N., Mucksavage, M. L., Shah, O., Morley, M., Laser, A., Mallick, N. H., Zaman, K. S., Ishaq, M., Rasheed, S. Z., Memon, F.-U.-R., ... Saleheen, D. (2016). Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study. Journal of the American College of Cardiology, 67(4), 407-416. https://doi.org/10.1016/j.jacc.2015.10.086

@article{2c74277418d24bbe88b202de406c2b92,

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.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 = "Coronary Disease/blood, Diabetes Mellitus, Type 2/blood, Global Health, Humans, Mendelian Randomization Analysis/methods, Morbidity/trends, Odds Ratio, Polymorphism, Single Nucleotide, Prognosis, Risk Assessment/methods, Risk Factors, Stroke/blood, Uric Acid/blood",

author = "Tanya Keenan and Wei Zhao and Asif Rasheed and Ho, {Weang K.} and Rainer Malik and Felix, {Janine F.} and Robin Young and Nabi Shah and Maria Samuel and Nasir Sheikh and Mucksavage, {Megan L} and Omar Shah and Michael Morley and Annika Laser and Mallick, {Nadeem Hayat} and Zaman, {Khan Shah} and Mohammad Ishaq and Rasheed, {Syed Zahed} and Fazal-Ur-Rehman Memon and Faisal Ahmed and Bashir Hanif and Lakhani, {Muhammad Shakir} and Muhammad Fahim and Madiha Ishaq and Shardha, {Naresh Kumar} and Naveeduddin Ahmed and Khalid Mahmood and Waseem Iqbal and Saba Akhtar and Rabia Raheel and O'Donnell, {Christopher J.} and Christian Hengstenberg and Winifred M{\"a}rz and Sekar Kathiresan and Nilesh Samani and Anuj Goel and Hopewell, {Jemma C.} and John Chambers and Yu-Ching Cheng and Pankaj Sharma and Qiong Yang and Jonathan Rosand and Boncoraglio, {Giorgio B.} and Kazmi, {Shahana Urooj} and Hakon Hakonarson and Anna K{\"o}ttgen and Andreas Kalogeropoulos and Philippe Frossard and Ayeesha Kamal and Martin Dichgans and Cappola, {Thomas P.} and Reilly, {Muredach P.} and John Danesh and Rader, {Daniel J.} and Voight, {Benjamin F.} and Danish Saleheen",

year = "2016",

month = feb,

day = "2",

doi = "10.1016/j.jacc.2015.10.086",

language = "English",

volume = "67",

pages = "407--416",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier",

number = "4",

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Keenan, T, Zhao, W, Rasheed, A, Ho, WK, Malik, R, Felix, JF, Young, R, Shah, N, Samuel, M, Sheikh, N, Mucksavage, ML, Shah, O, Morley, M, Laser, A, Mallick, NH, Zaman, KS, Ishaq, M, Rasheed, SZ, Memon, F-U-R, Ahmed, F, Hanif, B, Lakhani, MS, Fahim, M, Ishaq, M, Shardha, NK, Ahmed, N, Mahmood, K, Iqbal, W, Akhtar, S, Raheel, R, O'Donnell, CJ, Hengstenberg, C, März, W, Kathiresan, S, Samani, N, Goel, A, Hopewell, JC, Chambers, J, Cheng, Y-C, Sharma, P, Yang, Q, Rosand, J, Boncoraglio, GB, Kazmi, SU, Hakonarson, H, Köttgen, A, Kalogeropoulos, A, Frossard, P, Kamal, A, Dichgans, M, Cappola, TP, Reilly, MP, Danesh, J, Rader, DJ, Voight, BF & Saleheen, D 2016, 'Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study', Journal of the American College of Cardiology, vol. 67, no. 4, pp. 407-416. https://doi.org/10.1016/j.jacc.2015.10.086

TY - JOUR

T1 - Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study

AU - Keenan, Tanya

AU - Zhao, Wei

AU - Rasheed, Asif

AU - Ho, Weang K.

AU - Malik, Rainer

AU - Felix, Janine F.

AU - Young, Robin

AU - Shah, Nabi

AU - Samuel, Maria

AU - Sheikh, Nasir

AU - Mucksavage, Megan L

AU - Shah, Omar

AU - Morley, Michael

AU - Laser, Annika

AU - Mallick, Nadeem Hayat

AU - Zaman, Khan Shah

AU - Ishaq, Mohammad

AU - Rasheed, Syed Zahed

AU - Memon, Fazal-Ur-Rehman

AU - Ahmed, Faisal

AU - Hanif, Bashir

AU - Lakhani, Muhammad Shakir

AU - Fahim, Muhammad

AU - Ishaq, Madiha

AU - Shardha, Naresh Kumar

AU - Ahmed, Naveeduddin

AU - Mahmood, Khalid

AU - Iqbal, Waseem

AU - Akhtar, Saba

AU - Raheel, Rabia

AU - O'Donnell, Christopher J.

AU - Hengstenberg, Christian

AU - März, Winifred

AU - Kathiresan, Sekar

AU - Samani, Nilesh

AU - Goel, Anuj

AU - Hopewell, Jemma C.

AU - Chambers, John

AU - Cheng, Yu-Ching

AU - Sharma, Pankaj

AU - Yang, Qiong

AU - Rosand, Jonathan

AU - Boncoraglio, Giorgio B.

AU - Kazmi, Shahana Urooj

AU - Hakonarson, Hakon

AU - Köttgen, Anna

AU - Kalogeropoulos, Andreas

AU - Frossard, Philippe

AU - Kamal, Ayeesha

AU - Dichgans, Martin

AU - Cappola, Thomas P.

AU - Reilly, Muredach P.

AU - Danesh, John

AU - Rader, Daniel J.

AU - Voight, Benjamin F.

AU - Saleheen, Danish

PY - 2016/2/2

Y1 - 2016/2/2

N2 - 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.

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.

KW - Coronary Disease/blood

KW - Diabetes Mellitus, Type 2/blood

KW - Global Health

KW - Humans

KW - Mendelian Randomization Analysis/methods

KW - Morbidity/trends

KW - Odds Ratio

KW - Polymorphism, Single Nucleotide

KW - Prognosis

KW - Risk Assessment/methods

KW - Risk Factors

KW - Stroke/blood

KW - Uric Acid/blood

U2 - 10.1016/j.jacc.2015.10.086

DO - 10.1016/j.jacc.2015.10.086

M3 - Article

C2 - 26821629

SN - 0735-1097

VL - 67

SP - 407

EP - 416

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 4

ER -

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

Abstract

Keywords

UN SDGs

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