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 - Li, Jin
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
AU - Reilly, Muredach P.
AU - Danesh, John
AU - Rader, Daniel J.
AU - Voight, Benjamin F.
AU - Saleheen, Danish
N1 - Publisher Copyright:
© 2016 American College of Cardiology Foundation.
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 - genetic
KW - pleiotropy
KW - single nucleotide polymorphism
UR - https://www.scopus.com/pages/publications/84959420157
U2 - 10.1016/j.jacc.2015.10.086
DO - 10.1016/j.jacc.2015.10.086
M3 - Article
C2 - 26821629
AN - SCOPUS:84959420157
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 -