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

孟德尔随机化 医学 内科学 痛风 优势比 冲程(发动机) 混淆 单核苷酸多态性 糖尿病 高尿酸血症 心脏病学 内分泌学 尿酸 基因型 遗传学 遗传变异 基因 工程类 生物 机械工程
作者
Tanya E. Keenan,Wei Zhao,Asif Rasheed,Weang-Kee Ho,Rainer Malik,Janine F. Felix,Robin Young,Nabi Shah,Maria Samuel,Nasir Sheikh,Megan Mucksavage,Omar J. Shah,Jin Li,Michael P. 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,W. März,Sekar Kathiresan,Nilesh J. Samani,Anuj Goel,Jemma C. Hopewell,John C Chambers,Yu-Ching Cheng,Pankaj Sharma,Qiong Yang,Jonathan Rosand,Giorgio B. Boncoraglio,Shahana Urooj Kazmi,Håkon Håkonarson,Anna Köttgen,Andreas P. Kalogeropoulos,Philippe Frossard,Ayeesha Kamran Kamal,Martin Dichgans,Thomas P. Cappola,Muredach P. Reilly,John Danesh,Daniel J. Rader,Benjamin F. Voight,Danish Saleheen
出处
期刊:Journal of the American College of Cardiology [Elsevier BV]
卷期号:67 (4): 407-416 被引量:154
标识
DOI:10.1016/j.jacc.2015.10.086
摘要

Although epidemiological studies have reported positive associations between circulating urate levels and cardiometabolic diseases, causality remains uncertain.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).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.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.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.
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