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

被引：154

作者：

Keenan, Tanya ^{[1
,2
]}

Zhao, Wei ^{[1
]}

Rasheed, Asif ^{[3
]}

Ho, Weang K. ^{[4
]}

Malik, Rainer ^{[5
]}

Felix, Janine F. ^{[6
,7
]}

Young, Robin ^{[4
]}

Shah, Nabi ^{[3
]}

Samuel, Maria ^{[3
]}

Sheikh, Nasir ^{[4
]}

Mucksavage, Megan L. ^{[1
]}

Shah, Omar ^{[1
]}

Li, Jin ^{[8
]}

Morley, Michael ^{[9
]}

Laser, Annika ^{[10
,11
]}

Mallick, Nadeem Hayat ^{[12
]}

Zaman, Khan Shah ^{[13
]}

Ishaq, Mohammad ^{[14
]}

Rasheed, Syed Zahed ^{[14
]}

Memon, Fazal-ur-Rehman ^{[15
]}

Ahmed, Faisal ^{[16
]}

Hanif, Bashir ^{[17
]}

Lakhani, Muhammad Shakir ^{[17
]}

Fahim, Muhammad ^{[3
]}

Ishaq, Madiha ^{[3
]}

Shardha, Naresh Kumar ^{[3
]}

Ahmed, Naveeduddin ^{[18
]}

Mahmood, Khalid ^{[19
]}

Iqbal, Waseem ^{[20
]}

Akhtar, Saba ^{[3
]}

Raheel, Rabia ^{[3
]}

O'Donnell, Christopher J. ^{[21
,22
,23
]}

Hengstenberg, Christian ^{[24
]}

Maerz, Winifred ^{[25
,26
,27
,28
]}

Kathiresan, Sekar ^{[1
,2
,22
,23
,29
,30
]}

Samani, Nilesh ^{[31
]}

Goel, Anuj ^{[32
]}

Hopewell, Jemma C. ^{[33
]}

Chambers, John ^{[34
]}

Cheng, Yu-Ching ^{[35
]}

Sharma, Pankaj ^{[36
,37
]}

Yang, Qiong ^{[38
]}

Rosand, Jonathan ^{[39
]}

Boncoraglio, Giorgio B. ^{[40
]}

Kazmi, Shahana Urooj ^{[41
]}

Hakonarson, Hakon ^{[8
]}

Koettgen, Anna ^{[42
,43
]}

Kalogeropoulos, Andreas ^{[44
]}

Frossard, Philippe ^{[3
]}

Kamal, Ayeesha ^{[45
]}

机构：

[1] Univ Penn, Translat Med & Human Genet, Perelman Sch Med, Philadelphia, PA 19104 USA

[2] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA

[3] Ctr Noncommunicable Dis, Karachi, Pakistan

[4] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England

[5] Univ Munich, Med Ctr, Inst Stroke & Dementia Res ISD, Munich, Germany

[6] Erasmus MC, Dept Epidemiol, Univ Med Ctr Rotterdam, Amsterdam, Netherlands

[7] NGI NCHA, Leiden, Netherlands

[8] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[9] Univ Penn, Dept Med, Philadelphia, PA 19104 USA

[10] Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany

[11] Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany

[12] Punjab Inst Cardiol, Lahore, Pakistan

[13] Natl Inst Cardiovasc Dis, Karachi, Pakistan

[14] Karachi Inst Heart Dis, Karachi, Pakistan

[15] Red Crescent Inst Cardiol, Hyderabad, Andhra Pradesh, Pakistan

[16] Liaquat Natl Hosp, Dept Cardiol, Karachi, Pakistan

[17] Tabba Heart Inst, Dept Cardiol, Karachi, Pakistan

[18] Liaquat Natl Hosp, Dept Neurol, Karachi, Pakistan

[19] Dow Univ Hlth Sci, Civil Hosp, Dept Med, Karachi, Pakistan

[20] Lahore Gen Hosp, Dept Med, Lahore, Pakistan

[21] NHLBI, Framingham Heart Study, Framingham, MA USA

[22] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA

[23] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[24] Univ Hosp Regensburg, Internal Med Cardiol 2, Regensburg, Germany

[25] Med Univ Graz, Clin Inst Med, Graz, Austria

[26] Med Univ Graz, Chem Lab Diagnost, Graz, Austria

[27] Heidelberg Univ, Mannheim Med Fac, Med Clin 5, Mannheim, Germany

[28] Synlab Lab Serv GmbH, Synlab Acad, Mannheim, Germany

[29] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[30] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[31] Univ Leicester, Glenfield Gen Hosp, Dept Cardiovasc Sci, Clin Sci Wing, Leicester, Leics, England

[32] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[33] Univ Oxford, Div Cardiovasc Sci, Oxford, England

[34] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England

[35] Univ Maryland, Sch Med, Dept Med, Baltimore VA Med Ctr, Baltimore, MD 21201 USA

[36] Univ London Imperial Coll Sci Technol & Med, London, England

[37] Hammersmith Hosp, London, England

[38] Boston Univ, Sch Publ Hlth, Boston, MA USA

[39] Massachusetts Gen Hosp, Div Neurocrit Care, Boston, MA 02114 USA

[40] Fdn IRCCS Ist Neurol, Dept Cerebrovasc Dis, Milan, Italy

[41] Univ Karachi, Dept Microbiol, Karachi, Pakistan

[42] Univ Freiburg, Renal Div, Univ Med Ctr Freiburg, Hugstetter Str 55, D-79106 Freiburg, Germany

[43] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[44] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA

[45] Aga Khan Univ, Div Neurol, Dept Med, Karachi, Pakistan

[46] Univ Penn, Cardiovasc Div, Perelman Sch Med, Philadelphia, PA 19104 USA

[47] Univ Penn, Dept Syst Pharmacol & Translat Therapeut, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA

[48] Univ Penn, Dept Genet, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA

[49] Univ Penn, Dept Biostat & Epidemiol, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA

来源：

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY | 2016年 / 67卷 / 04期

关键词：

genetic; pleiotropy; single nucleotide polymorphism; GENOME-WIDE ASSOCIATION; ISCHEMIC-HEART-DISEASE; URIC-ACID; GENETIC-VARIANTS; COMMON VARIANTS; BLOOD-PRESSURE; INCREASED RISK; LOCI; HYPERURICEMIA; METAANALYSIS;

D O I：

10.1016/j.jacc.2015.10.086

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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. (C) 2016 by the American College of Cardiology Foundation.

引用

页码：407 / 416

页数：10

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