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

被引：148

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

共 49 条

[1] Hundreds of variants clustered in genomic loci and biological pathways affect human height
Allen, Hana Lango
Estrada, Karol
Lettre, Guillaume
Berndt, Sonja I.
Weedon, Michael N.
Rivadeneira, Fernando
Willer, Cristen J.
Jackson, Anne U.
Vedantam, Sailaja
Raychaudhuri, Soumya
Ferreira, Teresa
Wood, Andrew R.
Weyant, Robert J.
Segre, Ayellet V.
Speliotes, Elizabeth K.
Wheeler, Eleanor
Soranzo, Nicole
Park, Ju-Hyun
Yang, Jian
Gudbjartsson, Daniel
Heard-Costa, Nancy L.
Randall, Joshua C.
Qi, Lu
Smith, Albert Vernon
Maegi, Reedik
Pastinen, Tomi
Liang, Liming
Heid, Iris M.
Luan, Jian'an
Thorleifsson, Gudmar
Winkler, Thomas W.
Goddard, Michael E.
Lo, Ken Sin
Palmer, Cameron
Workalemahu, Tsegaselassie
Aulchenko, Yurii S.
Johansson, Asa
Zillikens, M. Carola
Feitosa, Mary F.
Esko, Tonu
Johnson, Toby
Ketkar, Shamika
Kraft, Peter
Mangino, Massimo
Prokopenko, Inga
Absher, Devin
Albrecht, Eva
Ernst, Florian
Glazer, Nicole L.
Hayward, Caroline
[J]. NATURE, 2010, 467 (7317) : 832 - 838
[2] A map of human genome variation from population-scale sequencing
Altshuler, David
Durbin, Richard M.
Abecasis, Goncalo R.
Bentley, David R.
Chakravarti, Aravinda
Clark, Andrew G.
Collins, Francis S.
De la Vega, Francisco M.
Donnelly, Peter
Egholm, Michael
Flicek, Paul
Gabriel, Stacey B.
Gibbs, Richard A.
Knoppers, Bartha M.
Lander, Eric S.
Lehrach, Hans
Mardis, Elaine R.
McVean, Gil A.
Nickerson, DebbieA.
Peltonen, Leena
Schafer, Alan J.
Sherry, Stephen T.
Wang, Jun
Wilson, Richard K.
Gibbs, Richard A.
Deiros, David
Metzker, Mike
Muzny, Donna
Reid, Jeff
Wheeler, David
Wang, Jun
Li, Jingxiang
Jian, Min
Li, Guoqing
Li, Ruiqiang
Liang, Huiqing
Tian, Geng
Wang, Bo
Wang, Jian
Wang, Wei
Yang, Huanming
Zhang, Xiuqing
Zheng, Huisong
Lander, Eric S.
Altshuler, David L.
Ambrogio, Lauren
Bloom, Toby
Cibulskis, Kristian
Fennell, Tim J.
Gabriel, Stacey B.
[J]. NATURE, 2010, 467 (7319) : 1061 - 1073
[3] [Anonymous], AM J MED
[4] Epidemiology of Gout in Women Fifty-two-Year Followup of a Prospective Cohort
Bhole, Vidula
de Vera, Mary
Rahman, M. Mushfiqur
Krishnan, Eswar
Choi, Hyon
[J]. ARTHRITIS AND RHEUMATISM, 2010, 62 (04): : 1069 - 1076
[5] Hyperuricemia and increased risk of ischemic heart disease in a large Chinese cohort
Chuang, Shao-Yuan
Chen, Jiunn-Horng
Yeh, Wen-Ting
Wu, Chih-Cheng
Pan, Wen-Harn
[J]. INTERNATIONAL JOURNAL OF CARDIOLOGY, 2012, 154 (03) : 316 - 321
[6] Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease
Clarke, Robert
Peden, John F.
Hopewell, Jemma C.
Kyriakou, Theodosios
Goel, Anuj
Heath, Simon C.
Parish, Sarah
Barlera, Simona
Franzosi, Maria Grazia
Rust, Stephan
Bennett, Derrick
Silveira, Angela
Malarstig, Anders
Green, Fiona R.
Lathrop, Mark
Gigante, Bruna
Leander, Karin
de Faire, Ulf
Seedorf, Udo
Hamsten, Anders
Collins, Rory
Watkins, Hugh
Farrall, Martin
[J]. NEW ENGLAND JOURNAL OF MEDICINE, 2009, 361 (26) : 2518 - 2528
[7] Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals
Dastani, Zari
Hivert, Marie-France
Timpson, Nicholas
Perry, John R. B.
Yuan, Xin
Scott, Robert A.
Henneman, Peter
Heid, Iris M.
Kizer, Jorge R.
Lyytikainen, Leo-Pekka
Fuchsberger, Christian
Tanaka, Toshiko
Morris, Andrew P.
Small, Kerrin
Isaacs, Aaron
Beekman, Marian
Coassin, Stefan
Lohman, Kurt
Qi, Lu
Kanoni, Stavroula
Pankow, James S.
Uh, Hae-Won
Wu, Ying
Bidulescu, Aurelian
Rasmussen-Torvik, Laura J.
Greenwood, Celia M. T.
Ladouceur, Martin
Grimsby, Jonna
Manning, Alisa K.
Liu, Ching-Ti
Kooner, Jaspal
Mooser, Vincent E.
Vollenweider, Peter
Kapur, Karen A.
Chambers, John
Wareham, Nicholas J.
Langenberg, Claudia
Frants, Rune
Willems-vanDijk, Ko
Oostra, Ben A.
Willems, Sara M.
Lamina, Claudia
Winkler, Thomas W.
Psaty, Bruce M.
Tracy, Russell P.
Brody, Jennifer
Chen, Ida
Viikari, Jorma
Kahonen, Mika
Pramstaller, Peter P.
[J]. PLOS GENETICS, 2012, 8 (03):
[8] Large-scale association analysis identifies new risk loci for coronary artery disease
Deloukas, Panos
Kanoni, Stavroula
Willenborg, Christina
Farrall, Martin
Assimes, Themistocles L.
Thompson, John R.
Ingelsson, Erik
Saleheen, Danish
Erdmann, Jeanette
Goldstein, Benjamin A.
Stirrups, Kathleen
Koenig, Inke R.
Cazier, Jean-Baptiste
Johansson, Asa
Hall, Alistair S.
Lee, Jong-Young
Willer, Cristen J.
Chambers, John C.
Esko, Tonu
Folkersen, Lasse
Goel, Anuj
Grundberg, Elin
Havulinna, Aki S.
Ho, Weang K.
Hopewell, Jemma C.
Eriksson, Niclas
Kleber, Marcus E.
Kristiansson, Kati
Lundmark, Per
Lyytikainen, Leo-Pekka
Rafelt, Suzanne
Shungin, Dmitry
Strawbridge, Rona J.
Thorleifsson, Gudmar
Tikkanen, Emmi
Van Zuydam, Natalie
Voight, Benjamin F.
Waite, Lindsay L.
Zhang, Weihua
Ziegler, Andreas
Absher, Devin
Altshuler, David
Balmforth, Anthony J.
Barroso, Ines
Braund, Peter S.
Burgdorf, Christof
Claudi-Boehm, Simone
Cox, David
Dimitriou, Maria
Do, Ron
[J]. NATURE GENETICS, 2013, 45 (01) : 25 - U52
[9] New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk
Dupuis, Josee
Langenberg, Claudia
Prokopenko, Inga
Saxena, Richa
Soranzo, Nicole
Jackson, Anne U.
Wheeler, Eleanor
Glazer, Nicole L.
Bouatia-Naji, Nabila
Gloyn, Anna L.
Lindgren, Cecilia M.
Magi, Reedik
Morris, Andrew P.
Randall, Joshua
Johnson, Toby
Elliott, Paul
Rybin, Denis
Thorleifsson, Gudmar
Steinthorsdottir, Valgerdur
Henneman, Peter
Grallert, Harald
Dehghan, Abbas
Hottenga, Jouke Jan
Franklin, Christopher S.
Navarro, Pau
Song, Kijoung
Goel, Anuj
Perry, John R. B.
Egan, Josephine M.
Lajunen, Taina
Grarup, Niels
Sparso, Thomas
Doney, Alex
Voight, Benjamin F.
Stringham, Heather M.
Li, Man
Kanoni, Stavroula
Shrader, Peter
Cavalcanti-Proenca, Christine
Kumari, Meena
Qi, Lu
Timpson, Nicholas J.
Gieger, Christian
Zabena, Carina
Rocheleau, Ghislain
Ingelsson, Erik
An, Ping
O'Connell, Jeffrey
Luan, Jian'an
Elliott, Amanda
[J]. NATURE GENETICS, 2010, 42 (02) : 105 - U32
[10] Modeling effects of SGLT-2 inhibitor dapagliflozin treatment versus standard diabetes therapy on cardiovascular and microvascular outcomes
Dziuba, J.
Alperin, P.
Racketa, J.
Iloeje, U.
Goswami, D.
Hardy, E.
Perlstein, I.
Grossman, H. L.
Cohen, M.
[J]. DIABETES OBESITY & METABOLISM, 2014, 16 (07) : 628 - 635

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