Tanya Keenan1, Wei Zhao2, Asif Rasheed3, Weang K Ho4, Rainer Malik5, Janine F Felix6, Robin Young4, Nabi Shah3, Maria Samuel3, Nasir Sheikh4, Megan L Mucksavage2, Omar Shah2, Jin Li7, Michael Morley8, Annika Laser9, Nadeem Hayat Mallick10, Khan Shah Zaman11, Mohammad Ishaq12, Syed Zahed Rasheed12, Fazal-Ur-Rehman Memon13, Faisal Ahmed14, Bashir Hanif15, Muhammad Shakir Lakhani15, Muhammad Fahim3, Madiha Ishaq3, Naresh Kumar Shardha3, Naveeduddin Ahmed16, Khalid Mahmood17, Waseem Iqbal18, Saba Akhtar3, Rabia Raheel3, Christopher J O'Donnell19, Christian Hengstenberg20, Winifred März21, Sekar Kathiresan22, Nilesh Samani23, Anuj Goel24, Jemma C Hopewell25, John Chambers26, Yu-Ching Cheng27, Pankaj Sharma28, Qiong Yang29, Jonathan Rosand30, Giorgio B Boncoraglio31, Shahana Urooj Kazmi32, Hakon Hakonarson7, Anna Köttgen33, Andreas Kalogeropoulos34, Philippe Frossard3, Ayeesha Kamal35, Martin Dichgans5, Thomas Cappola36, Muredach P Reilly37, John Danesh4, Daniel J Rader2, Benjamin F Voight38, Danish Saleheen39. 1. Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. 2. Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 3. Center for Non-Communicable Diseases, Karachi, Pakistan. 4. Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 5. Ludwig-Maximilians-University Munich, Medical Center, Institute for Stroke and Dementia Research (ISD), Munich, Germany. 6. Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, the Netherlands and The Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging (NGI-NCHA), Leiden, the Netherlands. 7. Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 8. Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 9. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum München, Neuherberg, Germany. 10. Punjab Institute of Cardiology, Lahore, Pakistan. 11. National Institute of Cardiovascular Diseases, Karachi, Pakistan. 12. Karachi Institute of Heart Diseases, Karachi, Pakistan. 13. Red Crescent Institute of Cardiology, Hyderabad, Pakistan. 14. Department of Cardiology, Liaquat National Hospital, Karachi, Pakistan. 15. Department of Cardiology, Tabba Heart Institute, Karachi, Pakistan. 16. Department of Neurology, Liaquat National Hospital, Karachi, Pakistan. 17. Department of Medicine, Dow University of Health Sciences, Civil Hospital, Karachi, Pakistan. 18. Department of Medicine, Lahore General Hospital, Lahore, Pakistan. 19. National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts. 20. Internal Medicine II - Cardiology, University Hospital of Regensburg, Regensburg, Germany. 21. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria; Medical Clinic V, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany; Synlab Academy, Synlab Laboratory Services GmbH, Mannheim, Germany. 22. Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts; Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts. 23. Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield General Hospital, Leicester, United Kingdom. 24. Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, United Kingdom. 25. Division of Cardiovascular Science, Oxford University, Oxford, United Kingdom. 26. School of Public Health, Imperial College, London, United Kingdom. 27. Department of Medicine, University of Maryland School of Medicine, Baltimore VA Medical Center, Baltimore, Maryland. 28. Imperial College London & Hammersmith Hospitals, London, United Kingdom. 29. School of Public Health, Boston University, Boston, Massachusetts. 30. Division of Neurocritical Care, Massachusetts General Hospital, Boston, Massachusetts. 31. Department of Cerebrovascular Diseases, Fondazione IRCCS Istituto Neurologico, Milan, Italy. 32. Department of Microbiology, University of Karachi, Karachi, Pakistan. 33. Renal Division, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. 34. Division of Cardiology, School of Medicine, Emory University, Atlanta, Georgia. 35. Division of Neurology, Department of Medicine, Aga Khan University, Karachi, Pakistan. 36. Cardiovascular Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 37. Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Cardiovascular Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 38. Department of Systems Pharmacology and Translational Therapeutics and Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: bvoight@upenn.edu. 39. Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Non-Communicable Diseases, Karachi, Pakistan; Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: saleheen@mail.med.upenn.edu.
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.
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.
Authors: Nicholas L Smith; Janine F Felix; Alanna C Morrison; Serkalem Demissie; Nicole L Glazer; Laura R Loehr; L Adrienne Cupples; Abbas Dehghan; Thomas Lumley; Wayne D Rosamond; Wolfgang Lieb; Fernando Rivadeneira; Joshua C Bis; Aaron R Folsom; Emelia Benjamin; Yurii S Aulchenko; Talin Haritunians; David Couper; Joanne Murabito; Ying A Wang; Bruno H Stricker; John S Gottdiener; Patricia P Chang; Thomas J Wang; Kenneth M Rice; Albert Hofman; Susan R Heckbert; Ervin R Fox; Christopher J O'Donnell; Andre G Uitterlinden; Jerome I Rotter; James T Willerson; Daniel Levy; Cornelia M van Duijn; Bruce M Psaty; Jacqueline C M Witteman; Eric Boerwinkle; Ramachandran S Vasan Journal: Circ Cardiovasc Genet Date: 2010-05-05
Authors: Seo Young Kim; James P Guevara; Kyoung Mi Kim; Hyon K Choi; Daniel F Heitjan; Daniel A Albert Journal: Arthritis Care Res (Hoboken) Date: 2010-02 Impact factor: 4.794
Authors: Nicole Soranzo; Serena Sanna; Eleanor Wheeler; Christian Gieger; Dörte Radke; Josée Dupuis; Nabila Bouatia-Naji; Claudia Langenberg; Inga Prokopenko; Elliot Stolerman; Manjinder S Sandhu; Matthew M Heeney; Joseph M Devaney; Muredach P Reilly; Sally L Ricketts; Alexandre F R Stewart; Benjamin F Voight; Christina Willenborg; Benjamin Wright; David Altshuler; Dan Arking; Beverley Balkau; Daniel Barnes; Eric Boerwinkle; Bernhard Böhm; Amélie Bonnefond; Lori L Bonnycastle; Dorret I Boomsma; Stefan R Bornstein; Yvonne Böttcher; Suzannah Bumpstead; Mary Susan Burnett-Miller; Harry Campbell; Antonio Cao; John Chambers; Robert Clark; Francis S Collins; Josef Coresh; Eco J C de Geus; Mariano Dei; Panos Deloukas; Angela Döring; Josephine M Egan; Roberto Elosua; Luigi Ferrucci; Nita Forouhi; Caroline S Fox; Christopher Franklin; Maria Grazia Franzosi; Sophie Gallina; Anuj Goel; Jürgen Graessler; Harald Grallert; Andreas Greinacher; David Hadley; Alistair Hall; Anders Hamsten; Caroline Hayward; Simon Heath; Christian Herder; Georg Homuth; Jouke-Jan Hottenga; Rachel Hunter-Merrill; Thomas Illig; Anne U Jackson; Antti Jula; Marcus Kleber; Christopher W Knouff; Augustine Kong; Jaspal Kooner; Anna Köttgen; Peter Kovacs; Knut Krohn; Brigitte Kühnel; Johanna Kuusisto; Markku Laakso; Mark Lathrop; Cécile Lecoeur; Man Li; Mingyao Li; Ruth J F Loos; Jian'an Luan; Valeriya Lyssenko; Reedik Mägi; Patrik K E Magnusson; Anders Mälarstig; Massimo Mangino; María Teresa Martínez-Larrad; Winfried März; Wendy L McArdle; Ruth McPherson; Christa Meisinger; Thomas Meitinger; Olle Melander; Karen L Mohlke; Vincent E Mooser; Mario A Morken; Narisu Narisu; David M Nathan; Matthias Nauck; Chris O'Donnell; Konrad Oexle; Nazario Olla; James S Pankow; Felicity Payne; John F Peden; Nancy L Pedersen; Leena Peltonen; Markus Perola; Ozren Polasek; Eleonora Porcu; Daniel J Rader; Wolfgang Rathmann; Samuli Ripatti; Ghislain Rocheleau; Michael Roden; Igor Rudan; Veikko Salomaa; Richa Saxena; David Schlessinger; Heribert Schunkert; Peter Schwarz; Udo Seedorf; Elizabeth Selvin; Manuel Serrano-Ríos; Peter Shrader; Angela Silveira; David Siscovick; Kjioung Song; Timothy D Spector; Kari Stefansson; Valgerdur Steinthorsdottir; David P Strachan; Rona Strawbridge; Michael Stumvoll; Ida Surakka; Amy J Swift; Toshiko Tanaka; Alexander Teumer; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Anke Tönjes; Gianluca Usala; Veronique Vitart; Henry Völzke; Henri Wallaschofski; Dawn M Waterworth; Hugh Watkins; H-Erich Wichmann; Sarah H Wild; Gonneke Willemsen; Gordon H Williams; James F Wilson; Juliane Winkelmann; Alan F Wright; Carina Zabena; Jing Hua Zhao; Stephen E Epstein; Jeanette Erdmann; Hakon H Hakonarson; Sekar Kathiresan; Kay-Tee Khaw; Robert Roberts; Nilesh J Samani; Mark D Fleming; Robert Sladek; Gonçalo Abecasis; Michael Boehnke; Philippe Froguel; Leif Groop; Mark I McCarthy; W H Linda Kao; Jose C Florez; Manuela Uda; Nicholas J Wareham; Inês Barroso; James B Meigs Journal: Diabetes Date: 2010-09-21 Impact factor: 9.461
Authors: Aslihan Yerlikaya; Tuncay Dagel; Christopher King; Masanari Kuwabara; Miguel A Lanaspa; Ana Andres-Hernando; Adrian Covic; Jacek Manitius; Alan A Sag; Mehmet Kanbay Journal: Int Urol Nephrol Date: 2017-02-16 Impact factor: 2.370
Authors: Guanjie Chen; Daniel Shriner; Ayo P Doumatey; Jie Zhou; Amy R Bentley; Lin Lei; Adebowale Adeyemo; Charles N Rotimi Journal: Hum Mol Genet Date: 2020-02-01 Impact factor: 6.150
Authors: Di Cheng; Chunyan Hu; Rui Du; Hongyan Qi; Lin Lin; Xueyan Wu; Lina Ma; Kui Peng; Mian Li; Min Xu; Yu Xu; Yufang Bi; Weiqing Wang; Yuhong Chen; Jieli Lu Journal: Front Med Date: 2020-04-29 Impact factor: 4.592
Authors: Richard J Johnson; George L Bakris; Claudio Borghi; Michel B Chonchol; David Feldman; Miguel A Lanaspa; Tony R Merriman; Orson W Moe; David B Mount; Laura Gabriella Sanchez Lozada; Eli Stahl; Daniel E Weiner; Glenn M Chertow Journal: Am J Kidney Dis Date: 2018-02-27 Impact factor: 8.860
Authors: Alessandro Volpe; Chang Ye; Anthony J Hanley; Philip W Connelly; Bernard Zinman; Ravi Retnakaran Journal: J Clin Endocrinol Metab Date: 2020-03-01 Impact factor: 5.958