Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study.

Autor:	van der Laan SW; Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: s.w.vanderlaan-2@umcutrecht.nl., Fall T; Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden., Soumaré A; INSERM U1219 Team Vintage, University of Bordeaux, Bordeaux, France., Teumer A; Department SHIP-KEF, Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK, German Centre for Cardiovascular Research) partner site, Greifswald, Germany., Sedaghat S; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands., Baumert J; Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany., Zabaneh D; Department of Genetics, Environment and Evolution, University College London, London, United Kingdom; Genetics Institute, University College London, London, United Kingdom., van Setten J; Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands., Isgum I; Image Sciences Institute, University Medical Center Utrecht, Utrecht, the Netherlands., Galesloot TE; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands., Arpegård J; Department of Emergency Medicine, Karolinska University Hospital-Solna, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden., Amouyel P; INSERM, University of Lille, Lille, France; Institut Pasteur de Lille, Lille, France., Trompet S; Department of Cardiology C5-P, Leiden University Medical Center, Leiden, the Netherlands; Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands., Waldenberger M; Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Research Unit of Molecular Epidemiology Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany., Dörr M; Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK, German Centre for Cardiovascular Research) partner site, Greifswald, Germany; Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany., Magnusson PK; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., Giedraitis V; Department of Public Health/Geriatrics, Uppsala University, Uppsala, Sweden., Larsson A; Department of Medical Sciences, Uppsala University, Uppsala, Sweden., Morris AP; Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom., Felix JF; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands., Morrison AC; Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health Science Center, Houston, Texas., Franceschini N; Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina., Bis JC; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington., Kavousi M; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands., O'Donnell C; Department of Cardiology, Boston Veterans Administration Healthcare, West Roxbury, Massachusetts; National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, Massachusetts., Drenos F; Centre for Cardiovascular Genetics, Institute of Cardiovascular Sciences; University College London, London, United Kingdom; MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom., Tragante V; Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands., Munroe PB; National Institute for Health Research Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom., Malik R; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany., Dichgans M; Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Worrall BB; Departments of Neurology and Health Evaluation Sciences, University of Virginia, Charlottesville, Virginia., Erdmann J; Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany., Nelson CP; Department of Cardiovascular Sciences, University of Leicester, British Heart Foundation Cardiovascular Research Centre, Glenfield Hospital, Leicester, United Kingdom; National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom., Samani NJ; Department of Cardiovascular Sciences, University of Leicester, British Heart Foundation Cardiovascular Research Centre, Glenfield Hospital, Leicester, United Kingdom; National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom., Schunkert H; Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; DZHK, German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany., Marchini J; Department of Statistics, University of Oxford, Oxford, United Kingdom., Patel RS; The Genetic Epidemiology Research Group, Institute of Cardiovascular Science, University College London, London, United Kingdom; Bart's Heart Centre, London, United Kingdom; Farr Institute of Health Informatics, University College London, London, United Kingdom., Hingorani AD; The Genetic Epidemiology Research Group, Institute of Cardiovascular Science, University College London, London, United Kingdom., Lind L; Department of Medical Sciences, Uppsala University, Uppsala, Sweden., Pedersen NL; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden., de Graaf J; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands., Kiemeney LA; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands., Baumeister SE; Department SHIP-KEF, Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; Institute for Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany., Franco OH; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands., Hofman A; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands., Uitterlinden AG; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands., Koenig W; Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK, German Centre for Cardiovascular Research) partner site, Greifswald, Germany; Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany., Meisinger C; Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany., Peters A; Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK, German Centre for Cardiovascular Research) partner site, Greifswald, Germany; Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany., Thorand B; Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany., Jukema JW; Department of Cardiology C5-P, Leiden University Medical Center, Leiden, the Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, the Netherlands., Eriksen BO; Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway; Section of Nephrology, University Hospital of North Norway, Tromsø, Norway., Toft I; Section of Nephrology, University Hospital of North Norway, Tromsø, Norway., Wilsgaard T; Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway., Onland-Moret NC; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands., van der Schouw YT; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands., Debette S; INSERM U1219 Team Vintage, University of Bordeaux, Bordeaux, France., Kumari M; Biological and Social Epidemiology, Institute for Social and Economic Research, University of Essex, Essex, United Kingdom., Svensson P; Department of Emergency Medicine, Karolinska University Hospital-Solna, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden., van der Harst P; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, the Netherlands; Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Kivimaki M; Department of Epidemiology and Public Health, University College London, London, United Kingdom., Keating BJ; Department of Surgery, Division of Transplantation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Sattar N; University of Glasgow, Glasgow, Scotland., Dehghan A; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands., Reiner AP; Department of Epidemiology, University of Washington, Seattle, Washington., Ingelsson E; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California., den Ruijter HM; Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands., de Bakker PI; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands., Pasterkamp G; Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands; Laboratory of Clinical Chemistry and Hematology, Division of Laboratories and Pharmacy, University Medical Center Utrecht, Utrecht, the Netherlands., Ärnlöv J; Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden., Holmes MV; Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom. Electronic address: michael.holmes@ndph.ox.ac.uk., Asselbergs FW; Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, the Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom. Electronic address: f.w.asselbergs@umcutrecht.nl.
Jazyk:	angličtina
Zdroj:	Journal of the American College of Cardiology [J Am Coll Cardiol] 2016 Aug 30; Vol. 68 (9), pp. 934-45.
DOI:	10.1016/j.jacc.2016.05.092
Abstrakt:	Background: Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. Objectives: The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. Methods: We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. Results: Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. Conclusions: Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD. (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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