title: Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study.
abstract: 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.
  
  
  
  The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: s.w.vanderlaan-2@umcutrecht.nl.
authors: Sander W
authors: SW
authors: van der Laan
authors: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
authors: Tove
authors: T
authors: Fall
authors: INSERM U1219 Team Vintage, University of Bordeaux, Bordeaux, France.
authors: Aicha
authors: A
authors: Soumaré
authors: 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.
authors: Alexander
authors: A
authors: Teumer
authors: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Sanaz
authors: S
authors: Sedaghat
authors: Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Jens
authors: J
authors: Baumert
authors: Department of Genetics, Environment and Evolution, University College London, London, United Kingdom; Genetics Institute, University College London, London, United Kingdom.
authors: Delilah
authors: D
authors: Zabaneh
authors: Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: Jessica
authors: J
authors: van Setten
authors: Image Sciences Institute, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: Ivana
authors: I
authors: Isgum
authors: Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
authors: Tessel E
authors: TE
authors: Galesloot
authors: Department of Emergency Medicine, Karolinska University Hospital-Solna, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors: Johannes
authors: J
authors: Arpegård
authors: INSERM, University of Lille, Lille, France; Institut Pasteur de Lille, Lille, France.
authors: Philippe
authors: P
authors: Amouyel
authors: Department of Cardiology C5-P, Leiden University Medical Center, Leiden, the Netherlands; Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
authors: Stella
authors: S
authors: Trompet
authors: 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.
authors: Melanie
authors: M
authors: Waldenberger
authors: 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.
authors: Marcus
authors: M
authors: Dörr
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Patrik K
authors: PK
authors: Magnusson
authors: Department of Public Health/Geriatrics, Uppsala University, Uppsala, Sweden.
authors: Vilmantas
authors: V
authors: Giedraitis
authors: Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors: Anders
authors: A
authors: Larsson
authors: Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors: Andrew P
authors: AP
authors: Morris
authors: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Janine F
authors: JF
authors: Felix
authors: Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health Science Center, Houston, Texas.
authors: Alanna C
authors: AC
authors: Morrison
authors: Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina.
authors: Nora
authors: N
authors: Franceschini
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington.
authors: Joshua C
authors: JC
authors: Bis
authors: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Maryam
authors: M
authors: Kavousi
authors: Department of Cardiology, Boston Veterans Administration Healthcare, West Roxbury, Massachusetts; National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, Massachusetts.
authors: Christopher
authors: C
authors: O'Donnell
authors: 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.
authors: Fotios
authors: F
authors: Drenos
authors: Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: Vinicius
authors: V
authors: Tragante
authors: National Institute for Health Research Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom.
authors: Patricia B
authors: PB
authors: Munroe
authors: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany.
authors: Rainer
authors: R
authors: Malik
authors: Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
authors: Martin
authors: M
authors: Dichgans
authors: Departments of Neurology and Health Evaluation Sciences, University of Virginia, Charlottesville, Virginia.
authors: Bradford B
authors: BB
authors: Worrall
authors: Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
authors: Jeanette
authors: J
authors: Erdmann
authors: 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.
authors: Christopher P
authors: CP
authors: Nelson
authors: 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.
authors: Nilesh J
authors: NJ
authors: Samani
authors: Deutsches Herzzentrum München, Technische Universität München, Munich, Germany; DZHK, German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany.
authors: Heribert
authors: H
authors: Schunkert
authors: Department of Statistics, University of Oxford, Oxford, United Kingdom.
authors: Jonathan
authors: J
authors: Marchini
authors: 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.
authors: Riyaz S
authors: RS
authors: Patel
authors: The Genetic Epidemiology Research Group, Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors: Aroon D
authors: AD
authors: Hingorani
authors: Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors: Lars
authors: L
authors: Lind
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Nancy L
authors: NL
authors: Pedersen
authors: Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors: Jacqueline
authors: J
authors: de Graaf
authors: Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
authors: Lambertus A L M
authors: LA
authors: Kiemeney
authors: Department SHIP-KEF, Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany; Institute for Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.
authors: Sebastian E
authors: SE
authors: Baumeister
authors: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Oscar H
authors: OH
authors: Franco
authors: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Albert
authors: A
authors: Hofman
authors: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: André G
authors: AG
authors: Uitterlinden
authors: 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.
authors: Wolfgang
authors: W
authors: Koenig
authors: Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Christa
authors: C
authors: Meisinger
authors: 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.
authors: Annette
authors: A
authors: Peters
authors: Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors: Barbara
authors: B
authors: Thorand
authors: Department of Cardiology C5-P, Leiden University Medical Center, Leiden, the Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, the Netherlands.
authors: J Wouter
authors: JW
authors: Jukema
authors: Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway; Section of Nephrology, University Hospital of North Norway, Tromsø, Norway.
authors: Bjørn Odvar
authors: BO
authors: Eriksen
authors: Section of Nephrology, University Hospital of North Norway, Tromsø, Norway.
authors: Ingrid
authors: I
authors: Toft
authors: Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway.
authors: Tom
authors: T
authors: Wilsgaard
authors: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: N Charlotte
authors: NC
authors: Onland-Moret
authors: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: Yvonne T
authors: YT
authors: van der Schouw
authors: INSERM U1219 Team Vintage, University of Bordeaux, Bordeaux, France.
authors: Stéphanie
authors: S
authors: Debette
authors: Biological and Social Epidemiology, Institute for Social and Economic Research, University of Essex, Essex, United Kingdom.
authors: Meena
authors: M
authors: Kumari
authors: Department of Emergency Medicine, Karolinska University Hospital-Solna, Stockholm, Sweden; Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors: Per
authors: P
authors: Svensson
authors: 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.
authors: Pim
authors: P
authors: van der Harst
authors: Department of Epidemiology and Public Health, University College London, London, United Kingdom.
authors: Mika
authors: M
authors: Kivimaki
authors: Department of Surgery, Division of Transplantation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Brendan J
authors: BJ
authors: Keating
authors: University of Glasgow, Glasgow, Scotland.
authors: Naveed
authors: N
authors: Sattar
authors: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
authors: Abbas
authors: A
authors: Dehghan
authors: Department of Epidemiology, University of Washington, Seattle, Washington.
authors: Alex P
authors: AP
authors: Reiner
authors: 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.
authors: Erik
authors: E
authors: Ingelsson
authors: Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
authors: Hester M
authors: HM
authors: den Ruijter
authors: 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.
authors: Paul I W
authors: PI
authors: de Bakker
authors: 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.
authors: Gerard
authors: G
authors: Pasterkamp
authors: Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
authors: Johan
authors: J
authors: Ärnlöv
authors: 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.
authors: Michael V
authors: MV
authors: Holmes
authors: 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.
authors: Folkert W
authors: FW
authors: Asselbergs
mesh_terms: D000368:Aged; D000483:Alleles; D002318:Cardiovascular Diseases / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D055316:Cystatin C / Q000097:blood / Q000235:genetics*; D005838:Genotype; D014943:Global Health; D006801:Humans; D015994:Incidence; D057182:Mendelian Randomization Analysis / Q000379:methods*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D055316:Cystatin C
keywords: coronary heart disease; genetics; heart failure; ischemic stroke