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      Cystatin C and Cardiovascular Disease : A Mendelian Randomization Study

      research-article
      , MSc a , , PhD b , , PhD c , , PhD d , e , , MSc f , , PhD g , , PhD h , i , , PhD a , , PhD j , , PhD k , , MD l , m , , MD, PhD n , o , , PhD p , q , , PhD, MPH g , r , , MD e , s , , PhD t , , PhD u , , MD, PhD v , , PhD w , x , , PhD f , , PhD y , , MD, MPH z , , PhD aa , , MD, PhD f , , MD, MPH bb , cc , , PhD dd , ee , , PhD ff , , PhD gg , , PhD hh , , MD, PhD hh , ii , , MD, PhD jj ,   , PhD kk , , PhD ll , mm , , PhD ll , mm , , MD, PhD nn , oo , , PhD pp , , MD, PhD qq , rr , ss , , MD, PhD qq , , MD, PhD v , , PhD t , , MD, PhD k , tt , , PhD k , , PhD d , uu , , MD, PhD f , , MD, PhD f , , PhD vv , , MD, PhD e , nn , ww , , MD, MPH g , , PhD, MSc e , g , , PhD, MPH g , , MD, PhD p , xx , , MD, PhD yy , zz , , MD, PhD zz , , PhD aaa , , PhD bbb , , PhD bbb , , MD, PhD c , , PhD ccc , , MD, PhD l , m , , MD, PhD xx , ddd , eee ,   , MD, MA fff , , PhD ggg , , MD, PhD hhh , , MD, PhD f , , MD, MSc iii , , MD, PhD jjj , kkk , , PhD a , , PhD bbb , lll , , MD, PhD a , mmm , , PhD b , , MD, PhD nnn , , MD, PhD ff , xx , ooo
      Journal of the American College of Cardiology
      coronary heart disease, genetics, heart failure, ischemic stroke

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          Abstract

          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.

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          Most cited references50

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          Measuring inconsistency in meta-analyses.

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            The Genotype-Tissue Expression (GTEx) project.

            Genome-wide association studies have identified thousands of loci for common diseases, but, for the majority of these, the mechanisms underlying disease susceptibility remain unknown. Most associated variants are not correlated with protein-coding changes, suggesting that polymorphisms in regulatory regions probably contribute to many disease phenotypes. Here we describe the Genotype-Tissue Expression (GTEx) project, which will establish a resource database and associated tissue bank for the scientific community to study the relationship between genetic variation and gene expression in human tissues.
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              Mendelian randomization: using genes as instruments for making causal inferences in epidemiology.

              Observational epidemiological studies suffer from many potential biases, from confounding and from reverse causation, and this limits their ability to robustly identify causal associations. Several high-profile situations exist in which randomized controlled trials of precisely the same intervention that has been examined in observational studies have produced markedly different findings. In other observational sciences, the use of instrumental variable (IV) approaches has been one approach to strengthening causal inferences in non-experimental situations. The use of germline genetic variants that proxy for environmentally modifiable exposures as instruments for these exposures is one form of IV analysis that can be implemented within observational epidemiological studies. The method has been referred to as 'Mendelian randomization', and can be considered as analogous to randomized controlled trials. This paper outlines Mendelian randomization, draws parallels with IV methods, provides examples of implementation of the approach and discusses limitations of the approach and some methods for dealing with these.
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                Author and article information

                Journal
                8301365
                4429
                J Am Coll Cardiol
                J. Am. Coll. Cardiol.
                Journal of the American College of Cardiology
                0735-1097
                1558-3597
                6 April 2017
                30 August 2016
                30 August 2017
                : 68
                : 9
                : 934-945
                Affiliations
                [a ]Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands
                [b ]Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden
                [c ]INSERM U1219 Team Vintage, University of Bordeaux, Bordeaux, France
                [d ]Department SHIP-KEF, Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany
                [e ]Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK, German Centre for Cardiovascular Research) partner site, Greifswald, Germany
                [f ]Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
                [g ]Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
                [h ]Department of Genetics, Environment and Evolution, University College London, London, United Kingdom
                [i ]Genetics Institute, University College London, London, United Kingdom
                [j ]Image Sciences Institute, University Medical Center Utrecht, Utrecht, the Netherlands
                [k ]Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
                [l ]Department of Emergency Medicine, Karolinska University Hospital-Solna, Stockholm, Sweden
                [m ]Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
                [n ]INSERM, University of Lille, Lille, France
                [o ]Institut Pasteur de Lille, Lille, France
                [p ]Department of Cardiology C5-P, Leiden University Medical Center, Leiden, the Netherlands
                [q ]Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
                [r ]Research Unit of Molecular Epidemiology Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
                [s ]Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany
                [t ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
                [u ]Department of Public Health/Geriatrics, Uppsala University, Uppsala, Sweden
                [v ]Department of Medical Sciences, Uppsala University, Uppsala, Sweden
                [w ]Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom
                [x ]Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
                [y ]Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health Science Center, Houston, Texas
                [z ]Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina
                [aa ]Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington
                [bb ]Department of Cardiology, Boston Veterans Administration Healthcare, West Roxbury, Massachusetts
                [cc ]National Heart, Lung, and Blood Institute Framingham Heart Study, Framingham, Massachusetts
                [dd ]Centre for Cardiovascular Genetics, Institute of Cardiovascular Sciences; University College London, London, United Kingdom
                [ee ]MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
                [ff ]Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands
                [gg ]National Institute for Health Research Cardiovascular Biomedical Research Unit, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
                [hh ]Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-University Munich, Munich, Germany
                [ii ]Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
                [jj ]Departments of Neurology and Health Evaluation Sciences, University of Virginia, Charlottesville, Virginia
                [kk ]Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany
                [ll ]Department of Cardiovascular Sciences, University of Leicester, British Heart Foundation Cardiovascular Research Centre, Glenfield Hospital, Leicester, United Kingdom
                [mm ]National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom
                [nn ]Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
                [oo ]DZHK, German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany
                [pp ]Department of Statistics, University of Oxford, Oxford, United Kingdom
                [qq ]The Genetic Epidemiology Research Group, Institute of Cardiovascular Science, University College London, London, United Kingdom
                [rr ]Bart’s Heart Centre, London, United Kingdom
                [ss ]Farr Institute of Health Informatics, University College London, London, United Kingdom
                [tt ]Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
                [uu ]Institute for Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany
                [vv ]Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
                [ww ]Department of Internal Medicine II–Cardiology, University of Ulm Medical Center, Ulm, Germany
                [xx ]Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, the Netherlands
                [yy ]Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway
                [zz ]Section of Nephrology, University Hospital of North Norway, Tromsø, Norway
                [aaa ]Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway
                [bbb ]Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
                [ccc ]Biological and Social Epidemiology, Institute for Social and Economic Research, University of Essex, Essex, United Kingdom
                [ddd ]Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
                [eee ]Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
                [fff ]Department of Epidemiology and Public Health, University College London, London, United Kingdom
                [ggg ]Department of Surgery, Division of Transplantation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
                [hhh ]University of Glasgow, Glasgow, Scotland
                [iii ]Department of Epidemiology, University of Washington, Seattle, Washington
                [jjj ]Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden
                [kkk ]Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California
                [lll ]Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
                [mmm ]Laboratory of Clinical Chemistry and Hematology, Division of Laboratories and Pharmacy, University Medical Center Utrecht, Utrecht, the Netherlands
                [nnn ]Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
                [ooo ]Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom
                Author notes
                REPRINT REQUESTS AND CORRESPONDENCE: Dr. Sander W. van der Laan, Laboratory of Experimental Cardiology, Division Heart and Lungs, University Medical Center of Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands. s.w.vanderlaan-2@ 123456umcutrecht.nl . OR Dr. Michael V. Holmes, Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, United Kingdom. michael.holmes@ 123456ndph.ox.ac.uk . OR Prof. Dr. Folkert W. Asselbergs, Department of Cardiology, Division Heart and Lungs, University Medical Center of Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands. f.w.asselbergs@ 123456umcutrecht.nl
                [*]

                Mr. van der Laan and Drs. Fall, Ärnlöv, Holmes, and Asselbergs are joint first and senior authors.

                [†]

                Our friend and colleague Ingrid Toft passed away last year; she was heavily involved in the cystatin C project for the Tromsø study.

                Article
                NIHMS859782
                10.1016/j.jacc.2016.05.092
                5451109
                27561768
                7cda85c4-856e-44e4-9725-064eb5f9faab

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Categories
                Article

                Cardiovascular Medicine
                coronary heart disease,genetics,heart failure,ischemic stroke
                Cardiovascular Medicine
                coronary heart disease, genetics, heart failure, ischemic stroke

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