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Cystatin C and Cardiovascular Disease A Mendelian Randomization Study

van der Laan, SW; Fall, T; Soumare, A; Teumer, A; Sedaghat, S; Baumert, J; Zabaneh, D; ... Asselbergs, FW; + view all (2016) Cystatin C and Cardiovascular Disease A Mendelian Randomization Study. Journal of the American College of Cardiology , 68 (9) pp. 934-945. 10.1016/j.jacc.2016.05.092. Green open access

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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.

Type: Article
Title: Cystatin C and Cardiovascular Disease A Mendelian Randomization Study
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jacc.2016.05.092
Publisher version: http://dx.doi.org/10.1016/j.jacc.2016.05.092
Language: English
Additional information: © 2016 The Authors. Published by Elsevier Inc. on behalf of the American College of Cardiology Foundation. This is an open access article under CC BY-NC-ND license (http: //creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Cardiovascular System & Cardiology, coronary heart disease, genetics, heart failure, ischemic stroke, CHRONIC KIDNEY-DISEASE, GENOME-WIDE ASSOCIATION, CORONARY-ARTERY-DISEASE, INCIDENT HEART-FAILURE, BODY-MASS INDEX, SUSCEPTIBILITY LOCI, CHARGE CONSORTIUM, COMMON VARIANTS, ISCHEMIC-STROKE, RISK
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Epidemiology and Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Epidemiology and Health > Epidemiology and Public Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics
URI: https://discovery.ucl.ac.uk/id/eprint/1514697
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