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van der Laan, S.W.* ; Fall, T.* ; Soumare, A.* ; Teumer, A.* ; Sedaghat, S.* ; Baumert, J.J. ; Zabaneh, D.* ; van Setten, J.* ; Isgum, I.* ; Galesloot, T.E.* ; Arpegård, J.* ; Amouyel, P.* ; Trompet, S.* ; Waldenberger, M. ; Dörr, M.* ; Magnusson, P.K.* ; Giedraitis, V.* ; Larsson, A.* ; Morris, A.P.* ; Felix, J.F.* ; Morrison, A.C.* ; Franceschini, N.* ; Bis, J.C.* ; Kavousi, M.* ; O'Donnell, C.* ; Drenos, F.* ; Tragante, V.* ; Munroe, P.B.* ; Malik, R.* ; Dichgans, M.* ; Worrall, B.B.* ; Erdmann, J.* ; Nelson, C.P.* ; Samani, N.J.* ; Schunkert, H.* ; Marchini, J.* ; Patel, R.S.* ; Hingorani, A.D.* ; Lind, L.* ; Pedersen, N.L.* ; de Graaf, J.* ; Kiemeney, L.A.* ; Baumeister, S.E.* ; Franco, O.H.* ; Hofman, A.* ; Uitterlinden, A.G.* ; Koenig, W.* ; Meisinger, C. ; Peters, A. ; Thorand, B. ; Jukema, J.W.* ; Eriksen, B.O.* ; Toft, I.* ; Wilsgaard, T.* ; Onland-Moret, N.C.* ; van der Schouw, Y.T.* ; Debette, S.* ; Kumari, M.* ; Svensson, P.* ; van der Harst, P.* ; Kivimaki, M.* ; Keating, B.J.* ; Sattar, N.* ; Dehghan, A.* ; Reiner, A.P.* ; Ingelsson, E.* ; den Ruijter, H.M.* ; de Bakker, P.I.* ; Pasterkamp, G.* ; Ärnlöv, J.* ; Holmes, M.V.* ; Asselbergs, F.W.*

Cystatin C and cardiovascular disease: A mendelian randomization study.

J. Am. Coll. Cardiol. 68, 934-945 (2016)
Publ. Version/Full Text DOI PMC
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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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords 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
ISSN (print) / ISBN 0735-1097
e-ISSN 1558-3597
Journal Journal of the American College of Cardiology
Quellenangaben Volume: 68, Issue: 9, Pages: 934-945 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)