Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study

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Title:	Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study
Author(s):	Laan, S.W. van der; Fall, T.; Soumare, A.; Teumer, A.; Sedaghat, S.; Baumert, J.; Zabaneh, D.; Setten, J. van; Isgum, I.; Galesloot, T.E. ; Arpegard, J.; Amouyel, P.; Trompet, S.; Waldenberger, M.; Dorr, 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.; Graaf, J. de ; Kiemeney, L.A.L.M. ; 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.; Schouw, Y.T. van der; Debette, S.; Kumari, M.; Svensson, P.; Harst, P. van der; Kivimaki, M.; Keating, B.J.; Sattar, N.; Dehghan, A.; Reiner, A.P.; Ingelsson, E.; Ruijter, H.M. Den; Bakker, P.I. de; Pasterkamp, G.; Arnlov, J.; Holmes, M.V.; Asselbergs, F.W.
Publication year:	2016
Source:	Journal of the American College of Cardiology, vol. 68, iss. 9, (2016), pp. 934-945
ISSN:	0735-1097
DOI:	https://doi.org/10.1016/j.jacc.2016.05.092
Publication type:	Article / Letter to editor
Please use this identifier to cite or link to this item : https://hdl.handle.net/2066/172252
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Subject:	Radboudumc 15: Urological cancers RIHS: Radboud Institute for Health Sciences Radboudumc 16: Vascular damage RIHS: Radboud Institute for Health Sciences
Organization:	Health Evidence Internal Medicine Urology
Journal title:	Journal of the American College of Cardiology
Volume:	vol. 68
Issue:	iss. 9
Page start:	p. 934
Page end:	p. 945
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 x 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 x 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 x 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.