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Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study

van der Laan, SW and Fall, T and Soumaré, A and Teumer, A and Sedaghat, S and Baumert, J and Zabaneh, D and van Setten, J and Isgum, I and Galesloot, TE and Arpegård, J and Amouyel, P and Trompet, S and Waldenberger, M and Dörr, M and Magnusson, PK and Giedraitis, V and Larsson, A and Morris, AP and Felix, JF and Morrison, AC and Franceschini, N and Bis, JC and Kavousi, M and O'Donnell, C and Drenos, F and Tragante, V and Munroe, PB and Malik, R and Dichgans, M and Worrall, BB and Erdmann, J and Nelson, CP and Samani, NJ and Schunkert, H and Marchini, J and Patel, RS and Hingorani, AD and Lind, L and Pedersen, NL and de Graaf, J and Kiemeney, LALM and Baumeister, SE and Franco, OH and Hofman, A and Uitterlinden, AG and Koenig, W and Meisinger, C and Peters, A and Thorand, B and Jukema, JW and Eriksen, BO and Toft, I and Wilsgaard, T and Onland-Moret, NC and van der Schouw, YT and Debette, S and Kumari, M and Svensson, P and van der Harst, P and Kivimaki, M and Keating, BJ and Sattar, N and Dehghan, A and Reiner, AP and Ingelsson, E and den Ruijter, HM and de Bakker, PIW and Pasterkamp, G and Ärnlöv, J and Holmes, MV and Asselbergs, FW (2016) 'Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study.' Journal of the American College of Cardiology, 68 (9). 934 - 945. ISSN 0735-1097

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Abstract

© 2016 The Authors 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.

Item Type: Article
Subjects: H Social Sciences > H Social Sciences (General)
R Medicine > R Medicine (General)
Divisions: Faculty of Social Sciences > Institute for Social and Economic Research
Depositing User: Jim Jamieson
Date Deposited: 26 Aug 2016 14:14
Last Modified: 12 Jun 2019 00:15
URI: http://repository.essex.ac.uk/id/eprint/17471

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