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Title: | Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study |
Authors: | van der Laan, SW Fall, T Soumaré, A Teumer, A Sedaghat, S Baumert, J Zabaneh, D van Setten, J Isgum, I Galesloot, TE Arpegård, J Amouyel, P Trompet, S Waldenberger, M Dörr, M Magnusson, PK Giedraitis, V Larsson, A Morris, AP Felix, JF Morrison, AC Franceschini, N Bis, JC Kavousi, M O'Donnell, C Drenos, F Tragante, V Munroe, PB Malik, R Dichgans, M Worrall, BB Erdmann, J Nelson, CP Samani, NJ Schunkert, H Marchini, J Patel, RS Hingorani, AD Lind, L Pedersen, NL de Graaf, J Kiemeney, LALM Baumeister, SE Franco, OH Hofman, A Uitterlinden, AG Koenig, W Meisinger, C Peters, A Thorand, B Jukema, JW Eriksen, BO Toft, I Wilsgaard, T Onland-Moret, NC van der Schouw, YT Debette, S Kumari, M Svensson, P van der Harst, P Kivimaki, M Keating, BJ Sattar, N Dehghan, A Reiner, AP Ingelsson, E den Ruijter, HM de Bakker, PIW Pasterkamp, G Ärnlöv, J Holmes, MV Asselbergs, FW |
Keywords: | Coronary;Heart disease;Genetics;Heart failure;Ischemic stroke |
Issue Date: | 2017 |
Publisher: | Elsevier |
Citation: | Journal of the American College of Cardiology, 2016, 68 (9), pp. 934 - 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 × 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. |
URI: | http://bura.brunel.ac.uk/handle/2438/18852 |
DOI: | http://dx.doi.org/10.1016/j.jacc.2016.05.092 |
ISSN: | 0735-1097 1558-3597 |
Appears in Collections: | Dept of Life Sciences Research Papers |
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