Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study
van der Laan, Sander W; Fall, Tove; Soumaré, Aicha; Teumer, Alexander; Sedaghat, Sanaz; Baumert, Jens; Zabaneh, Delilah; van Setten, Jessica; Isgum, Ivana; Galesloot, Tessel E; Arpegård, Johannes; Amouyel, Philippe; Trompet, Stella; Waldenberger, Melanie; Dörr, Marcus; Magnusson, Patrik K; Giedraitis, Vilmantas; Larsson, Anders; Morris, Andrew P; Felix, Janine F; Morrison, Alanna C; Franceschini, Nora; Bis, Joshua C; Kavousi, Maryam; O'Donnell, Christopher; Drenos, Fotios; Tragante, Vinicius; Munroe, Patricia B; Malik, Rainer; Dichgans, Martin; Worrall, Bradford B; Erdmann, Jeanette; Nelson, Christopher P; Samani, Nilesh J; Schunkert, Heribert; Marchini, Jonathan; Patel, Riyaz S; Hingorani, Aroon D; Lind, Lars; Pedersen, Nancy L; de Graaf, Jacqueline; Kiemeney, Lambertus A L M; Baumeister, Sebastian E; Franco, Oscar H; Hofman, Albert; Uitterlinden, André G; Koenig, Wolfgang; Meisinger, Christa; Peters, Annette; Thorand, Barbara; Jukema, J Wouter; Eriksen, Bjørn Odvar; Toft, Ingrid; Wilsgaard, Tom; Onland-Moret, N Charlotte; van der Schouw, Yvonne T; Debette, Stéphanie; Kumari, Meena; Svensson, Per; van der Harst, Pim; Kivimaki, Mika; Keating, Brendan J; Sattar, Naveed; Dehghan, Abbas; Reiner, Alex P; Ingelsson, Erik; den Ruijter, Hester M; de Bakker, Paul I W; Pasterkamp, Gerard; Ärnlöv, Johan; Holmes, Michael V; Asselbergs, Folkert W
(2016) Journal of the American College of Cardiology, volume 68, issue 9, pp. 934 - 945
(Article)
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
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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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Keywords: coronary heart disease, genetics, heart failure, ischemic stroke, Journal Article, Multicenter Study
ISSN: 0735-1097
Publisher: Elsevier USA
Note: Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
(Peer reviewed)