Cystatin C and cardiovascular disease: a Mendelian randomization study
Permanent link
https://hdl.handle.net/10037/10354Date
2016-08-30Type
Journal articleTidsskriftartikkel
Peer reviewed
Author
van der Laan, Sander W; Fall, Tove; Sourmare, Aicha; Teumer, Alexander; Sedaghat, Sanaz; Baumert, Jens; Zahaneh, 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 J.; 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; Kivimäki, 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.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 ¼ 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n ¼ 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 ¼ 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 ¼ 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 ¼ 0.994), which was statistically different from the observational estimate (p ¼ 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. (J Am Coll Cardiol 2016;68:934–45) © 2016 The Authors. Published by Elsevier Inc. on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
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 ¼ 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n ¼ 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 ¼ 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 ¼ 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 ¼ 0.994), which was statistically different from the observational estimate (p ¼ 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. (J Am Coll Cardiol 2016;68:934–45) © 2016 The Authors. Published by Elsevier Inc. on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Description
Source: doi: 10.1016/j.jacc.2016.05.092