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.

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Keywords coronary heart disease, genetics, heart failure, ischemic stroke
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Journal Journal of the American College of Cardiology
Grant This work was funded by the European Commission 7th Framework Programme; grant id fp7/601456 - Exploitation of genomic variants affecting coronary artery disease and stroke risk for therapeutic intervention (CVGENES-AT-TARGET)
Van Der Laan, S.W, Fall, M, Soumaré, A, Teumer, A, Sedaghat, S, Baumert, J, … Asselbergs, F.W. (2016). Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study. Journal of the American College of Cardiology, 68(9), 934–945. doi:10.1016/j.jacc.2016.05.092