A Mendelian Randomization Study of Cystatin C and CVD

Study Questions:

Is cystatin C causally related to cardiovascular disease (CVD)?


The authors used Mendelian randomization to investigate whether cystatin C is causally related to CVD. Data from 15 prospective cohort trials (n = 76,481) and genetic data from 43 studies (n = 252,216) were used in the analysis. Common genetic variants in the CST3 gene were used as an instrument variable to test the causal effect of circulating cystatin C on CVD. The primary outcome was CVD, defined as a composite of coronary heart disease, ischemic stroke, and heart failure.


In total, 19,394 cardiovascular events were recorded. A total of 37,126 persons had measures of serum cystatin C. The genetic variable showed a strong association with serum cystatin C. Observational meta-analysis showed a dose-dependent relationship between cystatin C concentrations and CVD: per doubling of cystatin C concentration, the risk of CVD increased (relative risk [RR], 2.33; 95% confidence interval [CI], 2.08-2.62; p = 1.28 x 10-47). After adjustment for age, sex, high-density lipoprotein, body mass index, systolic blood pressure, estimated glomerular filtration rate, and smoking, there remained an independent, but diminished relationship between cystatin C and CVD (RR, 1.82; 95% CI, 1.56-2.13; p = 2.12 x 10-14). In Mendelian randomization analysis, there was no evidence for a causal relationship between cystatin C and CVD (odds ratio = 1.00 per doubling of cystatin C; 95% CI, 0.82-1.22; p = 0.994).


While data from cohort studies suggest a causal relationship between cystatin C and CVD, Mendelian randomization analysis did not support a causal role for cystatin C and CVD.


In this study, the genetic variation that affects the serum concentration of cystatin C was used as a variable to evaluate the effect of lifelong elevation in cystatin C on CVD risk, with the rationale that the distribution of alleles and genetic information is not influenced by disease status and should be free of confounding by CVD risk factors. Despite observational analyses revealing a strong association between cystatin C and CVD, the Mendelian randomization analysis failed to show a causal relationship. Thus, the association observed in observational studies between cystatin C and CVD may be explained by residual confounding and/or reverse causality rather than a true effect of cystatin C on CVD.

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