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Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study
Sander W van der Laan1, Tove Fall2, Aicha Soumaré3
1Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.
Insights
High cystatin C levels are linked to cardiovascular disease (CVD) risk, but Mendelian randomization studies found no causal relationship. Therefore, therapies targeting cystatin C may not prevent CVD.
Area of Science:
- Cardiovascular epidemiology
- Genetic epidemiology
- Biomarker research
Background:
- Elevated circulating cystatin C is linked to cardiovascular disease (CVD) risk, independent of kidney function.
- The causal nature of this association remains unclear, with possibilities including confounding or reverse causation.
Purpose of the Study:
- To investigate the causal relationship between cystatin C and CVD in the general population using Mendelian randomization.
Main Methods:
- Utilized data from 16 prospective cohorts (76,481 participants) for cystatin C measures and 43 studies (252,216 participants) for CVD events.
- Employed the common variant rs911119 in CST3 as a genetic instrumental variable to assess the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure.
Main Results:
- Observational analyses showed an association between cystatin C and CVD risk (RR 1.82 per doubling; p < 2.12 × 10⁻¹⁴).
- The genetic variant rs911119 influenced cystatin C levels (6.13% decrease per allele; p < 5.95 × 10⁻²¹¹).
- Mendelian randomization analysis revealed no evidence of a causal role for cystatin C in CVD (causal RR 1.00 per doubling; p = 0.994), differing significantly from the observational estimate (p < 1.6 × 10⁻⁵).
Conclusions:
- Mendelian randomization studies do not support a causal link between cystatin C and the development of CVD.
- Therapeutic strategies aimed at reducing circulating cystatin C levels are unlikely to be effective in preventing cardiovascular disease.
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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