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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.
Journal of the American College of Cardiology
|August 27, 2016
Summary
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.
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