Cystatin C and Cardiovascular Disease: A Mendelian Randomization Study.
van der Laan SW., Fall T., Soumaré A., Teumer A., Sedaghat S., Baumert J., Zabaneh D., van Setten J., Isgum I., Galesloot TE., Arpegård J., Amouyel P., Trompet S., Waldenberger M., Dörr M., Magnusson PK., Giedraitis V., Larsson A., Morris AP., Felix JF., Morrison AC., Franceschini N., Bis JC., Kavousi M., O'Donnell C., Drenos F., Tragante V., Munroe PB., Malik R., Dichgans M., Worrall BB., Erdmann J., Nelson CP., Samani NJ., Schunkert H., Marchini J., Patel RS., Hingorani AD., Lind L., Pedersen NL., de Graaf J., Kiemeney LA., Baumeister SE., Franco OH., Hofman A., Uitterlinden AG., Koenig W., Meisinger C., Peters A., Thorand B., Jukema JW., Eriksen BO., Toft I., Wilsgaard T., Onland-Moret NC., van der Schouw YT., Debette S., Kumari M., Svensson P., van der Harst P., Kivimaki M., Keating BJ., Sattar N., Dehghan A., Reiner AP., Ingelsson E., den Ruijter HM., de Bakker PI., Pasterkamp G., Ärnlöv J., Holmes MV., Asselbergs FW.
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.