Cystatin C Predicts Incident Cardiovascular Disease in Twins

BACKGROUND: Cystatin C is associated with both renal function and atherosclerotic cardiovascular disease (ASCVD). We have previously shown a genetic correlation between cystatin C and prevalent ASCVD. The objective of this article is to study whether variation in cystatin C or creatinine predicts incident ASCVD when controlled for genetic factors. METHODS AND RESULTS: The predictive value of cystatin C and creatinine for incident ASCVD was studied in 11 402 Swedish twins, free of CVD at baseline, in an adjusted Cox‐regression model during a median follow‐up of 71 months. Twin pairs discordant for incident stroke, myocardial infarction and ASCVD during follow‐up were identified and within‐pair comparisons regarding cystatin C and creatinine levels were performed. We also investigated whether contact frequency and degree of shared environment influences were associated with similarity in cystatin C levels. In univariate analysis, cystatin C predicted incident ASCVD hazard ratio 1.57, 95% CI 1.47–1.67. When adjusted for traditional Framingham risk factors as covariates, cystatin C remained a predictor of incident stroke hazard ratio 1.45, 95% CI (1.25–1.70), ASCVD hazard ratio 1.26, 95% CI (1.13–1.41), and myocardial infarction hazard ratio 1.16, 95% CI (1.01–1.33). In twins discordant for incident stroke, cystatin C at baseline was higher in the twin who experienced a stroke compared to the healthy co‐twin (1.11±0.3 mg/L versus 1.06±0.3 mg/L), whereas creatinine was lower in the twin who developed CVD compared to their healthy co‐twins (76.1±16.9 μmol/L versus 79.4±20.3 μmol/L). CONCLUSIONS: Variation in cystatin C relates to incident ASCVD and to stroke when adjusted for genetic confounding. In identical twins, cystatin C may be a sensitive marker of early hypertensive end‐organ damage and small‐vessel disease, whereas creatinine level may reflect nutritional status. The findings in disease‐discordant monozygotic twins indicate that unique, possibly preventable, environmental factors are important.