Abstract
Erythritol, a widely used nonnutritive sweetener, has been linked to increased cardiovascular risk in observational studies. However, whether erythritol causally contributes to arterial and venous thrombotic diseases remains unclear. We performed a 2-sample Mendelian randomization (MR) study using 60 independent single nucleotide polymorphisms strongly associated with erythritol from a genome-wide association study of 8167 European individuals. Summary statistics for coronary heart disease, ischemic stroke, venous thromboembolism (VTE), pulmonary embolism (PE), and deep vein thrombosis (DVT) were obtained from the FinnGen consortium. The inverse-variance weighted method was the primary analysis, supplemented by MR-Egger, weighted median, and mode-based sensitivity analyses. Pleiotropy and heterogeneity were assessed. Genetically predicted higher erythritol levels were significantly associated with increased risks of coronary heart disease (odds ratio [OR] = 1.077, 95% confidence interval [CI]: 1.060-1.090) and ischemic stroke (OR = 1.157, 95% CI: 1.135-1.179), with consistent findings across sensitivity analyses and no evidence of pleiotropy. A suggestive association was observed for DVT (OR = 1.117, 95% CI: 1.077-1.158); however, causal effect directions for VTE and PE were inconsistent across MR methods. Additionally, MR-Egger intercept tests indicated potential horizontal pleiotropy for DVT, VTE, and PE. Our study suggests a potential role of erythritol in increasing the risk of coronary heart disease, ischemic stroke, and venous thromboembolism, which warrants further investigation.