BACKGROUND AND AIMS: The causality between myeloperoxidase (MPO) and cardiovascular disease still remains unclear. We performed a two-sample Mendelian randomization (MR) study to estimate the potential causal effect of MPO on the risks of ischemic stroke, ischemic stroke subtypes, heart failure (HF), and atrial fibrillation (AF).
METHODS AND RESULTS: Seventeen independent single-nucleotide polymorphisms associated with MPO levels were identified as instrumental variables from a European-descent genome-wide association study. Summary-level data on ischemic stroke originated from the Multiancestry Genome-wide Association Study of Stroke Consortium with 440 328 European individuals. We used the inverse-variance weighted method to assess the potential causality of plasma MPO with ischemic stroke and its subtypes in the main analysis. Genetically determined higher plasma MPO concentration was significantly associated with increased risks of ischemic stroke (odds ratio [OR] per standard deviation [SD] increase, 1.05; 95% confidence interval [CI], 1.02-1.09; P = 0.002) and cardioembolic stroke (CES) (OR per SD increase, 1.10; 95% CI, 1.03-1.18; P = 0.005), but was not associated with risks of large artery stroke or small vessel stroke. In the secondary analysis, MPO was associated with a high risk of HF (OR per SD increase, 1.05; 95% CI, 1.02-1.07; P = 0.001) and AF (OR per SD increase, 1.04; 95% CI, 1.01-1.07; P = 0.004). MR-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses further confirmed these findings.
CONCLUSION: High plasma MPO levels were potentially associated with increased risks of ischemic stroke, CES, HF, and AF, suggesting that MPO plays an important role in the development of cardiovascular disease.
