Causal associations of serum matrix metalloproteinase‐8 level with ischaemic stroke and ischaemic stroke subtypes: a Mendelian randomization study.

Background and purpose: Elevated serum matrix metalloproteinase‐8 (MMP‐8) concentrations are associated with high risk of vascular disease, but the causality remains unclear. A two‐sample Mendelian randomization (MR) study was performed to examine the causal effect of serum MMP‐8 concentrations on the risk of ischaemic stroke, ischaemic stroke subtypes and coronary artery disease. Methods: Ten independent single‐nucleotide polymorphisms related to serum MMP‐8 concentrations were identified as instrumental variables from a genome‐wide association study of 6049 European subjects. Genetic association estimates for ischaemic stroke were obtained from the Multiancestry Genome‐wide Association Study of Stroke consortium with 446,696 European individuals. The inverse‐variance weighted method was applied to assess the causal associations of serum MMP‐8 with ischaemic stroke and its subtypes in the main analysis. Results: No significant causal association was observed for MMP‐8 levels with total ischaemic stroke, large artery stroke or cardioembolic stroke. Genetically determined 1 – unit higher log‐transformed serum MMP‐8 concentration was associated with an increased risk of small vessel stroke (odds ratio 1.25; 95% confidence interval 1.12–1.39; p < 0.001). In secondary analysis, a similar adverse impact was reported for MMP‐8 on coronary artery disease (odds ratio 1.05; 95% confidence interval 1.01–1.10; p = 0.017). Sensitivity analyses further confirmed the relationship between serum MMP‐8 level and small vessel stroke and coronary artery disease. Mendelian randomization Egger regression showed no evidence of pleiotropic bias. Conclusions: High serum MMP‐8 concentrations were causally associated with increased risks of small vessel stroke and coronary artery disease. The mechanism underlying the effect of serum MMP‐8 on the vascular system requires further investigation. [ABSTRACT FROM AUTHOR]