Circulating Vitamin K(1) Levels in Relation to Ischemic Stroke and Its Subtypes: A Mendelian Randomization Study

Vitamin K plays a crucial role in blood coagulation, and hypercoagulability has been linked to atherosclerosis-related vascular disease. We used the Mendelian randomization study design to examine whether circulating vitamin K(1) (phylloquinone) levels are associated with ischemic stroke. Four single-nucleotide polymorphisms associated with vitamin K(1) levels were used as instrumental variables. Summary-level data for large artery atherosclerotic stroke (n = 4373 cases), small vessel stroke (n = 5386 cases), cardioembolic stroke (n = 7193 cases), and any ischemic stroke (n = 34,217 cases and 404,630 non-cases) were available from the MEGASTROKE consortium. Genetically-predicted circulating vitamin K(1) levels were associated with large artery atherosclerotic stroke but not with any other subtypes or ischemic stroke as a whole. The odds ratios per genetically predicted one nmol/L increase in natural log-transformed vitamin K(1) levels were 1.31 (95% confidence interval (CI) 1.12–1.53; p = 7.0 × 10(−4)) for large artery atherosclerotic stroke, 0.98 (95% CI 0.85–1.12; p = 0.73) for small vessel stroke, 1.01 (95% CI 0.90–1.14; p = 0.84) for cardioembolic stroke, and 1.05 (95% CI 0.99–1.11; p = 0.11) for any ischemic stroke. These findings indicate that genetic predisposition to higher circulating vitamin K(1) levels is associated with an increased risk of large artery atherosclerotic stroke.