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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 K₁ (phylloquinone) levels are associated with ischemic stroke. Four single-nucleotide polymorphisms associated with vitamin K₁ levels were used as instrumental variables. Summary-level data for large artery atherosclerotic stroke (<i>n</i> = 4373 cases), small vessel stroke (<i>n</i> = 5386 cases), cardioembolic stroke (<i>n</i> = 7193 cases), and any ischemic stroke (<i>n</i> = 34,217 cases and 404,630 non-cases) were available from the MEGASTROKE consortium. Genetically-predicted circulating vitamin K₁ 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 K₁ levels were 1.31 (95% confidence interval (CI) 1.12&#8315;1.53; <i>p</i> = 7.0 &#215; 10^&#8722;4) for large artery atherosclerotic stroke, 0.98 (95% CI 0.85&#8315;1.12; <i>p</i> = 0.73) for small vessel stroke, 1.01 (95% CI 0.90&#8315;1.14; <i>p</i> = 0.84) for cardioembolic stroke, and 1.05 (95% CI 0.99&#8315;1.11; <i>p</i> = 0.11) for any ischemic stroke. These findings indicate that genetic predisposition to higher circulating vitamin K₁ levels is associated with an increased risk of large artery atherosclerotic stroke.