Abstract
Objective- Cardiovascular disease, including coronary artery disease (CAD) and ischemic stroke, is the leading cause of death worldwide. This Mendelian randomization study uses genetic variants as instruments to investigate whether there is a causal effect of genetically determined platelet count on CAD and ischemic stroke risk. Approach and Results- A genome-wide association study of 166 066 subjects was used to identify instruments and genetic association estimates for platelet count. Genetic association estimates for CAD and ischemic stroke were obtained from genome-wide association studies, including 60 801 CAD cases and 123 504 controls, and 60 341 ischemic stroke cases and 454 450 controls, respectively. The inverse-variance weighted meta-analysis of ratio method Mendelian randomization estimates was the main method used to obtain estimates for the causal effect of genetically determined platelet count on risk of cardiovascular outcomes. We found no significant Mendelian randomization effect of genetically determined platelet count on risk of CAD (odds ratio of CAD per SD unit increase in genetically determined platelet count, 1.01; 95% CI, 0.98-1.04; P=0.60). However, higher genetically determined platelet count was causally associated with an increased risk of ischemic stroke (odds ratio, 1.07; 95% CI, 1.04-1.11; P<1×10-5), including all major ischemic stroke subtypes. Similar results were obtained in sensitivity analyses more robust to the inclusion of pleiotropic genetic variants. Conclusions- This Mendelian randomization study found evidence that higher genetically determined platelet count is causally associated with higher risk of ischemic stroke.
Highlights
Some of the discrepancy in the findings between CAD and ischemic stroke may relate to the caliber of the respective vessels, with coronary arteries generally having a larger diameter than cerebral arteries,[32,33] with potential implications on the pathophysiology of thrombus formation
The CAD-MR analyses may have been affected by pleiotropic SNPs, with the MR-Egger test for this just missing statistical significance (P=0.05), and the MR-Egger estimate that adjusted for this approaching statistical significance (OR, 1.11; 95% CI, 0.99– 1.24; P=0.08)
Comparisons of clot structure between stroke subtypes suggest that cardioembolic strokes have greater proportions of platelets[34] and fibrin[35] than large-artery strokes, consistent with the findings reported here
Summary
While some observational work has found an association between a higher platelet count and risk of CAD,[36] and a higher platelet count in cases of MI or unstable angina compared with controls,[8] others studies have reported no significant difference in platelet count between cases and controls for CAD or MI.[37,38,39] a cohort study of hemodialysis patients found that higher platelet count was associated with a lower risk of CAD,[39] and it is unclear whether this is generalizable to healthy individuals, other studies have reported a higher platelet count to be associated with lower risk of MI.[9,40] Of note, case-control studies may be affected by the measurement of platelet count after the incident case of CAD, which may limit interpretation because of possible reverse causation. Yaghoubi et al[40] measured platelet count up to 24 hours after symptom onset in MI or unstable angina, while Panwar et al[8] measured platelet count up to 24 hours after admission with an MI or unstable angina eve
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