Genetically predicted high serum sex hormone-binding globulin levels are associated with lower ischemic stroke risk: A sex-stratified Mendelian randomization study.

OBJECTIVE: Cross-sectional and cohort studies have found insufficient evidence of a causal relationship between sex hormone-binding globulin and ischemic stroke, only associations. Here, we performed a sex-stratified, bidirectional, two-sample Mendelian randomization analysis to evaluate whether a causal relationship exists between sex hormone-binding globulin and ischemic stroke. METHODS: Single-nucleotide polymorphisms associated with sex hormone-binding globulin and ischemic stroke were screened from genome-wide association studies summary data as instrumental variables to enable a bidirectional, two-sample Mendelian randomization study design. Inverse-variance weighted analysis was used as the main method to evaluate potential causality, and additional methods, including the weighted median and MR-Egger tests, were used to validate the Mendelian randomization results. Cochran's Q statistic, MR-Egger intercept test, and Mendelian Randomization-Pleiotropy Residual Sum and Outlier global test were used as sensitivity analysis techniques to assure the reliability of the results. Multivariable analysis was used to show the robustness of the results with key theorized confounders. RESULTS: Inverse-variance weighted analysis showed that genetically predicted higher serum sex hormone-binding globulin levels were associated with significantly decreased risk of ischemic stroke in males (odds radio = 0.934, 95 % confidence interval = 0.885-0.985, P = 0.012) and females (odds radio = 0.924, 95 % confidence interval = 0.868-0.983, P = 0.013). In an analysis of ischemic stroke subtypes, genetically predicted higher serum sex hormone-binding globulin levels were also associated with significantly decreased risk of small-vessel occlusion in both males (odds radio = 0.849, 95 % confidence interval = 0.759-0.949, P = 0.004) and females (odds radio = 0.829, 95 % confidence interval = 0.724-0.949, P = 0.006). The association remained in sensitivity analyses and multivariable analyses. The reverse analysis suggested an association between genetically predicted risk of cardioembolism and increased serum sex hormone-binding globulin in females (Beta = 0.029 nmol/L, Standard Error = 0.010, P = 0.003). CONCLUSION: Our findings provide new insight into the etiology of ischemic stroke and suggest that modulating serum sex hormone-binding globulin may be a therapeutic strategy to protect against ischemic stroke.

Recurrent ischemic stroke from reversible extracranial internal carotid artery and middle cerebral artery vasospasm: A case report.

Idiopathic internal carotid artery (ICA) vasospasm is a rare cause of ischemic stroke. Its pathophysiology remains unclear and diagnostic and treatment protocols are yet to be defined. A 45-year-old male, presenting with recurrent transient dizziness, blurred vision, and speech disturbances, was diagnosed with recurrent ischemic stroke caused by bilateral ICA and middle cerebral artery (MCA) vasospasm, and the vascular ultrasound and imaging techniques have grabbed the reversible changes in a short time. This case underscores the importance of considering idiopathic ICA vasospasm as a potential cause of recurrent ischemic stroke, even in the absence of common diagnostic markers. The case also indicates the possible, albeit rare, involvement of the MCA in this condition. Therefore, it is crucial to maintain a high index of suspicion for idiopathic ICA vasospasm in similar clinical presentations and to explore more inclusive diagnostic criteria.