Circulating sex hormone-binding globulin levels and ischemic stroke risk: a Mendelian randomization study

Area of Science:

• Endocrinology
• Neurology
• Genetics

Background:

• Conflicting findings exist on the protective role of sex hormone-binding globulin (SHBG) against ischemic stroke (IS).
• Mendelian randomization (MR) offers a robust method to investigate causal relationships, overcoming limitations of observational studies.

Purpose of the Study:

• To determine the causal effect of circulating SHBG on various subtypes of ischemic stroke (IS).
• To explore potential mediating roles of glycemic and lipid profiles in the SHBG-IS relationship.
• To identify therapeutic targets for stroke prevention.

Main Methods:

• Utilized Mendelian randomization (MR) analysis with inverse variance weighted (IVW), weighted median, and MR-Egger methods.
• Assessed causal effects of SHBG on any IS (AIS), cardioembolic stroke (CES), large artery stroke (LAS), and small vessel stroke (SVS).
• Conducted two-step MR to evaluate mediation by HbA1c, fasting glucose, fasting insulin, and lipid profiles. Performed sensitivity analyses including Cochrane's Q test and MR-Egger intercept test.

Main Results:

• SHBG was found to significantly reduce the risk of small vessel stroke (SVS) (OR=0.60, P=4.60E-05).
• No significant causal associations were observed between SHBG and AIS, CES, or LAS.
• Mediation analysis suggested that glycated hemoglobin (HbA1c) may be a key mediator in the protective effect of SHBG against SVS.

Conclusions:

• Circulating SHBG levels appear to causally reduce SVS risk, potentially through a mechanism involving lower HbA1c.
• Individuals with low SHBG levels are advised to prioritize glycemic control to mitigate their risk of SVS.
• These findings highlight SHBG as a potential biomarker and therapeutic target for SVS prevention.