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

Purpose Previous studies have presented conflicting findings regarding the protective effects of circulating sex hormone-binding globulin (SHBG) on ischemic stroke (IS). This study aimed to assess the causal effect of SHBG on IS using Mendelian randomization (MR) analysis and to identify potential mediators.Methods First, the causal effect of SHBG on any IS (AIS), cardioembolic stroke (CES), large artery stroke (LAS), and small vessel stroke (SVS) was assessed by inverse variance weighed (IVW) method. Two additional MR methods (weighted median and MR-Egger) were used to supplement the IVW results. Subsequently, a two-step MR was further performed to assess whether three glycemic profiles [fasting glucose, fasting insulin, and glycated hemoglobin (HbA1c)] and five lipid profiles (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, non-HDL cholesterol, total cholesterol, and triglycerides) mediated the causal effect. Furthermore, Cochrane's Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis were performed for sensitivity analyses.Results The IVW results showed that SHBG significantly reduced SVS risk (odds ratio= 0.60, 95% confidence interval: 0.47-0.77, P = 4.60E-05). The weighted median and MR-Egger results were parallel to IVW. However, no significant associations were found between SHBG and AIS, CES, and LAS. Mediation analysis indicated that HbA1c may be involved in SHBG reducing SVS risk. Sensitivity tests demonstrated the reliability of causal estimates.Conclusions Circulating SHBG levels may decrease SVS risk by lowering HbA1c levels. Therefore, individuals with low circulating SHBG levels should focus on glycemic control to reduce future SVS risk. Key messages What is already known on this topic: Ischemic stroke (IS) is a prevailing cause of mortality and disability. Observational studies have produced conflicting results regarding the association between sex hormone-binding globulin (SHBG) and IS. What this study adds: The present Mendelian randomization analysis found that circulating SHBG levels attenuated the risk of small vessel stroke and that this effect may be mediated by lowering glycated hemoglobin levels. Further enrichment analyses suggest that insulin-like growth factor/insulin-like growth factor binding proteins may be involved in this process. However, no causal association was found between SHBG and large vessel stroke or cardioembolic stroke. How this study might affect research, practice, or policy: Individuals with low circulating SHBG levels should focus on glycemic control to reduce the risk of small vessel stroke in the future.

Automated summary

This study used Mendelian randomization analysis to find that circulating SHBG levels attenuated the risk of small vessel stroke, possibly mediated by lowering glycated hemoglobin levels. Further analysis suggests that insulin-like growth factor/insulin-like growth factor binding proteins may be involved in this process. However, there was no causal association found between SHBG and large vessel stroke or cardioembolic stroke.