Abstract: BACKGROUND: In recent years, increasing evidence has shown that insulin-like growth factors may be associated with ischemic stroke. However, the causal association between insulin-like growth factors and ischemic stroke and its subtypes remain unclear.
OBJECTIVE: To explore the causal association between insulin-like growth factors and ischemic stroke and its subtypes by Mendelian randomization.
METHODS: We obtained genome-wide association study (GWAS) data for insulin-like growth factor from the IEU OpenGWAS database (developed by the MRC Integrative Epidemiology Unit at the University of Bristol, UK, which focuses on integrating data from epidemiology, genetics, and biostatistics), and acquired GWAS data for ischemic stroke and its subtypes (large artery stroke, cardioembolic stroke, and small vessel stroke) from the MEGASTROKE database (a collaborative initiative by the International Stroke Genetics Consortium aimed at meta-analyzing GWAS data for stroke and its subtypes). We performed two-way Mendelian randomization analysis to explore the causal association between 14 insulin-like growth factors and ischemic stroke and its subtypes. The inverse variance weighted method was used as the main statistical method. Cochran’s Q test and MR-Egger regression were used to evaluate the pleiotropy and heterogeneity.
RESULTS AND CONCLUSION: (1) Results of the forward Mendelian randomization analysis showed no significant causal association between any insulin-like growth factors and the risk of ischemic stroke, large artery stroke, or small vessel stroke (all P > 0.05). However, insulin-like growth factor-binding protein 7 exhibited a negative causal relationship with cardioembolic stroke (odds ratio=0.82, 95% confidence interval=0.74–0.91, P=0.006), indicating that insulin-like growth factor-binding protein 7 is a protective factor against cardioembolic stroke. Results of the reverse Mendelian randomization analysis revealed no reverse causal relationship between ischemic stroke, large artery stroke, cardioembolic stroke, or small vessel stroke and insulin-like growth factors. (2) The findings provide epidemiological evidence on the association between insulin-like growth factors and ischemic stroke and its subtypes, highlighting the potential role of insulin-like growth factors in the pathogenesis and progression of different stroke subtypes. This study offers valuable insights for research on insulin-like growth factors and ischemic stroke in Chinese populations, contributing to a deeper understanding of the pathological mechanisms underlying ischemic stroke and suggesting novel perspectives for its prevention and treatment.

Key words: insulin-like growth factors, ischemic stroke, large artery stroke, cardioembolic stroke, small vessel stroke, Mendelian randomization, causality, engineered tissue construction