A comprehensive contribution of genetic variations of the insulin-like growth factor 1 signalling pathway to stroke susceptibility.

Background And Aims: The insulin-like growth factor (IGF)-1 signalling pathway has been implicated in the pathogenesis of atherosclerosis; however, the mechanism underlying its role in stroke remains unexplained. Herein, we aimed to explore the effects of genetic polymorphisms in the IGF1 pathway on stroke in the Chinese Han population.

Methods: Twenty-six single-nucleotide polymorphisms (SNPs) in IGF1 pathway genes were genotyped in a case-control study consisting of 2070 stroke cases and 2243 controls. Main genetic effects and gene-gene interactive effects of the IGF1 pathway were evaluated. Weighted genetic risk scores (wGRS) were computed, and the associations between wGRS and gene expression were analysed.

Results: The variants at GHRH rs6032470 were significantly associated with high risk of hemorrhagic stroke (HS), and the adjusted OR (95%CI) was 1.368 (1.136-1.647). Significant additive interaction between rs6032470 and gender was detected for HS and ischemic stroke (IS). The association of rs6032470 and stroke was stronger in males than in females. Additionally, a significant gene-gene interaction of rs6032470-rs1874479 (IGFBP1) in relation to HS risk was identified (p < 0.05). IGF1 mRNA expression was significantly upregulated in IS, while it was linearly downregulated across rs6214 genotypes. In addition, IGFBP3 transcript variant 2 mRNA level was negatively correlated with wGRS (r = -0.285, p = 0.005).

Conclusions: Our findings indicated that the IGF1 signalling pathway genes potentiated the risk of stroke through both main effects and gene-gene interactions. The genetic effect of GHRH rs6032470 on stroke was gender dependent. The wGRS of IGF1 pathway genes may be an independent predictor of stroke risk.