Department of Epidemiology and Biostatistics, School of Public Health, Wannan Medical College, Wuhu, 241001, China.
Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
Atherosclerosis. 2020 Mar;296:59-65. doi: 10.1016/j.atherosclerosis.2020.01.009. Epub 2020 Jan 18.
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.
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.
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).
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.
胰岛素样生长因子（IGF）-1 信号通路与动脉粥样硬化的发病机制有关；然而，其在中风中作用的机制仍未阐明。在此，我们旨在探讨 IGF1 通路中的遗传多态性对汉族人群中风的影响。
在一项病例对照研究中，对 2070 例中风病例和 2243 例对照进行了 IGF1 通路基因的 26 个单核苷酸多态性（SNP）的基因分型。评估了 IGF1 通路的主要遗传效应和基因-基因交互作用。计算了加权遗传风险评分（wGRS），并分析了 wGRS 与基因表达之间的关系。
GHRH rs6032470 中的变异与出血性中风（HS）的高风险显著相关，调整后的 OR（95%CI）为 1.368（1.136-1.647）。在 HS 和缺血性中风（IS）中，检测到 rs6032470 与性别之间存在显著的加性交互作用。rs6032470 与中风的关联在男性中强于女性。此外，还发现了 rs6032470-rs1874479（IGFBP1）与 HS 风险的显著基因-基因交互作用（p<0.05）。IS 中 IGF1 mRNA 表达显著上调，而 rs6214 基因型则呈线性下调。此外，IGFBP3 转录变体 2 mRNA 水平与 wGRS 呈负相关（r=-0.285，p=0.005）。
我们的研究结果表明，IGF1 信号通路基因通过主要效应和基因-基因相互作用增强了中风的风险。GHRH rs6032470 对中风的遗传效应具有性别依赖性。IGF1 通路基因的 wGRS 可能是中风风险的独立预测因子。
