■缺血性卒中(IS)是全球范围内致残和死亡的主要原因。越来越多的证据表明血压之间有很强的关联,血糖,循环脂质,和是。尽管如此,这3个危险因素与IS的遗传关联仍然难以捉摸.
■我们筛选了与血压相关的基因工具,血糖,和循环脂质,并将它们与IS全基因组关联研究数据配对,以进行孟德尔随机化分析。然后对孟德尔随机化阳性结果进行共定位分析。随后,我们利用基因表达综合数据集进行差异表达分析,旨在鉴定差异表达的相关基因。我们通过4个机器学习模型确定了这些差异表达相关基因的重要性得分,并基于这些发现构建了列线图。
■孟德尔随机分析的综合结果表明,血压(收缩压:比值比[OR],1.02[95%CI,1.01-1.02];舒张压:OR,1.03[95%CI,1.03-1.04])和一些循环脂质(低密度脂蛋白胆固醇:OR,1.06[95%CI,1.01-1.12];apoA1:OR,0.95[95%CI,0.92-0.98];apoB:OR,1.05[95%CI,1.01-1.09];二十碳五烯酸:OR,2.36[95%CI,1.41-3.96])与IS发作风险有因果关系。我们在IS的背景下鉴定了73个与血压和循环脂质相关的基因,和16是差异表达的相关基因。FURIN,MAN2A2,HDDC3,ALDH2和TOMM40被鉴定为用于构建列线图的特征基因,该列线图提供了IS发作风险的定量预测。
■这项研究表明,血压之间存在因果关系,某些循环脂质,以及IS的发展。这些因果关系的潜在机制涉及脂质代谢的调节,血压,DNA修复和甲基化,细胞凋亡和自噬,免疫炎症,和神经元保护,在其他人中。
UNASSIGNED: Ischemic stroke (IS) is a major cause of disability and mortality worldwide. Increasing evidence suggests a strong association between blood pressure, blood glucose, circulating lipids, and IS. Nonetheless, the genetic association of these 3 risk factors with IS remains elusive.
UNASSIGNED: We screened genetic instruments related to blood pressure, blood glucose, and circulating lipids and paired them with IS genome-wide association study data to conduct Mendelian randomization analysis. Positive Mendelian randomization findings were then subjected to colocalization analysis. Subsequently, we utilized the Gene Expression Omnibus data set to perform differential expression analysis, aiming to identify differentially expressed associated genes. We determined the importance scores of these differentially expressed associated genes through 4 machine learning models and constructed a nomogram based on these findings.
UNASSIGNED: The combined results of the Mendelian randomization analysis indicate that blood pressure (systolic blood pressure: odds ratio [OR], 1.02 [95% CI, 1.01-1.02]; diastolic blood pressure: OR, 1.03 [95% CI, 1.03-1.04]) and some circulating lipids (low-density lipoprotein cholesterol: OR, 1.06 [95% CI, 1.01-1.12]; apoA1: OR, 0.95 [95% CI, 0.92-0.98]; apoB: OR, 1.05 [95% CI, 1.01-1.09]; eicosapentaenoic acid: OR, 2.36 [95% CI, 1.41-3.96]) have causal relationships with the risk of IS onset. We identified 73 genes that are linked to blood pressure and circulating lipids in the context of IS, and 16 are differentially expressed associated genes. FURIN, MAN2A2, HDDC3, ALDH2, and TOMM40 were identified as feature genes for constructing the nomogram that provides a quantitative prediction of the risk of IS onset.
UNASSIGNED: This study indicates that there are causal links between blood pressure, certain circulating lipids, and the development of IS. The potential mechanisms underlying these causal relationships involve the regulation of lipid metabolism, blood pressure, DNA repair and methylation, cell apoptosis and autophagy, immune inflammation, and neuronal protection, among others.