■脑动脉瘤是一种预后不良的高危脑血管疾病,可能与多种因素有关。本研究旨在使用孟德尔随机化(MR)方法探索线粒体相关蛋白与脑动脉瘤风险之间的关联。
■我们使用IEUOpenGWAS项目中的线粒体相关蛋白和芬兰脑动脉瘤数据库中的GWAS汇总统计数据(uIA,aSAH)。使用MR-Egger评估线粒体相关暴露与脑动脉瘤之间的关联,加权模式,IVW,简单模式和加权中位数法。反向MR评估反向因果关系,而敏感性分析检查了工具变量的异质性和多效性。使用FDR校正证实了与脑动脉瘤的显着因果关系。
■通过MR分析,我们确定了与aSAH风险增加相关的六种线粒体蛋白:AIF1(OR:1.394,95%CI:1.109-1.752,p=0.0044),CCDC90B(OR:1.318,95%CI:1.132-1.535,p=0.0004),TIM14(OR:1.272,95%CI:1.041-1.553,p=0.0186),NAGS(OR:1.219,95%CI:1.008-1.475,p=0.041),tRNAPusA(OR:1.311,95%CI:1.096-1.569,p=0.003),和MRM3(OR:1.097,95%CI:1.016-1.185,p=0.0175)。其中,CCDC90B,tRNAPusA,AIF1与aSAH风险增加存在显著的因果关系(FDRq<0.1)。三种线粒体蛋白与UIA的风险增加相关:CCDC90B(OR:1.309,95%CI:1.05-1.632,p=0.0165),tRNAPusA(OR:1.306,95%CI:1.007-1.694,p=0.0438),和MRM3(OR:1.13,95%CI:1.012-1.263,p=0.0303)。在反向MR研究中,只有一种线粒体蛋白,TIM14(OR:1.087,95%CI:1.004-1.177,p=0.04),与aSAH有因果关系。敏感性分析未显示异质性或多效性。结果表明,CCDC90B,tRNAPusA,MRM3可能是脑动脉瘤(破裂和未破裂)的常见危险因素,虽然AIF1和NAGS与aSAH的风险增加特别相关,与UIA无关。TIM14可能与aSAH相互作用。
■我们的发现证实了线粒体相关蛋白与脑动脉瘤之间的因果关系,为未来研究这种疾病的发病机制和治疗提供新的见解。
UNASSIGNED: Cerebral aneurysm is a high-risk cerebrovascular disease with a poor prognosis, potentially linked to multiple factors. This
study aims to explore the association between mitochondrial-associated proteins and the risk of cerebral aneurysms using Mendelian randomization (MR) methods.
UNASSIGNED: We used GWAS summary statistics from the IEU Open GWAS project for mitochondrial-associated proteins and from the Finnish database for cerebral aneurysms (uIA, aSAH). The association between mitochondrial-associated exposures and cerebral aneurysms was evaluated using MR-Egger, weighted mode, IVW, simple mode and weighted median methods. Reverse MR assessed reverse causal relationship, while sensitivity analyses examined heterogeneity and pleiotropy in the instrumental variables. Significant causal relationship with cerebral aneurysms were confirmed using FDR correction.
UNASSIGNED: Through MR analysis, we identified six mitochondrial proteins associated with an increased risk of aSAH: AIF1 (OR: 1.394, 95% CI: 1.109-1.752, p = 0.0044), CCDC90B (OR: 1.318, 95% CI: 1.132-1.535, p = 0.0004), TIM14 (OR: 1.272, 95% CI: 1.041-1.553, p = 0.0186), NAGS (OR: 1.219, 95% CI: 1.008-1.475, p = 0.041), tRNA PusA (OR: 1.311, 95% CI: 1.096-1.569, p = 0.003), and MRM3 (OR: 1.097, 95% CI: 1.016-1.185, p = 0.0175). Among these, CCDC90B, tRNA PusA, and AIF1 demonstrated a significant causal relationship with an increased risk of aSAH (FDR q < 0.1). Three mitochondrial proteins were associated with an increased risk of uIA: CCDC90B (OR: 1.309, 95% CI: 1.05-1.632, p = 0.0165), tRNA PusA (OR: 1.306, 95% CI: 1.007-1.694, p = 0.0438), and MRM3 (OR: 1.13, 95% CI: 1.012-1.263, p = 0.0303). In the reverse MR
study, only one mitochondrial protein, TIM14 (OR: 1.087, 95% CI: 1.004-1.177, p = 0.04), showed a causal relationship with aSAH. Sensitivity analysis did not reveal heterogeneity or pleiotropy. The results suggest that CCDC90B, tRNA PusA, and MRM3 may be common risk factors for cerebral aneurysms (ruptured and unruptured), while AIF1 and NAGS are specifically associated with an increased risk of aSAH, unrelated to uIA. TIM14 may interact with aSAH.
UNASSIGNED: Our findings confirm a causal relationship between mitochondrial-associated proteins and cerebral aneurysms, offering new insights for future research into the pathogenesis and treatment of this condition.