Liang Xin, Tong Xin, Miao Yan, Xue Xiaopeng, Liu Aihua, Guan Feng
Department of Neurosurgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Tob Induc Dis. 2024 Apr 30;22. doi: 10.18332/tid/186171. eCollection 2024.
We aim to assess the association between smoking behavior and intracranial aneurysms (IAs) and the effect of smoking cessation medications on IAs at the genetic level.
Causal effects of four phenotypes: 1) age at initiation of regular smoking, 2) cigarettes smoked per day, 3) smoking cessation, and 4) smoking initiation on IAs, were analyzed using two-sample inverse-variance weighted Mendelian randomization analyses. The effects of genes interacting with the smoking cessation medications were analyzed using cis-expression quantitative trait loci genetic instruments on IAs using summary statistics-based Mendelian randomization analyses. Colocalization analyses were then used to test whether the genes shared causal variants with IAs. The role of confounding phenotypes as potential causative mechanisms of IAs at these gene loci was tested.
Cigarettes smoked per day (OR=2.89; 95% CI:1.85-4.51) and smoking initiation on IAs (OR=4.64; 95% CI: 2.64-8.15) were significantly associated with IA risk. However, age at initiation of regular smoking (OR=0.54; 95% CI: 0.10-2.8) and smoking cessation (OR=6.80; 95% CI: 0.01-4812) had no overall effect on IAs. Of 88 genes that interacted with smoking cessation medications, two had a causal effect on IA risk. Genetic variants affecting HYKK levels showed strong evidence of colocalization with IA risk. Higher HYKK levels in the blood were associated with a lower IA risk. Gene target analyses revealed that cigarettes/day could be a main mediator of HYKK's effect on IA risk.
This study provides evidence supporting that smoking initiation on IAs and cigarettes/day may increase IA risk. Increased HYKK gene expression may reduce IA risk. This can be explained by the increased number of cigarettes consumed daily. HYKK could also reduce IA risk due to the positive effect of continuous abstinence and varenicline therapy on smoking cessation.
我们旨在评估吸烟行为与颅内动脉瘤（IA）之间的关联，以及戒烟药物在基因水平上对IA的影响。
使用两样本逆方差加权孟德尔随机化分析，分析四种表型的因果效应：1）开始规律吸烟的年龄，2）每日吸烟量，3）戒烟，4）开始吸烟对IA的影响。使用基于汇总统计的孟德尔随机化分析，利用顺式表达数量性状位点遗传工具分析与戒烟药物相互作用的基因对IA的影响。然后进行共定位分析，以检验这些基因是否与IA共享因果变异。测试了混杂表型作为这些基因位点上IA潜在致病机制的作用。
每日吸烟量（OR = 2.89；95%CI：1.85 - 4.51）和开始吸烟对IA（OR = 4.64；95%CI：2.64 - 8.15）与IA风险显著相关。然而，开始规律吸烟的年龄（OR = 0.54；95%CI：0.10 - 2.8）和戒烟（OR = 6.80；95%CI：0.01 - 4812）对IA没有总体影响。在与戒烟药物相互作用的88个基因中，有两个对IA风险有因果效应。影响HYKK水平的基因变异显示出与IA风险共定位的有力证据。血液中较高的HYKK水平与较低的IA风险相关。基因靶点分析表明，每日吸烟量可能是HYKK对IA风险影响的主要介导因素。
本研究提供的证据支持开始吸烟和每日吸烟量可能增加IA风险。HYKK基因表达增加可能降低IA风险。这可以通过每日吸烟量的增加来解释。由于持续戒烟和伐尼克兰治疗对戒烟的积极作用，HYKK也可能降低IA风险。
