摘要
目的:采用两样本孟德尔随机化(MR)方法评估耳鸣与阿尔茨海默病(AD)发病风险之间的潜在因果关系,并阐明其作用机制,为AD早期预警提供新思路。方法:利用全基因组关联研究(GWAS)数据库,搜索关键词“tinnitus”和“Alzheimer”,获取暴露因素耳鸣和结局AD的相关数据集,其中耳鸣数据集包括ukb-d-4803_11、ukb-d-4803_12、ukb-d-4803_13、ukb-b-14254和ukb-a-384,AD数据集包括ieu-b-5067、ieu-b-2、ieu-a-297、ebi-a-GCST90027158和ebi-a-GCST002245。筛选与耳鸣密切相关且独立的单核苷酸多态性(SNPs)作为工具变量(IVs),与AD相关的SNPs作为结局。采用逆方差加权法(IVW)进行MR分析,评估其比值比(OR)值、95%置信区间(CI)及P值,当P<0.05时提示存在显著因果关系。敏感性检测使用Cochran’s Q检验IVs的异质性,评估其Q值、df值和P值,当IVW分析法的P>0.05时,提示无显著异质性;采用MR-Egger截距检测水平多效性,当截距为0或接近0,且P>0.05时,提示无显著水平多效性;采用留一法进行敏感性分析,通过森林图、散点图、漏斗图和留一图进行结果可视化。结果:共筛选出286个SNPs作为IVs。所有的IVs满足F>10,提示不存在弱IVs,经过PhenoScanner网页工具筛选,所有SNPs与混杂因素无关。当耳鸣和AD数据集分别为ukb-d-4803和ebi-a-GCST90027158时,耳鸣与AD发病风险之间呈显著正相关关系(OR=1.842,95%CI=1.065~3.188,P=0.029);Cochran’s Q检验提示IVs不存在显著异质性(Q=9.788,df=10.000,P=0.459);MR-Egger截距表明无水平多效性(Egger intercept=-0.006,P=0.147);留一法显示结果稳定,未检测出对结果影响大的SNPs。结论:耳鸣与AD的发病风险之间存在正向因果关系。神经炎症伴随不同程度的小胶质细胞持续激活,可能是耳鸣与AD的共同发病机制。抑郁症也可能作为上游因素,过度激活了下丘脑-垂体-肾上腺(HPA)轴,从而导致耳鸣与AD关系的进阶。
Objective:To evaluate the potential causal relationship between tinnitus and the risk of Alzheimer’s disease(AD)onset using the two-sample Mendelian randomization(MR)method and to clarify its mechanism of action,so as to provide new ideas for early warning of AD.Methods:Genomewide association study(GWAS)database was used to search the keywords“tinnitus”and“Alzheimer”to obtain the related datasets of exposure factor tinnitus and outcome AD;the tinnitus datasets included ukb-d-4803_11,ukb-d-4803_12,ukb-d-4803_13,ukb-b-14254 and ukb-a-384;the AD datasets included ieu-b-5067,ieu-b-2,ieu-a-297,ebi-a-GCST90027158 and ebi-a-GCST002245.The single nucleotide polymorphisms(SNPs)closely and independently associated with tinnitus were screened as instrumental variables(IVs),and the SNPs associated with AD were used as outcomes.Inverse variance weighted(IVW)method was used to conduct MR analysis to evaluate its odds ratio(OR)value,95%confidence interval(CI)and P value;P<0.05 indicated significant causal relationship.Sensitivity detection used Cochran’s Q test to detect the heterogeneity of IVs to evaluate its Q value,df value and P value;when IVW method P>0.05,it indicated no significant heterogeneity;MR-Egger intercept was used to detect horizontal pleiotropy;when the intercept was 0 or close to 0 and P>0.05,it indicated no significant horizontal pleiotropy;meanwhile,leave-one-out method was used for sensitivity analysis.Finally,visualization results were performed using forest plot,scatter plot,funnel plot and leave-one-out plot.Results:A total of 286 SNPs were screened as IVs.All instrumental variables satisfied F>10,suggesting no weak instrumental variable;after screening by PhenoScanner web tool,all SNPs were unrelated to confounding factors.When the tinnitus and AD datasets were ukb-d-4803 and ebi-a-GCST90027158 respectively,there was a significant positive correlation between tinnitus and the risk of AD onset(IVW:OR=1.842,95%CI:1.065-3.188,P=0.029);Cochran’s Q test suggested no significant heterogeneity of IVs(Q=9.788,df=10.000,P=0.459);MR-Egger intercept indicated no horizontal pleiotropy(Egger intercept=-0.006,P=0.147);leave-one-out method showed stable results,and no SNP with significant influence on the results was detected.Conclusion:There is a positive causal relationship between tinnitus and the risk of AD onset.Neuroinflammation accompanied by persistent microglial activation to varying degrees may be the common pathogenesis of tinnitus and AD;in addition,depression may also act as an upstream factor to hyperactivate the hypothalamic-pituitary-adrenal(HPA)axis,leading to the progression of relationship between tinnitus and AD.
作者
孙行云
李傅尧
李可心
时晶
SUN Xingyun;LI Fuyao;LI Kexin;SHI Jing(Department of Neurology,Dongzhimen Hospital,Beijing University of Chinese Medicine,Beijing 100700,China;Beijing Reseach Institute of Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing 100029,China)
出处
《吉林大学学报(医学版)》
北大核心
2025年第4期1052-1060,共9页
Journal of Jilin University:Medicine Edition
基金
国家自然科学基金青年科学基金项目(82405347)
北京中医药大学新教师基金项目(2024-JYB-XJSJJ-008)
北京中医药大学“解码中医”协同攻关项目(BZY-JMZY-2022-002)。
关键词
耳鸣
阿尔茨海默病
孟德尔随机化
全基因组关联研究
逆方差加权法
Tinnitus
Alzheimer disease
Mendelian randomization
Genome-wide association study
Inverse variance weighted method
