血浆代谢物介导炎症蛋白对阿尔茨海默病的因果效应：一项孟德尔随机化分析研究

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Abstract：ObjectiveToinvestigatethecausalrelationshipbetweeninflammatoryproteinsandAlzheimer'sdisease（ADand themediatingroleof plasma metabolitestherein.Methods Using Mendelianmandomization （MR）methodsand publicly availablegenome-wideasociationstudy（GWAS）data，weselected91singlenucleotidepolymorphisms （SNPs）thatwere strongly linked to inflammatoryproteins without reverse causalitywith ADastheoutcome.Abidirectional two-sample MR analysiswasperformed.InflammatoryproteinswithcausalinkstoADwereidentifiedviainversevarianceweighted（IVW） analysis.Amediation MRanalysis was thenperformedusing1400 plasma metabolites toassesstheirmediating roleinthis causal pathway.Results ThepreliminarybidirectionalMRanalysisidentified 3inflammatoryproteinsthathadapotential positivecausal asociationwithAD withoutreversecausality：Axin-1， C-X-C motif chemokine ligand1 （CXCL11），and interleukin-12β（IL-12β）.Elevated levelsof Axin-1 were positivelycausallyassociated withADrisk （OR=1.082， 95% CI： 1.009- 1.159; P=0.026）， while CXCL11 （OR=0.951， 95% CI： 0.914-0.990; P=0.026） and IL-12β （ OR=0.959 心 95% CI： 0.926-0.994; P=0.026 0 werenegativelycausallyassociatedwithADrisk.Sensitivityanalysesindicatedthatthesecausalefectsexhibitedno heterogeneityorpleiotropyInthemediationanalysis，18plasmametabolites withcausallinkstoADwereidentified，among which3plasmametabolitesexhibitedmediatingeffectsintheinflammatoryprotein-ADcausalrelationship.Methyl-4- hydroxybenzoate sulfate partiallymediated the effect between Axin-1 and AD （20.10%） .Pregnenetriolsulfatepartially mediated the effect between CXCL11 and AD （18.20%） ）. The ratio of spermidine to ornithine played an important mediating role between IL-12β and AD，with a mediating effect of 43.40% . Conclusion This study reveals how specific inflammatory proteins influence ADrisk via plasma metabolites and provides genetic evidence forinflammatory-metabolic interactions in AD to facilitate the identificationof potential biomarkersand targets for early detectionand interventionof AD.

Keywords： inflammatoryproteins;plasmametabolites;mendelianrandomization;Alzheimer'sdisease;mediatingefect

阿尔茨海默病（AD）是一种严重的神经退行性疾

病，是痴呆的最常见原因[]。（剩余14217字）