Causal association between frailty and coronary heart disease based on plasma proteomic mediation analysis

Yan Shikang; Kaidiriyan Kuribanjiang; Abudunaibi Wupuer; Peng Xing; Yang Lei

doi:10.3969/j.issn.1674-4055.2025.04.20

Abstract：Objective To identify the causal association and review the causal effect of plasma proteomic mediation between frailty and coronary heart disease(CHD),and provide potential drug targets for CHD targeted intervention in frailty patients.Methods The plasma proteome data were derived from UK Biobank Plasma Proteome Project(UKB-PPP),CHD data were obtained from CARDIoGRAMplusC4D consortium's genome-wide association study(GWAS)Meta-analysis based on 1000 genomes,and frailty data were sourced from summary GWAS data of frailty index(FI).The method of two-sample Mendelian randomization(TSMR)and Steiger test were employed to investigate the causal relationship and direction between FI and CHD.Proteome-wide Mendelian randomization and colocalization analysis were utilized to identify plasma proteins associated with coronary heart disease.The method of two-stage MR was used to review the causal mediating effect of plasma proteins between frailty and CHD.The analyses of pathway enrichment and PPI network were utilized to discuss potential pathophysiological mechanisms of CHD and the pharmacologically features of plasma proteins in causal association.Results Frailty increased CHD risk(OR=1.470,95%CI:1.099～1.966,P=0.009).APOF protein(mediation effect=0.72,48.98%)and PCSK9 protein(mediation effect=1.42,96.80%)could mediate the causal association between FI and CHD.The results of pathway enrichment showed that cholesterol metabolism and lipid transport could serve as mediating pathways in the development of CHD due to frailty.Conclusion APOF and PCSK9 proteins,as plasma proteins mediating the causal association between frailty and CHD,may provide potential drug targets for targeted intervention for CHD in frailty patients.