摘要Objective N6-methyladenosine(m6A)is a common epigenetic modification in eukaryotes.In this study,we explore the potential impact of m6A-associated single nucleotide polymorphisms(m6A-SNPs)on heart failure(HF).Methods Data from genome-wide association studies(GWAS)investigating HF in humans and from m6A-SNPs datasets were used to identify HF-associated m6A-SNPs.Their functions were explored using expression quantitative trait locus(eQTL),gene expression,and gene enrichment analyses.Mediation protein quantitative trait locus(pQTL)-Mendelian randomization(MR)was used to investigate the potential mechanism between critical protein levels and risk factors for HF.Results We screened 44 HF-associated m6A-SNPs,including 10 m6A-SNPs that showed eQTL signals and differential expressions in HF.The SNP rs1801270 in CDKN1A showed the strongest association with HF(P=7.75×10-6).Additionally,MR verified the genetic association between the CDKN1A protein and HF,as well as the mediating effect of blood pressure(BP)in this pathway.Higher circulating level of CDKN1A was associated with a lower risk of HF(odds ratio[OR]=0.82,95%confidence interval[CI]:0.69 to 0.99).The proportions of hypertension,systolic BP,and diastolic BP were 48.10%,28.94%,and 18.02%,respectively.Associations of PDIA6(P=1.30×10-2)and SMAD3(P=4.80×10-2)with HF were also detected.Conclusion Multiple HF-related m6A-SNPs were identified in this study.Genetic associations of CDKN1A and other proteins with HF and its risk factors were demonstrated,providing new ideas for further exploration of the molecular mechanisms of HF.