The Genetic Association between CDKN1A and Heart Failure:Genome-Wide Exploration of m6A-SNPs and Mendelian Randomization  

作　　者：Ziyi Yang Zhennan Lin Xiaotong Ning Xingbo Mo Laiyuan Wang Xiangfeng Lu Shufeng Chen 

机构地区：[1]Key Laboratory of Cardiovascular Epidemiology,Department of Epidemiology,Fuwai Hospital,National Center for Cardiovascular Diseases,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100037,China [2]Center for Genetic Epidemiology and Genomics,Department of Epidemiology,Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases,School of Public Health,Medical College of Soochow University,Suzhou 215123,Jiangsu,China

出　　处：《Biomedical and Environmental Sciences》2024年第12期1397-1408,共12页生物医学与环境科学（英文版）

基　　金：supported by the National Natural Science Foundation of China[82070473,82170480,82030102];Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences[2021-I2M-1-010].

摘　　要：Objective N6-methyladenosine(m^(6)A)is a common epigenetic modification in eukaryotes.In this study,we explore the potential impact of m^(6)A-associated single nucleotide polymorphisms(m^(6)A-SNPs)on heart failure(HF).Methods Data from genome-wide association studies(GWAS)investigating HF in humans and from m^(6)A-SNPs datasets were used to identify HF-associated m^(6)A-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 m^(6)A-SNPs,including 10 m^(6)A-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 m^(6)A-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.

关 键 词：Heart failure N6-methyladenosine modification Genome-wide association study Expression quantitative trait locus Mendelian randomization 

分 类 号：R541.6[医药卫生—心血管疾病]