The Genetic Association between CDKN1A and Heart Failure: Genome-Wide Exploration of m 6A-SNPs and Mendelian Randomization.

Ziyi Yang, Zhennan Lin, Xiaotong Ning, Xingbo Mo, Laiyuan Wang, Xiangfeng Lu, Shufeng Chen
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Abstract

Objective: N6-methyladenosine (m 6A) is a common epigenetic modification in eukaryotes. In this study, we explore the potential impact of m 6A-associated single nucleotide polymorphisms (m 6A-SNPs) on heart failure (HF).

Methods: Data from genome-wide association studies (GWAS) investigating HF in humans and from m 6A-SNPs datasets were used to identify HF-associated m 6A-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 6A-SNPs, including 10 m 6A-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 6A-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.

CDKN1A与心力衰竭之间的遗传关联:m 6A-SNPs的全基因组探索和孟德尔随机化。
目的:n6 -甲基腺苷(m6a)是真核生物中一种常见的表观遗传修饰。在这项研究中,我们探讨了m6a相关的单核苷酸多态性(m6a - snps)对心力衰竭(HF)的潜在影响。方法:利用研究人类HF的全基因组关联研究(GWAS)和m个6A-SNPs数据集的数据,鉴定HF相关的m个6A-SNPs。通过表达数量性状位点(eQTL)、基因表达和基因富集分析,探讨了它们的功能。采用中介蛋白数量性状位点(pQTL)-孟德尔随机化(MR)方法探讨关键蛋白水平与心衰危险因素之间的潜在机制。结果:我们筛选了44个HF相关的6a - snp,其中10个6a - snp在HF中显示了eQTL信号和差异表达。CDKN1A中SNP rs1801270与HF的相关性最强(P = 7.75 × 10 -6)。此外,MR证实了CDKN1A蛋白与HF之间的遗传关联,以及血压(BP)在这一途径中的介导作用。较高的CDKN1A循环水平与较低的HF风险相关(优势比[OR] = 0.82, 95%可信区间[CI]: 0.69 ~ 0.99)。高血压、收缩压和舒张压的比例分别为48.10%、28.94%和18.02%。PDIA6 (P = 1.30 × 10 -2)和SMAD3 (P = 4.80 × 10 -2)与HF也存在相关性。结论:本研究发现了多个hf相关的m 6a - snp。证实了CDKN1A等蛋白与HF及其危险因素的遗传关联,为进一步探索HF的分子机制提供了新的思路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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