CDKN1A as a target of senescence in heart failure: insights from a multiomics study

2024

Frontiers in Pharmacology, Vol 15 (2024)

BackgroundCardiomyocyte senescence plays a crucial role as a pathological mechanism in heart failure (HF). However, the exact triggering factors and underlying causes of HF onset and progression are still not fully understood.ObjectivesBy integrating multi-omics data, this study aimed to determine the genetic associations between cardiomyocyte and HF using cell senescence-related genes (SRGs).MethodsThe study utilized the CellAge database and the SenMayo dataset, combined with high-resolution single-cell RNA sequencing (scRNA-seq) data, to identify SRG and examine differences in cardiac cell expression. To explore the causal relationship with HF using Mendelian Randomization (MR). Genetic variations influencing gene expression, DNA methylation, and protein expression (cis-eQTL, cis-mQTL, and cis-pQTL) were analyzed using the two-sample MR (TSMR) and summary-data-based MR (SMR). Additionally, Bayesian colocalization analysis, germline genetic variation, and bulk RNA data were employed to strengthen the reliability of the results. The application potential of therapeutic targets is ultimately assessed by evaluating their druggability.ResultsThe expression of 39 SRGs in cardiomyocytes was identified. In the discovery set revealed that CDKN1A (OR = 1.09, 95% confidence interval (CI) 1.02–1.15, FDR = 0.048) could be causally related to HF, and the results are also replicated in the validation set (OR = 1.20, 95% confidence interval (CI) 1.10–1.30, FDR

article

English

Frontiers Media S.A., 2024.

heart failure, Mendelian randomization, cardiomyocyte, senescence, omics analysis, Therapeutics. Pharmacology, RM1-950