Exploring Targets for Heart Failure Using Mendelian Randomization, Colocalization, Summary Data-based Mendelian Randomization, and Drug Prediction

Summary

This study identified eight potential drug targets for heart failure through genetic analysis and explored candidate therapeutic compounds associated with these identified targets.

Abstract

Heart failure (HF) is a prevalent cardiovascular disease that significantly impairs quality of life in its advanced stages. Despite a variety of current treatment strategies, the disease burden of HF remains significant. Therefore, exploring novel therapeutic targets is urgently needed. This study utilized Mendelian randomization (MR) to evaluate the causal relationships between druggable genes and HF. Colocalization analysis and summary data-based Mendelian randomization (SMR) were conducted to further validate the relationship between them. Finally, 8 potential therapeutic targets for HF were identified, including 4 risk factors (CYP11A1, GALT, KCNH2, and METRN) and 4 protective factors (APOM, CHD4, IL11RA, and LPAR5). The GO enrichment, KEGG enrichment, and protein-protein interaction (PPI) network analysis indicated that these genes were primarily involved in metabolic regulation and cardiac electrophysiological processes. Moreover, potential drugs targeting these targets were identified using drug prediction and molecular docking, including mitotane, Adehl, Benzofurans, 1,3-Di-o-tolylguanidine, 96-69-5, and bromoenol lactone. Furthermore, PCR results also demonstrated that mitotane might be associated with CYP11A1 and KCNH2. Drugs designed based on these potential therapeutic targets may offer higher success rates and improve clinical outcomes.

Introduction

Heart failure (HF) is a prevalent cardiovascular syndrome defined by impaired ventricular filling or myocardial contractility, resulting in inadequate cardiac output to meet metabolic demands^1,2,3. Clinically, HF is characterized by pulmonary and systemic congestion, tissue hypoperfusion, and symptoms such as dyspnea, fatigue, and peripheral edema^1,4,5. Despite therapeutic advances, HF remains a leading cause of morbidity and mortality worldwide, affecting over 64 million individuals....

Protocol

All datasets used in this study were obtained from previously published studies with ethical approval. The reagents and the equipment used are listed in the Table of Materials.

1. Study design

The workflow of this study is illustrated in Figure 1. First, exposure data were obtained from the cis-eQTLs of druggable genes. Second, MR analysis was conducted to investigate the causal relationship between druggable genes and HF. Candidate therapeutic targets for HF were subsequently identified by colocalization and SMR analyses. Gene enrichment analysis and ....

Results

Mendelian randomization
The MR results evaluating the causal effects between druggable gene expression and HF were presented in Supplementary Table 3. An FDR-adjusted P value less than 0.05 was considered statistically significant. A total of 11 genes with significant causal associations with HF were identified (Figure 2). Among them, six genes were associated with an increased risk of HF, including CDKN1A (P_FDR: 0.03, OR: 1.293), CYP11A1 <.......

Discussion

This research systematically evaluated the causal effects of druggable genes on HF risk by using MR, identifying eight potential therapeutic targets. These included four protective factors (APOM, CHD4, IL11RA, and LPAR5) and four risk factors (CYP11A1, GALT, KCNH2, and METRN). These associations were further supported by colocalization analysis and SMR. Functional annotation through GO, KEGG enrichment, and PPI network analyses suggested that these genes may influence HF primarily through pathways related to metabolism a.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
2× Universal SYBR Green Fast qPCR Mix	Abclonal	RK21203
AC16	HyCyte	TCH-C119
AC16 cell-specific culture medium	HyCyte	TCH-G119
cDNA reverse kit	Abclonal	RK20400
CFX96™ Real-Time system	Bio-Rad Laboratories
Mitotane	TargetMol	T1199
Palmitic acid	TargetMol	T2908
RNA extraction kit	Abclonal	RK30120