Zhang Yayun, Feng Lu, Guan Xin, Zhu Zixiong, He Yubin, Li Xuewen
Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China.
Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China.
ESC Heart Fail. 2024 Dec;11(6):4185-4200. doi: 10.1002/ehf2.15019. Epub 2024 Aug 14.
Heart failure (HF) and non-alcoholic fatty liver disease (NAFLD) are significant global health issues with a complex interrelationship. This study investigates their shared biomarkers and causal relationships using bioinformatics and Mendelian randomization (MR) approaches.
We analysed NAFLD and HF datasets from the Gene Expression Omnibus (GEO). The GSE126848 dataset included 57 liver biopsy samples [14 healthy individuals, 12 obese subjects, 15 NAFL patients and 16 non-alcoholic steatohepatitis (NASH) patients]. The GSE24807 dataset comprised 12 NASH samples and 5 healthy controls. The GSE57338 dataset included 313 cardiac muscle samples [177 HF patients (95 ischaemic heart disease patients and 82 idiopathic dilated cardiomyopathy patients) and 136 healthy controls]. The GSE84796 dataset consisted of 10 end-stage HF patients and 7 healthy hearts procured from organ donors. We identified differentially expressed genes (DEGs) and constructed a protein-protein interaction (PPI) network. Functional pathways were elucidated through enrichment analyses using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and GeneMANIA annotation. Single nucleotide polymorphism (SNP) data for HF and NAFLD were sourced from genome-wide association studies (GWAS). The HF dataset included 486 160 samples (14 262 experimental and 471 898 control), and the NAFLD dataset comprised 377 988 samples (4761 experimental and 373 227 control). MR analysis investigates the causal interrelations.
Our analysis revealed 4032 DEGs from GSE126848 and 286 DEGs from GSE57338. The top 10 hub genes (CD163, VSIG4, CXCL10, FCER1G, FPR1, C1QB, CCR1, C1orf162, MRC1 and CD38) were significantly enriched in immune response, calcium ion concentration regulation and positive regulation of monocyte chemotaxis. CIBERSORT analysis indicated associations between these hub genes and natural killer (NK) cells and macrophages. Transcription factor (TF) target prediction for CD38, CXCL10 and CCR1 highlighted related TFs. A two-sample MR analysis confirmed a bidirectional causal relationship between NAFLD and HF. The main method [inverse variance weighted (IVW)] demonstrated a significant positive causal relationship between NAFLD and HF [P = 0.037; odds ratio (OR) = 1.024; 95% confidence interval (CI): 1.001 to 1.048]. Similarly, HF was associated with an increase in the risk of NAFLD (P < 0.001; OR = 1.117; 95% CI: 1.053 to 1.185).
Our findings reveal novel molecular signatures common to NAFLD and HF and confirm their bidirectional causality, highlighting the potential for targeted therapeutic interventions and prompting further investigation into their intricate relationship.
心力衰竭（HF）和非酒精性脂肪性肝病（NAFLD）是具有复杂相互关系的重大全球健康问题。本研究使用生物信息学和孟德尔随机化（MR）方法研究它们共同的生物标志物和因果关系。
我们分析了来自基因表达综合数据库（GEO）的NAFLD和HF数据集。GSE126848数据集包括57个肝活检样本[14名健康个体、12名肥胖受试者、15名NAFL患者和16名非酒精性脂肪性肝炎（NASH）患者]。GSE24807数据集包含12个NASH样本和5个健康对照。GSE57338数据集包括313个心肌样本[177名HF患者（95名缺血性心脏病患者和82名特发性扩张型心肌病患者）和136名健康对照]。GSE84796数据集由10名终末期HF患者和7个从器官供体获取的健康心脏组成。我们鉴定了差异表达基因（DEG）并构建了蛋白质-蛋白质相互作用（PPI）网络。通过使用基因本体论（GO）、京都基因与基因组百科全书（KEGG）和GeneMANIA注释进行富集分析来阐明功能途径。HF和NAFLD的单核苷酸多态性（SNP）数据来自全基因组关联研究（GWAS）。HF数据集包括486160个样本（14262个实验样本和471898个对照样本），NAFLD数据集包括377988个样本（4761个实验样本和373227个对照样本）。MR分析研究因果相互关系。
我们的分析从GSE126848中鉴定出4032个DEG，从GSE57338中鉴定出286个DEG。前10个枢纽基因（CD163、VSIG4、CXCL10、FCER1G、FPR1、C1QB、CCR1、C1orf162、MRC1和CD38）在免疫反应、钙离子浓度调节和单核细胞趋化性的正调节中显著富集。CIBERSORT分析表明这些枢纽基因与自然杀伤（NK）细胞和巨噬细胞之间存在关联。对CD38、CXCL10和CCR1的转录因子（TF）靶标预测突出了相关的TF。两样本MR分析证实了NAFLD与HF之间的双向因果关系。主要方法[逆方差加权（IVW）]显示NAFLD与HF之间存在显著的正因果关系[P = 0.
