Novel biomarkers related to mitochondrial permeability transition driven-necrosis in hypertrophic cardiomyopathy.

Background: The role of mitochondrial permeability transition driven necrosis-related genes (MPTDN-RGs) in hypertrophic cardiomyopathy (HCM) is unclear. This investigation combined transcriptomics and Mendelian randomization (MR) analysis to explore the association of MPTDN-RGs with HCM.

Methods: GSE36961 (training set), GSE141910 (validation set), and GSE174691 (single-cell dataset) were retrieved from Gene Expression Omnibus (GEO) database. This study is based on scRNA-seq and transcriptome sequencing (mRNA Sequencing, mRNA-seq) data combined with MR, and use MPTDN-RGs to identify genes of HCM.

Results: Based on 51 interaction genes overlapped by 250 module genes and 154 differentially expressed genes, the top 10 genes within protein-protein interaction (PPI) core network were regarded as candidate genes. ITGB2 and STAT3 were screened out as genes by multiple analysis methods. MR results revealed that ITGB2 was a risk factor, while STAT3 was a protective factor for HCM. Gene set enrichment analysis (GSEA) indicated that ITGB2 and STAT3 were involved in complement and coagulation cascade. Moreover, ITGB2 had the strongest positive and significant correlations with myeloid-derived suppressor cells and chemokine receptor. Single cell analysis showed that STAT3 was highly expressed in endothelial cells, while ITGB2 was significantly greater in dendritic cells. During the process of differentiation, the expression of ITGB2 and STAT3 were decreased, and dendritic cells gradually differentiated and matured to play a role in immune function.

Conclusion: To our knowledge, this is the first study to identify the novel genes related to MPTDN in HCM by combining transcriptomics and MR analysis. Two key genes play a critical role in HCM. ITGB2 and STAT3 deserve further investigation as potential therapeutic targets for HCM.