Complementary multi‐omics profiling of chronic thromboembolic pulmonary hypertension reveals immune cell alterations, epigenetic changes, and genetically supported candidate genes

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is driven by unresolved pulmonary arterial thrombi and involves complex processes such as vascular remodeling and immune dysregulation. Early identification of molecular markers may support more accurate diagnosis and individualized therapy. METHODS: We integrated anthropometric and biochemical data with single-cell RNA sequencing (scRNA-seq), DNA methylation, and Mendelian randomization (MR) analyses. scRNA-seq data were analyzed to determine altered cell populations and pathways. MR and colocalization analyses were conducted to identify genetically supported candidates related to CTEPH. RESULTS: scRNA-seq analysis revealed altered immune composition, with a modest increase in NK cells and an angiogenesis-associated enrichment of monocytes and HSC-G-CSF cells in CTEPH patients, accompanied by activation of toll-like receptor and MAPK signaling pathways. MR and colocalization identified several genetically associated genes-CLEC7A, TNFSF13B, LRP1, ETS1, and FGR-of which ETS1 and FGR demonstrated good diagnostic performance. DNA methylation analysis indicated marked alterations in chromatin assembly and epigenetic regulation. CONCLUSIONS: This multi-omics study highlights critical genes, epigenetic features, and immune-related cell populations associated with CTEPH. These findings improve understanding of disease mechanisms and offer potential biomarkers for early diagnosis and personalized management.