Abstract Body (Do not enter title and authors here): Background
Current genomics studies on chronic thromboembolic pulmonary hypertension (CTEPH) have primarily focused on European populations, with limited research conducted on East Asian populations. Although CTEPH is considered a complication of acute pulmonary thromboembolism (PTE), 25% of CTEPH have no prior history of PTE.
Aim
This study aimed to uncover the genetic basis of CTEPH and identify susceptibility loci and genes from the Chinese population, seeking to understand the shared and distinct genetic mechanisms between CTEPH and PTE.
Methods
The discovery cohort enrolled 412 CTEPH and 2000 controls for whole genome sequencing. Genome-wide association analysis (GWAS) and gene annotation were performed for common variants (MAF>5%) to identify susceptibility gene. The heritability of CTEPH was calculated using LDSC. Additionally, burden test was performed in rare variants (MAF<1%) to identify candidate genes. Bulk and single-cell transcriptome analyses were performed on PEA tissues from CTEPH and controls. Method scPagwas was used to integrate GWAS and transcriptomics data.
Results
A total of 1379 SNPs reached genome-wide significance (P<5×10^-8), and 217 risk loci were identified after Clumping. LDSC estimated a heritability of 0.1217 for CTEPH. FUMA and TWAS analysis mapped 708 susceptibility genes, of which 95 genes were suggested by both common and rare variants. Several CTEPH susceptibility genes, including CYP27C1, PROC, F2, LRP4, MPHOSPH9, SBNO1, EDEM2, PROCR, and ABO, have been previously reported to be associated with VTE. However, only ABO, F2, and HLA-DRA overlap with CTEPH susceptibility genes identified in European populations. The scPagwas indicated that monocyte-macrophage trait correlation scores were highest in the single cell profiles of CTEPH. The differentially expressed genes from transcriptomics and susceptibility genes, identified five key genes: SLC11A1, SLCO2B1, RILPL2, HCK, and CTSS. SLC11A1 is primarily distributed in monocytes and macrophages and regulates multiple immune inflammation processes, including reactive oxygen species and interleukin production, and T cell differentiation. Disease-related pathways encompass the complement coagulation pathway, Th cell differentiation, and various autoimmune diseases.
Conclusion
CTEPH is influenced by genetic factors. Multiomics data suggest that abnormal immune responses mediated by high SCL11A1 expression in monocytes and macrophages may be a key mechanism in the development of CTEPH.