Genome-wide association analyses identified novel susceptibility loci for pulmonary embolism among Han Chinese population

Abstract

AbstractBackgroundA large proportion of pulmonary embolism (PE) heritability remains unexplained, particularly among the East Asian (EAS) population. Our study aims to expand the genetic architecture of PE and reveal more genetic determinants in Han Chinese.MethodsWe conducted the first genome-wide association study (GWAS) of PE in Han Chinese, then performed the GWAS meta-analysis based on the discovery and replication stages. To validate the effect of the risk allele, qPCR and Western blotting experiments were used to investigate possible changes in gene expression. Mendelian randomization (MR) analysis was employed to implicate pathogenic mechanisms, and a polygenic risk score (PRS) for PE risk prediction was generated.ResultsAfter meta-analysis of the discovery dataset (622 cases, 8853 controls) and replication dataset (646 cases, 8810 controls), GWAS identified 3 independent loci associated with PE, including the reported lociFGGrs2066865 (p-value = 3.81 × 10−14),ABOrs582094 (p-value = 1.16 × 10−10) and newly reported locusFABP2rs1799883 (p-value = 7.59 × 10−17). Previously reported 10 variants were successfully replicated in our cohort. Functional experiments confirmed thatFABP2-A163G(rs1799883) promoted the transcription and protein expression ofFABP2. Meanwhile, MR analysis revealed that high LDL-C and TC levels were associated with an increased risk of PE. Individuals with the top 10% of PRS had over a fivefold increased risk for PE compared to the general population.ConclusionsWe identifiedFABP2, related to the transport of long-chain fatty acids, contributing to the risk of PE and provided more evidence for the essential role of metabolic pathways in PE development.