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

Abstract

Background A 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. Methods We 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. Results After 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 loci FGG rs2066865 (p-value = 3.81 × 10−14), ABO rs582094 (p-value = 1.16 × 10−10) and newly reported locus FABP2 rs1799883 (p-value = 7.59 × 10−17). Previously reported 10 variants were successfully replicated in our cohort. Functional experiments confirmed that FABP2-A163G(rs1799883) promoted the transcription and protein expression of FABP2. 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. Conclusions We identified FABP2, 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.

Tissue‐type plasminogen activator (tPA) homozygous Tyr471His mutation associates with thromboembolic disease

“…Currently, there are insufficient data to verify the association of mutations in the PLAT gene with venous or arterial thrombosis. 38 , 39 According to the prediction, the mutation c.1411T>C (p.Y471H) in PLAT is predicted to be probably harmful ( http://genetics.bwh.harvard.edu/pph2/ ), which is consistent with our clinical findings and research results. However, it has also been reported that the heterozygous point mutation c.1411T>C in PLAT is likely to be a non‐pathogenic benign mutation ( http://www.gnomad‐sg.org/ ), which may be the reason why the parents and daughter of the proband did not have venous thromboembolism events despite carrying heterozygous point mutation c.1411T>C in PLAT .…”

Blood lipids mediate the effects of gut microbiome on endometriosis: a mendelian randomization study

“…In addition, the coagulation function might be another mechanism that should be noted. One GWAS study has reported that LDL and TC were associated with an increased risk of pulmonary embolism, suggesting the lipids traits were involved in coagulation pathways [ 59 ]. Another MR study has demonstrated the causal associations between ADAMTS13/vWF and the risk of endometriosis, suggesting the involvement of coagulation factors in endometriosis development [ 60 ].…”

Reply to author: “uric acid's influence on venous thromboembolism in East Asia”

“…2 We would like to address the specific points raised by Lixian Ji and Peng Shu as follows: Regarding the PE and VTE distinction : We acknowledge this oversight in our study and agree that it is crucial to specify that our study primarily focused on pulmonary embolism (PE) or PE with deep vein thrombosis (DVT). 3 , 4 By providing this clarification, we can prevent potential misconceptions and ensure that the implications of our findings are appropriately understood within the relevant context. On the instrumental variable clumping process : It should be noted that similar to GWAS studies, there is currently no standardized criterion for determining the appropriate clumping thresholds in Mendelian randomization (MR) research.…”

“…Regarding the PE and VTE distinction : We acknowledge this oversight in our study and agree that it is crucial to specify that our study primarily focused on pulmonary embolism (PE) or PE with deep vein thrombosis (DVT). 3 , 4 By providing this clarification, we can prevent potential misconceptions and ensure that the implications of our findings are appropriately understood within the relevant context.…”