Journal Article

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

Tang, Yongjun, Yang, Peiran, Zhang, Peng, Chen, Hong, Zhang, Yu, Xie, Wanmu, Lei, Jieping, Liu, Zhihong, Duan, Wenxin, Yang, Guoru, Fu, Xi, Zuo, Xianbo, Weng, Haoyi, Zhu, Ling, Zeng, Mian, Ying, Kejing, Gao, Qian, Liu, Bo, Zhen, Kaiyuan, Chen, Gang, Zhai, Zhenguo, Ji, Yingqun, Zhang, Nuofu, Wan, Jun, Wang, Dingyi, Deng, Chao, Dong, Lixia, Zhang, Ping, Zhang, Xiangyan, Pang, Wenyi, Xu, Qixia, Yang, Yuanhua, Huang, Qiang, Zhang, Yunxia, Wang, Shengfeng, Wu, Sinan, Zhang, Shuai, Li, Haobo, Shu, Shi, Yuan, Yadong, Zhu, Guangfa, Xia, Shuyue, Zhou, Geyu, Xu, Xiaomao, Zhang, Zhu, Yang, Xiaohong, Zhang, Meng, Wang, Chen

2023

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: ABO system / Analysis / Biomedicine / Care and treatment / China - epidemiology / Datasets / Diagnosis / Disease susceptibility / East Asian People - genetics / Embolism / Ethics / Fatty acids / Gene expression / Genetic aspects / Genetic Predisposition to Disease - genetics / Genome-wide association studies / Genome-Wide Association Study - methods / Genomes / Genotype / Genotype & phenotype / GWAS / Han Chinese / Health risk assessment / Heritability / Humans / Low density lipoprotein / Medicine / Medicine & Public Health / Meta-analysis / Metabolic pathways / Methods / Plasmids / Polymorphism, Single Nucleotide - genetics / Population studies / Pulmonary embolism / Pulmonary Embolism - epidemiology / Pulmonary Embolism - ethnology / Pulmonary Embolism - genetics / Pulmonary embolisms / Quality control / Replication / Research Article / Risk / Risk Factors / Thromboembolism / Western blotting