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

ABSTRACT: 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. 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. 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. 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.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC10116678 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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

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

BMC medicine 20230419 1

<h4>Background</h4>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.<h4>Methods</h4>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 Wester ...[more]

PMID: 37076872

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Project description:BackgroundPulmonary hypertension (PH) is a rare disease characterized by proliferation and occlusion of small pulmonary arterioles, which has been associated with a high mortality rate. The pathogenesis of PH is complex and incompletely understood, which includes both genetic and environmental factors that alter vascular structure and function.MethodsThus we aimed to reveal the potential genetic etiology of PH by targeting 143 tag SNPs of 14 candidate genes. Totally 208 individuals from Chinese Han population were enrolled in the present study, including 109 non-idiopathic PH patients and 99 healthy controls.ResultsThe data revealed that 2 SNPs were associated with PH overall susceptibility at p < 3×10- 4 after Bonferroni correction. The top hit was rs6557421 (p = 4.5×10- 9), located within Nox3 gene on chromosome 6. Another SNP rs3744439 located in Tbx4 gene, also showed evidence of association with PH susceptibility (p = 1.2×10- 6). The distribution of genotype frequencies of rs6557421 and rs3744439 have dramatic differences between PH patients and controls. Individuals with rs6557421 TT genotype had a 10.72-fold/14.20-fold increased risk to develop PH when compared with GG or GG/GT carriers in codominant or recessive model, respectively (TT versus GG: 95%CI = 4.79-24.00; TT versus GG/GT: 95%CI = 6.65-30.33). As for rs3744439, AG genotype only occurred in healthy controls but has not been observed in PH patients. We further validated the result by using 26 different populations from five regions around the globe, including African (AFR), American (AMR), East Asian (EAS), European (EUR), and South Asian (SAS). In consistent with the present case-control study's results, significantly different genotype frequencies of the observed SNPs existed between PH patients and healthy individuals from all over the world.ConclusionsThe results suggested that rs6557421 variant in Nox3 and rs3744439 variant in Tbx4 might have potential effect on individual susceptibility to pulmonary hypertension, which could lead to therapeutic or diagnosis approaches in PH.

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

Publications

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

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