Work

Potential neutrophil activation-related pathogenic genes in venous thromboembolism: a multi-omics Mendelian randomization study

Year: 2025

Type: article

Abstract: BACKGROUND: Venous thromboembolism (VTE) is a major cause of global morbidity and mortality, yet its underlying molecular mechanisms remain incompletely understood, limiting the development of novel targeted therapies. While neutrophil activation is implicated in VTE, its causal role and the key genetic drivers are poorly defined. This study aimed to bridge this knowledge gap using a multi-omics genetic approach. METHODS: We conducted a Summary-data-based Mendelian Randomization (SMR) study, integrating large-scale GWAS data for VTE with molecular QTL data (mQTL, eQTL, pQTL) for 996 neutrophil activation-related genes. Causal associations were identified using SMR and validated through colocalization analysis to distinguish robust causal links from linkage. RESULTS: Our analysis identified numerous causal associations at the methylation (223 sites), expression (41 genes), and protein (21 proteins) levels. Among these, PLAU, ALOX12, and LGALS3 emerged as key candidates due to evidence of epigenetic regulation of their gene expression. Specifically, increased PLAU expression showed a causal association with higher VTE risk (OR = 1.13, 95% CI = 1.04-1.24), a finding supported by strong colocalization evidence (PPH4 > 0.5). Similarly, elevated expression of ALOX12 (OR = 1.27, 95% CI = 1.07-1.51) and LGALS3 (OR = 1.44, 95% CI = 1.04-2.01) were causally linked to increased VTE susceptibility, although these expression-level associations did not meet our stringent threshold for colocalization. CONCLUSION: This study identifies PLAU, ALOX12, and LGALS3 as genetically prioritized, causal-candidate genes for VTE, enhancing our understanding of immunothrombosis and providing promising targets for future therapeutic development.

Source: International Journal of Surgery

DOI: 10.1097/js9.0000000000004473

Authors: Qian Chen, Li Zhang, Weiling Shou, Shengli Sun, Jiaying Fang, Ye Guo

Institutions: Chinese Academy of Medical Sciences & Peking Union Medical College, Peking Union Medical College Hospital

Language: English

Topic: Genetic Associations and Epidemiology

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,450