Genetic and biological determinants of pulmonary embolism: Insights from Mendelian randomization studies

Abstract

Pulmonary embolism (PE) is a common and potentially fatal thromboembolic disease contributing to a major global public health burden. Its pathogenesis involves multiple hemodynamic, inflammatory, metabolic, and genetic factors. The multifactorial nature of PE makes it difficult to infer the direct effects of risk factors using conventional statistical approaches because of potential confounding and reverse causality. Mendelian randomization (MR) uses genetic variants as instrumental variables to strengthen causal inference. This narrative review synthesizes the available MR literature concerning potential causative factors of PE, with particular emphasis on genetic and biological pathways. MR evidence suggests that matrix metalloproteinases (MMP)-19 may be associated with increased PE susceptibility, whereas MMP-12 may be associated with decreased susceptibility. Impaired kidney function showed a positive association with PE risk, and reduced HLA-DR⁺ NK cell traits were linked to PE pathogenesis. Among gut microbiota, Clostridium innocuum was associated with increased PE risk, whereas Butyricicoccus and Actinobacteria showed protective associations. No consistent causal associations were identified for type 2 diabetes, atrial fibrillation, or epigenetic age acceleration. Larger multiethnic studies integrating multi-omics data are needed to clarify mechanisms underlying PE pathogenesis.

Keywords: Pulmonary embolism; Mendelian randomization; Matrix metalloproteinases; Immune dysregulation; Renal dysfunction; Genetic epidemiology; Thrombosis; Risk factors

Core Tip: Mendelian randomization evidence indicates that matrix metalloproteinases (MMP)-19 may be associated with increased risk of pulmonary embolism (PE), while MMP-12 may exhibit an inverse association. Reduced kidney function appears to have a potential genetic association with PE susceptibility. Immune pathways involving HLA-DR-positive natural killer cell traits and gut microbiota-related factors, such as Clostridium innocuum, Butyricicoccus, and Actinobacteria, may also contribute to PE susceptibility. In contrast, no consistent associations were observed for type 2 diabetes mellitus, atrial fibrillation, or epigenetic age acceleration. These findings underscore emerging biological pathways in PE; however, they should be interpreted cautiously, as they are hypothesis-generating and require further validation.