Key result
Increased TAGLN2 protein abundance was associated with a higher risk of pulmonary arterial hypertension, with PFOS identified as a potential environmental upregulator.
Why the study?
Although genetic and environmental factors are implicated in idiopathic pulmonary arterial hypertension pathogenesis, the underlying mechanisms remain unclear.
Observational (n=345,935)
Answers are grounded in this paper and cite their sources.
This study identifies TAGLN2 as a genetically associated candidate gene for PAH and suggests that environmental pollutants like PFOS may target TAGLN2 to promote pulmonary artery smooth muscle cell proliferation.
Background Idiopathic pulmonary arterial hypertension (PAH) is a progressive cardiovascular disorder with high mortality. Although both genetic and environmental factors are implicated in its pathogenesis, the underlying mechanisms remain unclear. Methods We integrated transcriptomic data from PAH lung tissue, GWAS summary statistics, and QTL data for DNA methylation, gene expression, and plasma protein. Core dysregulated genes were first identified via differential expression and protein-protein interaction network analysis. Using summary-data-based Mendelian randomization (SMR), we systematically evaluated potential potential genetic associations between methylation, expression, or protein levels of candidate genes and PAH risk, with the HEIDI test to distinguish causality from pleiotropy. Key findings were validated by examining gene expression trends in two independent cohorts. Finally, reverse network toxicology was applied: environmental pollutants targeting identified genes were screened using the CTD, their binding potential assessed via molecular docking, and effects of a candidate pollutant on gene expression and cell proliferation validated in vitro in human pulmonary artery smooth muscle cells (HPASMCs). Results We identified 254 differentially expressed genes in PAH. Among these, TAGLN2 exhibited a significant positive association with PAH risk at three molecular levels—DNA methylation, gene expression, and plasma protein, suggesting a pathogenic role. Specifically, increased TAGLN2 protein abundance (HR = 9.00, 95% CI: 1.52–53.16) and gene expression levels (HR = 9.00, 95% CI: 1.52–53.16) were associated with higher PAH risk, while its methylation sites (e.g., cg13892570, cg16107628) showed a negative association. Validation in two independent cohorts confirmed that TAGLN2 expression was upregulated in the lung tissue of PAH patients. Reverse toxicology predicted eight environmental pollutants as potential TAGLN2-targeting agents, including PFOS, dibutyl phthalate, bisphenols, and benzo[a]pyrene. Molecular docking indicated that all these compounds could bind stably to the TAGLN2 protein (binding free energy < −5.0 kcal/mol), with PFOS exhibiting the strongest binding affinity (−8.9 kcal/mol). In vitro experiments showed that PFOS upregulated TAGLN2 mRNA expression in HPASMCs and promoted cell proliferation in a dose-dependent manner, providing preliminary correlative evidence. Conclusion This study prioritizes TAGLN2 as a genetically associated candidate gene for PAH and identifies environmental pollutants that may target TAGLN2. While the in vitro data show that PFOS upregulates TAGLN2 expression and promotes HPASMC proliferation, functional perturbation experiments are needed to establish a mechanistic requirement for TAGLN2. These findings provide hypothesis-generating insights into potential gene-environment interactions in PAH.
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You et al. (2026) conducted an observational in Pulmonary arterial hypertension (n=345,935). Increased TAGLN2 protein abundance vs. Lower TAGLN2 protein abundance was evaluated on Pulmonary arterial hypertension risk (HR 9.00, 95% CI 1.52-53.16, p=0.015). Increased TAGLN2 protein abundance was associated with a higher risk of pulmonary arterial hypertension, with PFOS identified as a potential environmental upregulator.
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