Abstract
BACKGROUND: Recent research increasingly highlights a strong correlation between systemic hypercoagulability and the risk of lung cancer (LC). However, whether this relationship is causal or merely coincidental remains uncertain. To address this, a Mendelian randomization (MR) analysis was undertaken to explore the connections between coagulation factors and LC. METHODS: Genome-wide association study (GWAS) summary statistics for LC subtypes were retrieved from European ancestry meta-analyses via the IEU Open GWAS project, encompassing three distinct histological subtypes: squamous cell carcinoma, adenocarcinoma, and small cell carcinoma. Bidirectional two sample MR analyses were performed using genome-wide significant single nucleotide polymorphisms (SNPs) as instrumental variables. To evaluate bidirectional causality between 14 coagulation factors and LC, including its subtypes, we applied multiple analytical methods, including inverse variance weighting (IVW), MR-Egger, weighted median, weighted mode, and simple mode. RESULTS: The IVW analysis revealed distinct causal associations between coagulation factors and LC subtypes. Elevated plasma levels of factor X (FX) demonstrated a significant risk effect for squamous cell carcinoma [odds ratio (OR) = 1.143, P = 0.006], while increased FVIII concentrations were positively associated with adenocarcinoma susceptibility (OR = 1.161, P = 0.049). Conversely, higher A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity exhibited a protective effect against adenocarcinoma development (OR = 0.781, P = 0.029). No statistically significant relationships were identified between any coagulation factors and small cell carcinoma. CONCLUSION: Leveraging GWAS data derived from large-scale population cohorts, our MR analysis revealed significant causal effects of FX, FVIII, and ADAMTS13 on LC risk. These findings suggest that these coagulation factors are involved in the development of LC and may represent potential therapeutic targets for the management of this complex disease.