Gene expression integration and similarity score-based modeling improve risk stratification in idiopathic venous thrombophilia.

BACKGROUND

Idiopathic venous thromboembolism (VTE) occurs in the absence of provoking factors, limiting the efficacy of current risk stratification. In parallel, the lack of integration between transcriptomic data and established risk factors prevents the identification of individuals with a high baseline predisposition.

OBJECTIVES

We aimed to improve risk stratification of idiopathic VTE beyond traditional clinical models by developing a similarity-based risk score that integrates transcriptomic profiles with conventional risk factors.

METHODS

We analyzed 790 individuals from the Genetic Analysis of Idiopathic Thrombophilia 2 familial study, including 70 participants with prior idiopathic VTE. Whole-blood RNA sequencing, known genetic variants, and clinical variables were integrated using supervised machine learning models (Elastic Net and XGBoost). Predictive gene expression features were evaluated through enrichment analyses. A unified similarity score combining both models was developed to identify control individuals who shared transcriptomic and clinical profiles with VTE cases.

RESULTS

In both models, von Willebrand factor abundance was the strongest predictor of VTE, followed by clinical factors (body mass index, ABO alleles, and age) and expression of 494 genes, including STS, FAM13A, GPRIN1, FLVCR2, FAM177B, and several long noncoding RNAs not previously linked to thrombosis. Known thrombosis-associated genes such as UQCRC2 and PRKRA were also identified. Significant enrichment was observed for cardiomyopathic Kyoto Encyclopedia of Genes and Genomes pathways and renal Human Protein Atlas terms. Similarity-based risk score construction improved classification, with 74% of VTE cases and 23% of controls assigned to the risk zone.

CONCLUSION

Multivariate integration via machine learning enhances VTE risk stratification, identifying novel transcriptomic signatures and lncRNA biomarkers that offer new strategies for VTE personalized prevention.