Combination of Biological Aging and Genetic Susceptibility Helps Identifying At‐Risk Population of Venous Thromboembolism: A Prospective Cohort Study of 394 041 Participants

Phenotypic age acceleration (PhenoAgeAccel) is a novel clinical aging indicator. This study was carried out to investigate the relationship between PhenoAgeAccel and the incidence of VTE, as well as to integrate PhenoAgeAccel with genetic susceptibility to improve risk stratification of VTE. The study included 394 041 individuals from the UK Biobank. Phenotypic age was calculated based on actual age and clinical biomarkers. PhenoAgeAccel presents the residual obtained from a linear regression of phenotypic age against actual age, reflecting the rate of aging. Significant associations were observed between PhenoAgeAccel and higher risk of VTE (Hazard ratio [HR] 1.37, 95% CI: 1.32–1.42), deep vein thrombosis (DVT, HR 1.35, 95% CI: 1.29–1.42), and PE (pulmonary embolism, HR 1.41, 95% CI: 1.34–1.48) in the findings. PhenoAgeAccel exhibited a significant additive interaction with genetic susceptibility. Biologically older participants with high genetic risk have a 3.83 (95% CI: 3.51–4.18) folds risk of VTE, a 3.59 (95% CI: 3.21–4.03) folds risk of DVT, and 4.39 (95% CI: 3.88–4.98) folds risk of PE, in comparison to biologically younger participants with low genetic risk. Mediation analyses indicated that PhenoAgeAccel mediated approximately 6% of the association between cancer and VTE, and about 20% of the association between obesity and VTE. Our study indicated that PhenoAgeAccel is significantly associated with higher risk of VTE, and can be combined with genetic risk to improve VTE risk stratification. Additionally, PhenoAgeAccel holds promise as a clinical biomarker for guiding targeted prevention and treatment strategies for VTE.