Abstract Body (Do not enter title and authors here): Introduction:
Venous thromboembolism (VTE) carries high morbidity and mortality, highlighting the importance of early risk identification and prevention. Whether a recent polygenic risk score (PRS) could help identify those at highest risk in a longitudinal, primary prevention population is unclear.

Hypothesis:
PRS is an independent predictor of VTE risk in a primary prevention population.

Methods:
We applied the 2023 VTE PRS by Ghouse et al containing over 1 million VTE-associated SNPs to 2 primary prevention trials, JUPITER and Women’s Genome Health Study (WGHS). We calculated the adjusted hazard ratio (aHR) of VTE per 1 higher standard deviation (SD) of PRS and by risk categories: low (bottom 20%), intermediate (middle 60%), and high (top 20%) in a multivariable model adjusted for cardiovascular and demographic factors.

Results:
JUPITER included 8,749 participants (67.8% men, median age 66) with a median follow-up of 2.3 years and 77 VTE events (annualized event rate [ER] 0.38%). WGHS included 22,650 women (median age 53) with a median follow-up of 20.5 years and 618 VTE events (annualized ER 0.13%). Each SD increase in VTE PRS was associated with a 34% higher risk of VTE in JUPITER (aHR 1.34, 95% CI 1.08-1.67; p < 0.01) and a 61% higher risk in WGHS (aHR 1.61 (1.5-1.73; p < 0.01). Those in the high PRS category were 3.3-fold more likely to develop VTE compared to those with low PRS (JUPITER: aHR 3.30, 1.38-7.88; p < 0.01 and WGHS: 3.27, 2.44-4.38; p < 0.01) (Fig A, B). In comparison, Factor V and prothrombin gene mutations were associated with aHRs of 1.58 and 2.45 in JUPITER and 1.42 and 1.75 in WGHS, respectively. Additionally, the PRS predicted VTE to a similar or greater degree than established clinical risk factors. Finally, Kaplan-Meier curves demonstrated early and sustained separation in VTE events between each PRS risk group (Fig C,D).

Conclusions:
In two large primary prevention cohorts, PRS was a strong and independent predictor of VTE, with the top 20% imparting greater risk than that of established monogenic thrombophilia.