Development and validation of a genetic probability for venous thromboembolism

Area of Science:

• Genetics
• Cardiovascular Medicine
• Bioinformatics

Background:

• Factor V Leiden (FVL) and prothrombin gene mutations (PGMs) are known risk factors for venous thromboembolism (VTE).
• Polygenic scores (PGSs) are emerging tools for assessing genetic predisposition to complex diseases.
• Current risk assessment tools often lack performance in diverse ancestral populations.

Purpose of the Study:

• To develop and validate an optimized risk-assessment tool for VTE.
• To integrate common genetic variants (PGSs) with known mutations (FVL/PGM) for improved VTE risk prediction.
• To ensure the tool's efficacy across diverse ancestral groups.

Main Methods:

• Multivariable analyses were conducted in the UK Biobank to assess VTE risk associated with FVL/PGM and PGS.
• A novel genetic probability for VTE (GenProb-VTE) was developed, combining PGS and FVL/PGM.
• The tool's performance was evaluated using VTE rates and net reclassification index, with validation in the Genomic Health Initiative cohort.

Main Results:

• FVL, PGM, and PGS were independently associated with VTE risk (P < .001) in over 432,000 UK Biobank participants.
• GenProb-VTE identified 1.5 times more high-risk individuals than FVL/PGM alone, with significantly improved risk reclassification (continuous net reclassification index = 0.10, P < .001).
• Validation in the Genomic Health Initiative confirmed GenProb-VTE's effectiveness in both European and non-European ancestry participants.

Conclusions:

• GenProb-VTE enhances VTE risk assessment by combining PGS with FVL/PGM.
• The tool demonstrates improved performance compared to FVL/PGM alone, particularly in diverse populations.
• GenProb-VTE offers a novel approach for genetic risk stratification of VTE.