| Title: | Development and validation of a genetic probability for venous thromboembolism |
| Journal: | Research and Practice in Thrombosis and Haemostasis |
| Published: | 27 Apr 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40496845/ |
| DOI: | https://doi.org/10.1016/j.rpth.2025.102876 |
Publication 15797
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Abstract
Background: Factor V Leiden (FVL) and prothrombin gene mutations (PGMs), as well as recently developed polygenic scores (PGSs), have been consistently associated with venous thromboembolism (VTE) risk in European ancestry populations.</p>
Objectives: This study aimed to develop an optimized risk-assessment tool combining mutations and PGS for diverse ancestry populations.</p>
Methods: The association of VTE risk with FVL/PGM and PGS was tested using multivariable analyses in the UK Biobank. A genetic probability for VTE (GenProb-VTE) combining PGS and FVL/PGM was developed. Its discriminative and reclassification performances over FVL/PGM alone were assessed using observed VTE rate and the continuous net reclassification index, respectively. Results were validated in the Genomic Health Initiative of Endeavor Health, an ancestry-diverse health care system-based biobank.</p>
Results: Among 432,831 participants in the UK Biobank, FVL, PGM, and PGS were significantly and independently associated with VTE risk (P < .001). Compared with FVL/PGM alone, GenProb-VTE identified 1.5 times more high-risk subjects whose observed VTE rates exceeded those of FVL/PGM carriers. GenProb-VTE also significantly reclassified VTE risk from the model with FVL/PGM alone, with continuous net reclassification index of 0.10 (P < .001). VTE risk was reclassified in FVL/PGM heterozygous carriers (51%) and homozygous/compound heterozygous carriers (46%) as well as noncarriers (14%). These results were validated among 16,341 participants in the Genomic Health Initiative, in participants of both European and non-European ancestry.</p>
Conclusion: GenProb-VTE, an optimized tool combining PGS with FVL/PGM, significantly improves VTE risk assessment compared with FVL/PGM alone in diverse ancestry populations. It provides a novel tool for genetic risk assessment of VTE.</p>
18 Authors
- Zhuqing Shi
- Ashley J. Mulford
- Huy Tran
- Michal Filipczak
- Song Gao
- Stevie Xie
- Jason Lobel
- Jun Wei
- Andrew S. Rifkin
- Annabelle Ashworth
- Siqun Lilly Zheng
- Clay Wiske
- David Duggan
- Brian T. Helfand
- Arman Qamar
- Alan R. Sanders
- Alfonso J. Tafur
- Jianfeng Xu
1 Application
| Application ID | Title |
|---|---|
| 50295 | Validity and performance of inherited risk assessment for common diseases using polygenic risk score, family history, and high-penetrance genes |
Enabling scientific discoveries that improve human health