A1 Refereed original research article in a scientific journal
Thrombosis Risk in Single and Double Heterozygous Carriers of Factor V Leiden and Prothrombin G20210A in FinnGen and the UK Biobank
Authors: Ryu Justine, Rämö Joel T., Jurgens Sean J., Niiranen Teemu, Sanna-Cherchi Simone, Bauer Kenneth A., Haj Amelia, Choi Seung Hoan, Palotie Aarno, Daly Mark, Ellinor Patrick T., Bendapudi Pavan K.
Publisher: Elsevier
Publication year: 2024
Journal: Blood
Journal name in source: Blood
Volume: 143
Issue: 23
First page : 2425
Last page: 2432
ISSN: 0006-4971
eISSN: 1528-0020
DOI: https://doi.org/10.1182/blood.2023023326
Web address : https://doi.org/10.1182/blood.2023023326
Abstract
The Factor V Leiden (FVL, rs6025) and prothrombin G20210A (PTGM, rs1799963) polymorphisms are two of the most well-studied genetic risk factors for venous thromboembolism (VTE). However, double heterozygosity (DH) for FVL and PTGM remains poorly understood, with prior studies in marked disagreement about the thrombosis risk conferred by the DH genotype. Utilizing multi-dimensional data from the UK Biobank (UKB) and the FinnGen biorepositories, we evaluated the clinical impact of DH carrier status across 937,939 individuals. We found that 662 participants (0.07%) were DH carriers. After adjustment for age, sex, and ancestry, DH individuals experienced a markedly elevated risk of VTE compared to wild-type individuals (OR=5.24, 95% CI: 4.01 - 6.84; P=4.8 x 10-34), which approximated the risk conferred by FVL homozygosity. A secondary analysis restricted to UKB participants (N=445,144) found that effect size estimates for the DH genotype remained largely unchanged (OR=4.53, 95% CI: 3.42 – 5.90; P<1 x 10-16) after adjustment for commonly cited VTE risk factors such as body mass index, blood type, and markers of inflammation. By contrast, the DH genotype was not associated with a significantly higher risk of any arterial thrombosis phenotype, including stroke, myocardial infarction, and peripheral artery disease. In summary, we leveraged population-scale genomic datasets to conduct the largest study to date of the DH genotype and were able to establish far more precise effect size estimates than previously possible. Our findings indicate that the DH genotype may occur as frequently as FVL homozygosity and confers a similarly increased risk of VTE.
The Factor V Leiden (FVL, rs6025) and prothrombin G20210A (PTGM, rs1799963) polymorphisms are two of the most well-studied genetic risk factors for venous thromboembolism (VTE). However, double heterozygosity (DH) for FVL and PTGM remains poorly understood, with prior studies in marked disagreement about the thrombosis risk conferred by the DH genotype. Utilizing multi-dimensional data from the UK Biobank (UKB) and the FinnGen biorepositories, we evaluated the clinical impact of DH carrier status across 937,939 individuals. We found that 662 participants (0.07%) were DH carriers. After adjustment for age, sex, and ancestry, DH individuals experienced a markedly elevated risk of VTE compared to wild-type individuals (OR=5.24, 95% CI: 4.01 - 6.84; P=4.8 x 10-34), which approximated the risk conferred by FVL homozygosity. A secondary analysis restricted to UKB participants (N=445,144) found that effect size estimates for the DH genotype remained largely unchanged (OR=4.53, 95% CI: 3.42 – 5.90; P<1 x 10-16) after adjustment for commonly cited VTE risk factors such as body mass index, blood type, and markers of inflammation. By contrast, the DH genotype was not associated with a significantly higher risk of any arterial thrombosis phenotype, including stroke, myocardial infarction, and peripheral artery disease. In summary, we leveraged population-scale genomic datasets to conduct the largest study to date of the DH genotype and were able to establish far more precise effect size estimates than previously possible. Our findings indicate that the DH genotype may occur as frequently as FVL homozygosity and confers a similarly increased risk of VTE.
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