Integration of hereditary thrombophilia data and polygenic risk scores into prognostic models improves differential diagnosis of CTEPH.
4 affiliations
- 1Centre for Biomedical Research and Technologies, Institute of Artificial Intelligence and Digital Sciences, HSE University, Moscow, Russia.
- 2City Clinical Hospital No 29 by N.E. Bauman, Moscow, Russia.
- 3Faculty of Physics, Lomonosov Moscow State University, Moscow, Russia.
- 4Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.
Abstract
Background
Differential diagnosis between pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) is crucial for treatment selection, particularly regarding surgical intervention. The prevalence of hereditary thrombophilias in Russian CTEPH patients and the utility of genetic data in differential diagnosis remain understudied.Objectives
To evaluate the prevalence of inherited thrombophilia among patients with CTEPH and PAH, to benchmark the results against published data from other cohorts, and to assess the potential utility of integrating genetic findings and polygenic risk score (PRS) parameters with clinical data for differentiating CTEPH from PAH.Methods
The study included 390 patients (252 PAH, 138 CTEPH). Whole-genome sequencing was performed to analyze classical thrombophilia genes (PROC, PROS1, SERPINC1, F2, F5, ADAMTS13, HRG, JAK2, PIGA, THBD, F9, FGA, FGB, FGG, CALR) and calculate VTE polygenic risk scores. A meta-analysis of 15 studies on hereditary thrombophilia prevalence in CTEPH was conducted. AutoML algorithm was used to construct diagnostic models.Results
Rare variants in thrombosis-associated genes were significantly more prevalent in patients with CTEPH than in those with PAH (12.3% vs. 1.2%, p < 0.001). Similarly, carriers of the common F5 and F2 thrombophilia variants were more frequent in the CTEPH group (15.9% vs. 6.3%, p = 0.002). Meta-analysis yielded pooled prevalence estimates in CTEPH of 3.0% for antithrombin deficiency, 3.6% for protein S deficiency, 4.7% for protein C deficiency, 7.9% for F5 Leiden, and 5.6% for F2 G20210A; these estimates were consistent with those reported in other populations. The clinical model yielded an ROC AUC of 0.883. The addition of PGS004854 and rare variants in thrombosis-associated genes increased the AUC to 0.951, representing an absolute increase of 0.068 (7.7%; p = 0.026). In the multivariable model, PGS004854 was the strongest positive genetic predictor of CTEPH (β = 1.869, p < 0.001).Conclusions
The genetic profile of CTEPH patients differs significantly from PAH, with a higher frequency of hereditary thrombotic risk factors. Integrating clinical data with polygenic risk scores and thrombophilia variants improves differential diagnosis accuracy and may optimize the clinical workup.
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BibTeX
@article{kubkin2026integration,
title = {{Integration of hereditary thrombophilia data and polygenic risk scores into prognostic models improves differential diagnosis of CTEPH.}},
author = {Yaroslav Kubkin and Dmitry Nikulin and Galina Okhrimenko and Larisa Minushkina and Elizaveta Dyachkova and Anna Lyzhenkova and Anna Danilova and Elena Dankovtseva and Irina Borovikova and Vladimir Zamyatin and Alexander Averyanov and Maria Poptsova and Dmitry Zateyshchikov},
journal = {Frontiers in cardiovascular medicine},
year = {2026},
month = oct,
doi = {10.3389/fcvm.2026.1887880},
url = {https://europepmc.org/article/MED/42898819},
note = {CC BY},
}
RIS
TY - JOUR
TI - Integration of hereditary thrombophilia data and polygenic risk scores into prognostic models improves differential diagnosis of CTEPH.
AU - Yaroslav Kubkin
AU - Dmitry Nikulin
AU - Galina Okhrimenko
AU - Larisa Minushkina
AU - Elizaveta Dyachkova
AU - Anna Lyzhenkova
AU - Anna Danilova
AU - Elena Dankovtseva
AU - Irina Borovikova
AU - Vladimir Zamyatin
AU - Alexander Averyanov
AU - Maria Poptsova
AU - Dmitry Zateyshchikov
PY - 2026
DA - 2026/10/05
JO - Frontiers in cardiovascular medicine
DO - 10.3389/fcvm.2026.1887880
UR - https://europepmc.org/article/MED/42898819
AB - Background Differential diagnosis between pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) is crucial for treatment selection, particularly regarding surgical intervention. The prevalence of hereditary thrombophilias in Russian CTEPH patients and the utility of genetic data in differential diagnosis remain understudied.Objectives To evaluate the prevalence of inherited thrombophilia among patients with CTEPH and PAH, to benchmark the results against published data from other cohorts, and to assess the potential utility of integrating genetic findings and polygenic risk score (PRS) parameters with clinical data for differentiating CTEPH from PAH.Methods The study included 390 patients (252 PAH, 138 CTEPH). Whole-genome sequencing was performed to analyze classical thrombophilia genes (PROC, PROS1, SERPINC1, F2, F5, ADAMTS13, HRG, JAK2, PIGA, THBD, F9, FGA, FGB, FGG, CALR) and calculate VTE polygenic risk scores. A meta-analysis of 15 studies on hereditary thrombophilia prevalence in CTEPH was conducted. AutoML algorithm was used to construct diagnostic models.Results Rare variants in thrombosis-associated genes were significantly more prevalent in patients with CTEPH than in those with PAH (12.3% vs. 1.2%, p < 0.001). Similarly, carriers of the common F5 and F2 thrombophilia variants were more frequent in the CTEPH group (15.9% vs. 6.3%, p = 0.002). Meta-analysis yielded pooled prevalence estimates in CTEPH of 3.0% for antithrombin deficiency, 3.6% for protein S deficiency, 4.7% for protein C deficiency, 7.9% for F5 Leiden, and 5.6% for F2 G20210A; these estimates were consistent with those reported in other populations. The clinical model yielded an ROC AUC of 0.883. The addition of PGS004854 and rare variants in thrombosis-associated genes increased the AUC to 0.951, representing an absolute increase of 0.068 (7.7%; p = 0.026). In the multivariable model, PGS004854 was the strongest positive genetic predictor of CTEPH (β = 1.869, p < 0.001).Conclusions The genetic profile of CTEPH patients differs significantly from PAH, with a higher frequency of hereditary thrombotic risk factors. Integrating clinical data with polygenic risk scores and thrombophilia variants improves differential diagnosis accuracy and may optimize the clinical workup.
SN - 2297-055X
ER -