A phenotype driven integrative framework uncovers molecular mechanisms of a rare hereditary thrombophilia
Аутори
Malod-Dognin, NoëlCeddia, Gaia
Gvozdenov, Maja
![](/themes/Mirageimagine/images/orcid.png)
Tomić, Branko
![](/themes/Mirageimagine/images/orcid.png)
Manevski Dunjić, Sofija
![](/themes/Mirageimagine/images/orcid.png)
Đorđević, Valentina
![](/themes/Mirageimagine/images/orcid.png)
Pržulj, Nataša
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
Antithrombin resistance is a rare subtype of hereditary thrombophilia caused by prothrombin gene variants, leading to thrombotic disorders. Recently, the Prothrombin Belgrade variant has been reported as a specific variant that leads to antithrombin resistance in two Serbian families with thrombosis. However, due to clinical data scarcity and the inapplicability of traditional genome-wide association studies (GWAS), a broader perspective on molecular and phenotypic mechanisms associated with the Prothrombin Belgrade variant is yet to be uncovered. Here, we propose an integrative framework to address the lack of genomic samples and support the genomic signal from the full genome sequences of five heterozygous subjects by integrating it with subjects’ phenotypes and the genes’ molecular interactions. Our goal is to identify candidate thrombophilia-related genes for which our subjects possess germline variants by focusing on the resulting gene clusters of our integrative framework. We app...lied a Non-negative Matrix Tri-Factorization-based method to simultaneously integrate different data sources, taking into account the observed phenotypes. In other words, our data-integration framework reveals gene clusters involved with this rare disease by fusing different datasets. Our results are in concordance with the current literature about antithrombin resistance. We also found candidate disease-related genes that need to be further investigated. CD320, RTEL1, UCP2, APOA5 and PROZ participate in healthy-specific or disease-specific subnetworks involving thrombophilia-annotated genes and are related to general thrombophilia mechanisms according to the literature. Moreover, the ADRA2A and TBXA2R subnetworks analysis suggested that their variants may have a protective effect due to their connection with decreased platelet activation. The results show that our method can give insights into antithrombin resistance even if a small amount of genetic data is available. Our framework is also customizable, meaning that it applies to any other rare disease.
Кључне речи:
Genetic networks / Genome annotation / Mutation / Platelets / Protein-protein interactions / Serine proteases / TGF-beta signaling cascade / Thrombosis / antithrombin resistance / Prothrombin Belgrade / thrombophilia / Non-negative Matrix Tri-Factorization-based methodИзвор:
Plos one, 2023, 18, 4, e0284084-Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200042 (Универзитет у Београду, Институт за молекуларну генетику и генетичко инжењерство) (RS-MESTD-inst-2020-200042)
URI
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0284084https://imagine.imgge.bg.ac.rs/handle/123456789/1920
Институција/група
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Malod-Dognin, Noël AU - Ceddia, Gaia AU - Gvozdenov, Maja AU - Tomić, Branko AU - Manevski Dunjić, Sofija AU - Đorđević, Valentina AU - Pržulj, Nataša PY - 2023 UR - https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0284084 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1920 AB - Antithrombin resistance is a rare subtype of hereditary thrombophilia caused by prothrombin gene variants, leading to thrombotic disorders. Recently, the Prothrombin Belgrade variant has been reported as a specific variant that leads to antithrombin resistance in two Serbian families with thrombosis. However, due to clinical data scarcity and the inapplicability of traditional genome-wide association studies (GWAS), a broader perspective on molecular and phenotypic mechanisms associated with the Prothrombin Belgrade variant is yet to be uncovered. Here, we propose an integrative framework to address the lack of genomic samples and support the genomic signal from the full genome sequences of five heterozygous subjects by integrating it with subjects’ phenotypes and the genes’ molecular interactions. Our goal is to identify candidate thrombophilia-related genes for which our subjects possess germline variants by focusing on the resulting gene clusters of our integrative framework. We applied a Non-negative Matrix Tri-Factorization-based method to simultaneously integrate different data sources, taking into account the observed phenotypes. In other words, our data-integration framework reveals gene clusters involved with this rare disease by fusing different datasets. Our results are in concordance with the current literature about antithrombin resistance. We also found candidate disease-related genes that need to be further investigated. CD320, RTEL1, UCP2, APOA5 and PROZ participate in healthy-specific or disease-specific subnetworks involving thrombophilia-annotated genes and are related to general thrombophilia mechanisms according to the literature. Moreover, the ADRA2A and TBXA2R subnetworks analysis suggested that their variants may have a protective effect due to their connection with decreased platelet activation. The results show that our method can give insights into antithrombin resistance even if a small amount of genetic data is available. Our framework is also customizable, meaning that it applies to any other rare disease. T2 - Plos one T1 - A phenotype driven integrative framework uncovers molecular mechanisms of a rare hereditary thrombophilia IS - 4 SP - e0284084 VL - 18 DO - 10.1371/journal.pone.0284084 ER -
@article{ author = "Malod-Dognin, Noël and Ceddia, Gaia and Gvozdenov, Maja and Tomić, Branko and Manevski Dunjić, Sofija and Đorđević, Valentina and Pržulj, Nataša", year = "2023", abstract = "Antithrombin resistance is a rare subtype of hereditary thrombophilia caused by prothrombin gene variants, leading to thrombotic disorders. Recently, the Prothrombin Belgrade variant has been reported as a specific variant that leads to antithrombin resistance in two Serbian families with thrombosis. However, due to clinical data scarcity and the inapplicability of traditional genome-wide association studies (GWAS), a broader perspective on molecular and phenotypic mechanisms associated with the Prothrombin Belgrade variant is yet to be uncovered. Here, we propose an integrative framework to address the lack of genomic samples and support the genomic signal from the full genome sequences of five heterozygous subjects by integrating it with subjects’ phenotypes and the genes’ molecular interactions. Our goal is to identify candidate thrombophilia-related genes for which our subjects possess germline variants by focusing on the resulting gene clusters of our integrative framework. We applied a Non-negative Matrix Tri-Factorization-based method to simultaneously integrate different data sources, taking into account the observed phenotypes. In other words, our data-integration framework reveals gene clusters involved with this rare disease by fusing different datasets. Our results are in concordance with the current literature about antithrombin resistance. We also found candidate disease-related genes that need to be further investigated. CD320, RTEL1, UCP2, APOA5 and PROZ participate in healthy-specific or disease-specific subnetworks involving thrombophilia-annotated genes and are related to general thrombophilia mechanisms according to the literature. Moreover, the ADRA2A and TBXA2R subnetworks analysis suggested that their variants may have a protective effect due to their connection with decreased platelet activation. The results show that our method can give insights into antithrombin resistance even if a small amount of genetic data is available. Our framework is also customizable, meaning that it applies to any other rare disease.", journal = "Plos one", title = "A phenotype driven integrative framework uncovers molecular mechanisms of a rare hereditary thrombophilia", number = "4", pages = "e0284084", volume = "18", doi = "10.1371/journal.pone.0284084" }
Malod-Dognin, N., Ceddia, G., Gvozdenov, M., Tomić, B., Manevski Dunjić, S., Đorđević, V.,& Pržulj, N.. (2023). A phenotype driven integrative framework uncovers molecular mechanisms of a rare hereditary thrombophilia. in Plos one, 18(4), e0284084. https://doi.org/10.1371/journal.pone.0284084
Malod-Dognin N, Ceddia G, Gvozdenov M, Tomić B, Manevski Dunjić S, Đorđević V, Pržulj N. A phenotype driven integrative framework uncovers molecular mechanisms of a rare hereditary thrombophilia. in Plos one. 2023;18(4):e0284084. doi:10.1371/journal.pone.0284084 .
Malod-Dognin, Noël, Ceddia, Gaia, Gvozdenov, Maja, Tomić, Branko, Manevski Dunjić, Sofija , Đorđević, Valentina, Pržulj, Nataša, "A phenotype driven integrative framework uncovers molecular mechanisms of a rare hereditary thrombophilia" in Plos one, 18, no. 4 (2023):e0284084, https://doi.org/10.1371/journal.pone.0284084 . .