The VKORC1 and CYP2C9 gene variants as pharmacogenetic factors in acenocoumarol therapy in Serbian patients - consideration of hypersensitivity and resistance
Introduction/Objective. Coumarin therapy represents one of the best models for applying pharmacogenetics. The contribution of factors influencing coumarin therapy can vary significantly between ethnic groups, which justifies conducting population-specific studies. The aim of this study was to analyz...
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| Format: | Article |
| Language: | English |
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Serbian Medical Society
2022-01-01
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| Series: | Srpski Arhiv za Celokupno Lekarstvo |
| Subjects: | |
| Online Access: | http://www.doiserbia.nb.rs/img/doi/0370-8179/2022/0370-81792200013R.pdf |
| _version_ | 1818141114679427072 |
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| author | Rakićević Ljiljana Kovač Mirjana Radojković Dragica Radojković Milica |
| author_facet | Rakićević Ljiljana Kovač Mirjana Radojković Dragica Radojković Milica |
| author_sort | Rakićević Ljiljana |
| collection | DOAJ |
| description | Introduction/Objective. Coumarin therapy represents one of the best models for applying pharmacogenetics. The contribution of factors influencing coumarin therapy can vary significantly between ethnic groups, which justifies conducting population-specific studies. The aim of this study was to analyze the influence of the most important genetic factors (VKORC1 and CYP2C9 genes) that affect coumarin therapy in patients from Serbia. Methods. A retrospective study involving 207 patients on acenocoumarol therapy was conducted. Genetic analyses were performed by direct sequencing. Influence on acenocoumarol dose of variants (VKORC1, CYP2C9*2, CYP2C9*3) causing hypersensitivity and VKORC1 variants causing resistance to acenocoumarol were analyzed. Multiple regression analysis was used to design a mathematical model for predicting individual drug dosage based on clinical-demographic and genetic data. Results. The study confirmed significant influence of the analyzed genetic factors on acenocoumarol maintenance dose. We designed mathematical model for predicting individual acenocoumarol dose and its unadjusted R2 was 61.8. In the testing cohort, our model gave R2 value of 42.6 and showed better prediction in comparison with model given by other authors. In the analyzed patients, nine different variants in the VKORC1 coding region were found. Among carriers of these variants 78% were completely resistant, and it was not possible to achieve therapeutic effect even with high doses of acenocoumarol. Conclusions. Population-specific model for prediction individual dose of acenocoumarol, may show advantages over protocols that are used in a generalized manner. Also, VKORC1 variants which cause coumarin resistance should be considered when planning therapy. |
| first_indexed | 2024-12-11T10:54:44Z |
| format | Article |
| id | doaj.art-1ee95969b4d2448a9e1b573a6851bffe |
| institution | Directory Open Access Journal |
| issn | 0370-8179 2406-0895 |
| language | English |
| last_indexed | 2024-12-11T10:54:44Z |
| publishDate | 2022-01-01 |
| publisher | Serbian Medical Society |
| record_format | Article |
| series | Srpski Arhiv za Celokupno Lekarstvo |
| spelling | doaj.art-1ee95969b4d2448a9e1b573a6851bffe2022-12-22T01:10:09ZengSerbian Medical SocietySrpski Arhiv za Celokupno Lekarstvo0370-81792406-08952022-01-011503-415616210.2298/SARH211118013R0370-81792200013RThe VKORC1 and CYP2C9 gene variants as pharmacogenetic factors in acenocoumarol therapy in Serbian patients - consideration of hypersensitivity and resistanceRakićević Ljiljana0Kovač Mirjana1https://orcid.org/0000-0001-6676-0561Radojković Dragica2Radojković Milica3University of Belgrade, Institute of Molecular Genetics and Genetic Engineering, Belgrade, SerbiaUniversity of Belgrade, Faculty of Medicine, Belgrade, Serbia + Blood Transfusion Institute of Serbia, Hemostasis department, Belgrade, SerbiaUniversity of Belgrade, Institute of Molecular Genetics and Genetic Engineering, Belgrade, Serbia;University of Belgrade, Faculty of Medicine, Belgrade, Serbia + Dr Dragiša Mišović - Dedinje University Clinical Hospital Center Clinic of Internal Medicine, Belgrade, SerbiaIntroduction/Objective. Coumarin therapy represents one of the best models for applying pharmacogenetics. The contribution of factors influencing coumarin therapy can vary significantly between ethnic groups, which justifies conducting population-specific studies. The aim of this study was to analyze the influence of the most important genetic factors (VKORC1 and CYP2C9 genes) that affect coumarin therapy in patients from Serbia. Methods. A retrospective study involving 207 patients on acenocoumarol therapy was conducted. Genetic analyses were performed by direct sequencing. Influence on acenocoumarol dose of variants (VKORC1, CYP2C9*2, CYP2C9*3) causing hypersensitivity and VKORC1 variants causing resistance to acenocoumarol were analyzed. Multiple regression analysis was used to design a mathematical model for predicting individual drug dosage based on clinical-demographic and genetic data. Results. The study confirmed significant influence of the analyzed genetic factors on acenocoumarol maintenance dose. We designed mathematical model for predicting individual acenocoumarol dose and its unadjusted R2 was 61.8. In the testing cohort, our model gave R2 value of 42.6 and showed better prediction in comparison with model given by other authors. In the analyzed patients, nine different variants in the VKORC1 coding region were found. Among carriers of these variants 78% were completely resistant, and it was not possible to achieve therapeutic effect even with high doses of acenocoumarol. Conclusions. Population-specific model for prediction individual dose of acenocoumarol, may show advantages over protocols that are used in a generalized manner. Also, VKORC1 variants which cause coumarin resistance should be considered when planning therapy.http://www.doiserbia.nb.rs/img/doi/0370-8179/2022/0370-81792200013R.pdfpharmacogeneticscoumarin derivativesacenocoumarolvkorc1cyp2c9 |
| spellingShingle | Rakićević Ljiljana Kovač Mirjana Radojković Dragica Radojković Milica The VKORC1 and CYP2C9 gene variants as pharmacogenetic factors in acenocoumarol therapy in Serbian patients - consideration of hypersensitivity and resistance Srpski Arhiv za Celokupno Lekarstvo pharmacogenetics coumarin derivatives acenocoumarol vkorc1 cyp2c9 |
| title | The VKORC1 and CYP2C9 gene variants as pharmacogenetic factors in acenocoumarol therapy in Serbian patients - consideration of hypersensitivity and resistance |
| title_full | The VKORC1 and CYP2C9 gene variants as pharmacogenetic factors in acenocoumarol therapy in Serbian patients - consideration of hypersensitivity and resistance |
| title_fullStr | The VKORC1 and CYP2C9 gene variants as pharmacogenetic factors in acenocoumarol therapy in Serbian patients - consideration of hypersensitivity and resistance |
| title_full_unstemmed | The VKORC1 and CYP2C9 gene variants as pharmacogenetic factors in acenocoumarol therapy in Serbian patients - consideration of hypersensitivity and resistance |
| title_short | The VKORC1 and CYP2C9 gene variants as pharmacogenetic factors in acenocoumarol therapy in Serbian patients - consideration of hypersensitivity and resistance |
| title_sort | vkorc1 and cyp2c9 gene variants as pharmacogenetic factors in acenocoumarol therapy in serbian patients consideration of hypersensitivity and resistance |
| topic | pharmacogenetics coumarin derivatives acenocoumarol vkorc1 cyp2c9 |
| url | http://www.doiserbia.nb.rs/img/doi/0370-8179/2022/0370-81792200013R.pdf |
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