Novel Gene Polymorphisms for Stable Warfarin Dose in a Korean Population: Genome-Wide Association Study
Warfarin has a narrow therapeutic window and high intra- and inter-individual variability. Considering that many published papers on genotype-guided dosing are derived from European populations, the aim of this study was to investigate novel genetic variants associated with the variability of stable...
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MDPI AG
2023-08-01
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| Online Access: | https://www.mdpi.com/2227-9059/11/8/2308 |
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| author | Jung Sun Kim Sak Lee Jeong Yee Kyemyung Park Eun Jeong Jang Byung Chul Chang Hye Sun Gwak |
| author_facet | Jung Sun Kim Sak Lee Jeong Yee Kyemyung Park Eun Jeong Jang Byung Chul Chang Hye Sun Gwak |
| author_sort | Jung Sun Kim |
| collection | DOAJ |
| description | Warfarin has a narrow therapeutic window and high intra- and inter-individual variability. Considering that many published papers on genotype-guided dosing are derived from European populations, the aim of this study was to investigate novel genetic variants associated with the variability of stable warfarin dose in the Korean population with cardiac valve replacement, using the GWAS approach. This retrospective cohort study was performed from January 1982 to December 2020 at the Severance Cardiovascular Hospital of Yonsei University College of Medicine. GWAS was performed to identify associations between genotypes and the warfarin maintenance dose, by comparing the allele frequency of genetic variants between individuals. Then, the extent of genetic and non-genetic factors on the dose variability was determined by multivariable regression analysis. The study enrolled 214 participants, and the most robust signal cluster was detected on chromosome 16 around <i>VKORC1.</i> Followed by <i>VKORC1</i>, three novel variants (<i>NKX2-6</i> rs310279, <i>FRAS1</i> rs4386623, and <i>FAM201A</i> rs1890109) showed an association with stable warfarin dose requirement in univariate analysis. The algorithm was constructed by using multivariable analysis that includes genetic and non-genetic factors, and it could explain 58.5% of the variations in stable warfarin doses. In this variability, <i>VKORC1</i> rs9934438 and <i>FRAS1</i> rs4386623 accounted for 33.0% and 9.9%, respectively. This GWAS analysis identified the fact that three novel variants (<i>NKX2-6</i> rs310279, <i>FRAS1</i> rs4386623, and <i>FAM201A</i> rs1890109) were associated with stable warfarin doses. Additional research is necessary to validate the results and establish personalized treatment strategies for the Korean population. |
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| spelling | doaj.art-a53db97e8ef4471cbe945c0002056a612023-12-03T15:06:36ZengMDPI AGBiomedicines2227-90592023-08-01118230810.3390/biomedicines11082308Novel Gene Polymorphisms for Stable Warfarin Dose in a Korean Population: Genome-Wide Association StudyJung Sun Kim0Sak Lee1Jeong Yee2Kyemyung Park3Eun Jeong Jang4Byung Chul Chang5Hye Sun Gwak6Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of KoreaDepartment of Thoracic and Cardiovascular Surgery, Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of KoreaGraduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of KoreaDepartment of Biomedical Engineering, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of KoreaGraduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of KoreaDepartment of Thoracic and Cardiovascular Surgery, Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of KoreaGraduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of KoreaWarfarin has a narrow therapeutic window and high intra- and inter-individual variability. Considering that many published papers on genotype-guided dosing are derived from European populations, the aim of this study was to investigate novel genetic variants associated with the variability of stable warfarin dose in the Korean population with cardiac valve replacement, using the GWAS approach. This retrospective cohort study was performed from January 1982 to December 2020 at the Severance Cardiovascular Hospital of Yonsei University College of Medicine. GWAS was performed to identify associations between genotypes and the warfarin maintenance dose, by comparing the allele frequency of genetic variants between individuals. Then, the extent of genetic and non-genetic factors on the dose variability was determined by multivariable regression analysis. The study enrolled 214 participants, and the most robust signal cluster was detected on chromosome 16 around <i>VKORC1.</i> Followed by <i>VKORC1</i>, three novel variants (<i>NKX2-6</i> rs310279, <i>FRAS1</i> rs4386623, and <i>FAM201A</i> rs1890109) showed an association with stable warfarin dose requirement in univariate analysis. The algorithm was constructed by using multivariable analysis that includes genetic and non-genetic factors, and it could explain 58.5% of the variations in stable warfarin doses. In this variability, <i>VKORC1</i> rs9934438 and <i>FRAS1</i> rs4386623 accounted for 33.0% and 9.9%, respectively. This GWAS analysis identified the fact that three novel variants (<i>NKX2-6</i> rs310279, <i>FRAS1</i> rs4386623, and <i>FAM201A</i> rs1890109) were associated with stable warfarin doses. Additional research is necessary to validate the results and establish personalized treatment strategies for the Korean population.https://www.mdpi.com/2227-9059/11/8/2308warfarin<i>FRAS1</i><i>FAM201A</i><i>NKX2-6</i>polymorphismGWAS |
| spellingShingle | Jung Sun Kim Sak Lee Jeong Yee Kyemyung Park Eun Jeong Jang Byung Chul Chang Hye Sun Gwak Novel Gene Polymorphisms for Stable Warfarin Dose in a Korean Population: Genome-Wide Association Study Biomedicines warfarin <i>FRAS1</i> <i>FAM201A</i> <i>NKX2-6</i> polymorphism GWAS |
| title | Novel Gene Polymorphisms for Stable Warfarin Dose in a Korean Population: Genome-Wide Association Study |
| title_full | Novel Gene Polymorphisms for Stable Warfarin Dose in a Korean Population: Genome-Wide Association Study |
| title_fullStr | Novel Gene Polymorphisms for Stable Warfarin Dose in a Korean Population: Genome-Wide Association Study |
| title_full_unstemmed | Novel Gene Polymorphisms for Stable Warfarin Dose in a Korean Population: Genome-Wide Association Study |
| title_short | Novel Gene Polymorphisms for Stable Warfarin Dose in a Korean Population: Genome-Wide Association Study |
| title_sort | novel gene polymorphisms for stable warfarin dose in a korean population genome wide association study |
| topic | warfarin <i>FRAS1</i> <i>FAM201A</i> <i>NKX2-6</i> polymorphism GWAS |
| url | https://www.mdpi.com/2227-9059/11/8/2308 |
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