CYP2A6 and GABRA2 Gene Polymorphisms are Associated With Dexmedetomidine Drug Response
Background: Dexmedetomidine is a commonly used clinical sedative; however, the drug response varies among individuals. Thus, the purpose of this study was to explore the association between dexmedetomidine response and gene polymorphisms related to drug-metabolizing enzymes and drug response (CYP2A6...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.943200/full |
| _version_ | 1811323140751491072 |
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| author | Chao Fang Chao Fang Wen Ouyang Youjie Zeng Qi Pei Yuhao Xia Siwan Luo Minghua Chen |
| author_facet | Chao Fang Chao Fang Wen Ouyang Youjie Zeng Qi Pei Yuhao Xia Siwan Luo Minghua Chen |
| author_sort | Chao Fang |
| collection | DOAJ |
| description | Background: Dexmedetomidine is a commonly used clinical sedative; however, the drug response varies among individuals. Thus, the purpose of this study was to explore the association between dexmedetomidine response and gene polymorphisms related to drug-metabolizing enzymes and drug response (CYP2A6, UGT2B10, UGT1A4, ADRA2A, ADRA2B, ADRA2C, GABRA1, GABRB2, and GLRA1).Methods: This study was a prospective cohort study. A total of 194 female patients aged 18–60 years, American Society of Anesthesiologists (ASA) score I-II, who underwent laparoscopy at the Third Xiangya Hospital of Central South University, were included. The sedative effect was assessed every 2 min using the Ramsay score, and the patient’s heart rate decrease within 20 min was recorded. Peripheral blood was collected from each participant to identify genetic variants in the candidate genes of metabolic and drug effects using the Sequenom MassARRAY® platform. Furthermore, additional peripheral blood samples were collected from the first 99 participants at multiple time points after dexmedetomidine infusion to perform dexmedetomidine pharmacokinetic analysis by Phoenix® WinNonlin 7.0 software.Results: Carriers of the minor allele (C) of CYP2A6 rs28399433 had lower metabolic enzyme efficiency and higher plasma concentrations of dexmedetomidine. In addition, the participants were divided into dexmedetomidine sensitive or dexmedetomidine tolerant groups based on whether they had a Ramsay score of at least four within 20 min, and CYP2A6 rs28399433 was identified to have a significant influence on the dexmedetomidine sedation sensitivity by logistic regression with Plink software [p = 0.003, OR (95% CI): 0.27 (0.11–0.65)]. C allele carriers were more sensitive to the sedative effects of dexmedetomidine than A allele carriers. GABRA2 rs279847 polymorphism was significantly associated with the degree of the heart rate decrease. In particular, individuals with the GG genotype had a 4-fold higher risk of heart rate abnormality than carriers of the T allele (OR = 4.32, 95% CI: 1.96–9.50, p = 0.00027).Conclusion:CYP2A6 rs28399433 polymorphism affects the metabolic rate of dexmedetomidine and is associated with susceptibility to the sedative effects of dexmedetomidine; GABRA2 rs279847 polymorphism is significantly associated with the degree of the heart rate decrease. |
| first_indexed | 2024-04-13T13:48:50Z |
| format | Article |
| id | doaj.art-4d2c6b35e69c4be892e97e5a15ca1030 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T13:48:50Z |
| publishDate | 2022-07-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-4d2c6b35e69c4be892e97e5a15ca10302022-12-22T02:44:23ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-07-011310.3389/fphar.2022.943200943200CYP2A6 and GABRA2 Gene Polymorphisms are Associated With Dexmedetomidine Drug ResponseChao Fang0Chao Fang1Wen Ouyang2Youjie Zeng3Qi Pei4Yuhao Xia5Siwan Luo6Minghua Chen7Department of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, ChinaHunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, ChinaDepartment of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Pharmacy, Third Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, ChinaBackground: Dexmedetomidine is a commonly used clinical sedative; however, the drug response varies among individuals. Thus, the purpose of this study was to explore the association between dexmedetomidine response and gene polymorphisms related to drug-metabolizing enzymes and drug response (CYP2A6, UGT2B10, UGT1A4, ADRA2A, ADRA2B, ADRA2C, GABRA1, GABRB2, and GLRA1).Methods: This study was a prospective cohort study. A total of 194 female patients aged 18–60 years, American Society of Anesthesiologists (ASA) score I-II, who underwent laparoscopy at the Third Xiangya Hospital of Central South University, were included. The sedative effect was assessed every 2 min using the Ramsay score, and the patient’s heart rate decrease within 20 min was recorded. Peripheral blood was collected from each participant to identify genetic variants in the candidate genes of metabolic and drug effects using the Sequenom MassARRAY® platform. Furthermore, additional peripheral blood samples were collected from the first 99 participants at multiple time points after dexmedetomidine infusion to perform dexmedetomidine pharmacokinetic analysis by Phoenix® WinNonlin 7.0 software.Results: Carriers of the minor allele (C) of CYP2A6 rs28399433 had lower metabolic enzyme efficiency and higher plasma concentrations of dexmedetomidine. In addition, the participants were divided into dexmedetomidine sensitive or dexmedetomidine tolerant groups based on whether they had a Ramsay score of at least four within 20 min, and CYP2A6 rs28399433 was identified to have a significant influence on the dexmedetomidine sedation sensitivity by logistic regression with Plink software [p = 0.003, OR (95% CI): 0.27 (0.11–0.65)]. C allele carriers were more sensitive to the sedative effects of dexmedetomidine than A allele carriers. GABRA2 rs279847 polymorphism was significantly associated with the degree of the heart rate decrease. In particular, individuals with the GG genotype had a 4-fold higher risk of heart rate abnormality than carriers of the T allele (OR = 4.32, 95% CI: 1.96–9.50, p = 0.00027).Conclusion:CYP2A6 rs28399433 polymorphism affects the metabolic rate of dexmedetomidine and is associated with susceptibility to the sedative effects of dexmedetomidine; GABRA2 rs279847 polymorphism is significantly associated with the degree of the heart rate decrease.https://www.frontiersin.org/articles/10.3389/fphar.2022.943200/fulldexmedetomidinepharmacogenomicspharmacokineticpharmacodynamicsGABA A receptorCYP2A6 |
| spellingShingle | Chao Fang Chao Fang Wen Ouyang Youjie Zeng Qi Pei Yuhao Xia Siwan Luo Minghua Chen CYP2A6 and GABRA2 Gene Polymorphisms are Associated With Dexmedetomidine Drug Response Frontiers in Pharmacology dexmedetomidine pharmacogenomics pharmacokinetic pharmacodynamics GABA A receptor CYP2A6 |
| title | CYP2A6 and GABRA2 Gene Polymorphisms are Associated With Dexmedetomidine Drug Response |
| title_full | CYP2A6 and GABRA2 Gene Polymorphisms are Associated With Dexmedetomidine Drug Response |
| title_fullStr | CYP2A6 and GABRA2 Gene Polymorphisms are Associated With Dexmedetomidine Drug Response |
| title_full_unstemmed | CYP2A6 and GABRA2 Gene Polymorphisms are Associated With Dexmedetomidine Drug Response |
| title_short | CYP2A6 and GABRA2 Gene Polymorphisms are Associated With Dexmedetomidine Drug Response |
| title_sort | cyp2a6 and gabra2 gene polymorphisms are associated with dexmedetomidine drug response |
| topic | dexmedetomidine pharmacogenomics pharmacokinetic pharmacodynamics GABA A receptor CYP2A6 |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.943200/full |
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