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, 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.