GABRA1 and GABRB2 Polymorphisms are Associated with Propofol Susceptibility

Zeng, Youjie; Cao, Si; Chen, Minghua; Fang, Chao; Ouyang, Wen

doi:10.2147/pgpm.s348170

Cited by 4 publications

(5 citation statements)

References 38 publications

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“…Zeng et al found that GABRB2 rs3816596 and GABRA1 rs4263535 polymorphisms were associated with susceptibility to propofol sedation. ABRA1 rs1157122 and GABRB2 rs76774144 polymorphisms were associated with the degree of blood pressure drop after propofol infusion ( Zeng et al, 2022 ). A previous study by our group found an association between GABAA1 receptor SNP rs2279020 and sensitivity to BIS.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms of pharmacogenetic candidate genes affect etomidate anesthesia susceptibility

Huang

et al. 2022

Front. Genet.

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Purpose: Etomidate is widely used in general anesthesia and sedation, and significant individual differences are observed during anesthesia induction. This study aimed to explore the molecular mechanisms of different etomidate susceptibility at the genetic level.Methods: 128 patients were enrolled in the study. The bispectral index (BIS), mean arterial pressure (MAP) and heart rate (HR) were recorded when the patients entered the operating room for 5 min, before the administration of etomidate, 30 s, 60 s, 90 s, 120 s and 150 s after the administration of etomidate, and the corresponding single nucleotide polymorphisms (SNPs) were analyzed.Results: Significant individual differences were observed in etomidate anesthesia. The results of two-way ANOVA showed that CYP2C9 rs1559, GABRB2 rs2561, GABRA2 rs279858, GABRA2 rs279863 were associated with the BIS value during etomidate anesthesia; UGT1A9 rs11692021 was associated with the Extended Observer’s Assessment of Alertness and Sedation (EOAA/S) score during etomidate anesthesia; GABRB2 rs2561 was associated with MAP. Multiple linear stepwise regression model results showed that CYP2C9 rs1559, GABRA2 rs279858 and GABRB2 rs2561 were associated with the BIS value and UGT1A9 rs11692021 was associated with the EOAA/S score; GABRB2 rs2561 was associated with MAP.Conclusion: GABRA2 rs279858, GABRB2 rs2561, CYP2C9 rs1559 and UGT1A9 rs11692021 are the SNPs with individual differences during etomidate anesthesia. This is the first to study the SNPs of etomidate, which can provide certain evidence for the future use of etomidate anesthesia and theoretical basis for precision anesthesia.

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Section: Discussionmentioning

confidence: 99%

Polymorphisms of pharmacogenetic candidate genes affect etomidate anesthesia susceptibility

Huang

et al. 2022

Front. Genet.

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“…Associations between the GABRA1 and GABRB2 genes and sensitivity to propofol were also determined. It has been shown that variants of GABRB2 rs3816596 and GABRA1 rs4263535 are associated with sensitivity to the sedative effect of propofol, and variants of GABRA1 rs1157122 and GABRB2 rs76774144 are associated with a lower degree of decrease in blood pressure after administration of propofol [20]. In addition, the CT/CC genotypes of GABRB1 rs4694846 were associated with heart rate instability, and the GG GABBR2 rs1167768 genotype was associated with greater instability of mean blood pressure values [21].…”

Section: Intravenous Anestheticsmentioning

confidence: 99%

“…Despite some positive correlation between specific genotypes and characteristics of propofol-induced anesthesia, the lack of reproducibility of the data limits the implementation of preoperative genetic screening to identify individuals requiring dose adjustment [20].…”

Section: Intravenous Anestheticsmentioning

confidence: 99%

“…The relevance of diff erent genotypes to the effi cacy of ketamine has been investigated in several in vitro and clinical studies [20,21,23]. According to one of the clinical studies, the CYP2B6*6 allele is associated with reduced clearance and, as a result, an increase in the concentration of ketamine in the blood plasma, which leads to a higher frequency of side eff ects [24].…”

Section: Intravenous Anestheticsmentioning

confidence: 99%

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Pharmacogenetics of Anesthesiological Support

Skavinska,

Fishchuk,

Cherniavska

et al. 2024

Neonatol. hìr. perinat. med.

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Pharmacogenetics studies the relationship between a person’s individual genetic characteristics and the human body’sresponse to the action of various drugs, particularly the occurrence of undesirable side eff ects. Thanks to the development of the latest technologies and methods, this branch of medical genetics and clinical pharmacology is developing very actively. Data are being accumulated, special databases are being created with the aim of creating individual genetic passports in the future, which will allow the selection of personalized treatment schemes.Anesthesiology is a special area of pharmacogenetic research because, more than any other medical specialty, it ischaracterized by polypharmacy-the simultaneous or sequential administration of many drugs. The same dose of a drug may be inadequate for some patients and may be life-threatening or cause unwanted side eff ects for others. Today, information about genetic factors is being used by clinicians to prescribe drugs to tailor drug therapy to a patient’s genome. In anesthesiology, the principles of pharmacogenetics have been explained for neuromuscular blocking agents, opioid metabolism, different types of anesthetics, and postoperative nausea and vomiting. On the other hand, a large number of anesthetics have a narrow therapeutic index.This review summarizes the most recent data from the scientifi c literature on the pharmacogenetics of diff erent types ofanesthetics. Inhalational anesthetics are halogenated derivatives of methyl ethyl ether, the exact mechanism of action of which is not yet fully understood. One of the rare but very serious side eff ects of all halogenated anesthetics is malignant hyperthermia, a genetically determined autosomal dominant disorder that manifests as a hypermetabolic response to drug administration. The dosage of intravenous anesthetics should also be carefully determined, taking into account the patient’s age, cardiovascular, hepatic, and renal status, concomitant drug therapy, and genetic factors. Ontogeny and genetic variability of drug-metabolizing enzymes are interrelated because genetic variability in drug-metabolizing enzyme expression cannot be assessed until the required protein is suffi ciently expressed. Pharmacogenetic variants may contribute to unpredictable drug exposure at the same weight- based drug dose.There are a number of potentially clinically applicable pharmacogenetic data in newborns, but more research is needed toconfi rm these fi ndings and understand how to incorporate them into clinical care.The selection of drugs and dosing regimens based on a patient’s pharmacogenomic profi le may be an important part of thefuture of medicine. Personalized treatment based on the specifi c variants in the genome will ultimately reduce the incidence of side eff ects and length of hospital stay for patients and save healthcare costs. Although pharmacogenomics and its application in clinical practice are still in their infancy, different variants and their implications for many clinical areas, including anesthesiology, are emerging every day.

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“…24 A single-nucleotide polymorphism can alter the function of a gene by affecting its expression or the structure of its coded protein. Relevant genes and some associated single-nucleotide polymorphisms involved in propofol pharmacodynamics and pharmacokinetics have been explored in hypothesis-driven candidate gene association studies focused on genes associated with GABA A receptors, [25][26][27] UGT1A9, CYP2B6, and CYP2C9, [28][29][30] but results have been inconsistent. The aim of this study was to identify genetic factors associated with dose requirements of propofol (mg • kg −1 • min −1 ) in a pseudosteady-state of general anesthesia (Entropy 40-60, GE Healthcare, Finland) by performing a genome-wide association study in a cohort of 1,000 women of Finnish origin undergoing breast cancer surgery.…”

Section: Genome-wide Study On Propofol Requirementsmentioning

confidence: 99%

Influence of Clinical and Genetic Factors on Propofol Dose Requirements: A Genome-wide Association Study

Ahlström,

Reiterä,

Jokela

et al. 2024

Anesthesiology

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Background Propofol is a widely used intravenous hypnotic. Dosing is mostly based on weight with great interindividual variation in consumption. Suggested factors affecting propofol requirements include age, gender, ethnicity, anxiety, alcohol consumption, smoking, and concomitant valproate use. Genetic factors have not been widely explored. Methods We studied 1000 women undergoing breast cancer surgery under propofol and remifentanil anesthesia. Depth of anesthesia was monitored with State Entropy TM. Propofol requirements during surgery were recorded. DNA from blood was genotyped with a genome-wide array. A multivariable linear regression model was used to assess the relevance of clinical variables and select those to be used as covariates in a genome-wide association study (GWAS). Imputed genotype data were used to explore selected loci further. In silico functional annotation was used to explore possible consequences of the discovered genetic variants. Additionally, previously reported genetic associations from candidate gene studies were tested. Results BMI, smoking status, alcohol use, remifentanil dose (ln(mgkg -1min -1)), and average state entropy during surgery remained statistically significant in the multivariable model. Two loci reached genome-wide significance (P < 5×10 -8). The most significant associations were for SNPs rs997989 (30 kb from ROBO3), likely affecting expression of another nearby gene FEZ1, and rs9518419, close to NALCN (sodium leak channel); rs10512538 near KCNJ2 encoding Kir2.1 potassium channel showed suggestive association (P = 4.7×10 -7). None of these SNPs are coding variants but possibly affect the regulation of nearby genes. None of the SNPs previously reported as affecting propofol pharmacokinetics or pharmacodynamics showed association in our data. Conclusion In this first GWAS exploring propofol requirements, we discovered novel genetic associations suggesting new biologically relevant pathways for propofol and general anesthesia. The roles of the gene products of ROBO3/FEZ1, NALCN and KCNJ2 in propofol anesthesia warrant further studies.

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GABRA1 and GABRB2 Polymorphisms are Associated with Propofol Susceptibility

Cited by 4 publications

References 38 publications

Polymorphisms of pharmacogenetic candidate genes affect etomidate anesthesia susceptibility

Polymorphisms of pharmacogenetic candidate genes affect etomidate anesthesia susceptibility

Pharmacogenetics of Anesthesiological Support

Influence of Clinical and Genetic Factors on Propofol Dose Requirements: A Genome-wide Association Study

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