Association of Polymorphisms in Pharmacogenetic Candidate Genes with Propofol Susceptibility

Abstract

Significant individual susceptibility to intravenous anesthetic propofol exists. The etiology of individual variability in the response to propofol may be influenced by genetic polymorphisms in metabolic and functional pathways. With current pharmacogenetics and modern molecular biology technologies, it is possible to study the influence of genetic polymorphisms on susceptibility to propofol. When inducing general anesthesia with intravenous propofol, high individual susceptibility to propofol was found. Using Sequenom MassARRAY single-nucleotide polymorphism (SNP) genotyping, we identified a mutation (rs6313) in the 5HT2A gene that was correlated to individual susceptibility to propofol effect-site concentration (Cep) and onset time of propofol induction. Carriers of the minor allele (G) of 5HT2A rs6313 required less propofol (20% decrease in Cep) and less time (40% decrease in onset time) to induce anesthesia. Moreover, associations were found between the gamma-aminobutyric acid (GABA) receptor SNP rs2279020 and the SCN9A SNP rs6746030 and the susceptibility of bispectral index (BIS) after propofol-induced anesthesia. In addition, dominant mutations in GABAA1 rs2279020, GABAA2 rs11503014, and CHRM2 rs1824024 were putatively associated with cardiovascular susceptibility to propofol anesthesia. No gene-gene interactions were found through a standardized measure of linkage disequilibrium and a multifactor dimensionality reduction analysis. Our results suggest that genetic polymorphisms related to mechanisms of propofol anesthesia are involved in propofol susceptibility.

THESIGNIFICANCE OF PHARMACOGENETIC TESTING FOR BETTER ANAESTHETIC OUTCOME AND LESSSURGICALSTRESS. Literature Review

“…Changing rs6746030 in SCN9A from G to A can change the function of the sodium channel; changes in glutamate release and intrinsic ionic conductivity resulted in greater susceptibility to propofol, which is shown by significantly lower BIS values after propofol-induced unconsciousness. This result may help clarify the role of SCN9A in propofol sensitivity [23].…”

“…Variation of the C-To-a rs2283265 polymorphism in HRM2 resulted in lower heart rate values. Changes from G to a rs2279020 in GABAA1 are accompanied by a lower BP curve after propofol anesthesia [23].…”

“…Studies by Lian and others have demonstrated that the influence of CYP2C9 polymorphism also contributed to changes in susceptibility to propofol. These observa-tions6 have shown that the enzymes involved in the metabolism of this hypnotic affect the susceptibility to it and that the total consumption of propofol can be disrupted by other substances, inducers or inhibitors of these enzymes used during surgery [23].…”

“…A g-to-A mutation in the rs2279020 gene in the GABA receptor can alter its pharmacological properties by changing the composition and location of subunits. When anesthetized with propofol, the minor a allele can cause a stronger inhibition in the brain in the carrier, which is manifested by higher BIS rates in these patients after loss of consciousness [23].…”

<p>Potential role of pharmacogenomics testing in the setting of enhanced recovery pathways after surgery</p>

“…Propofol, as one of the commonly used intravenous anesthetic agents, has variable pharmacokinetics attributed to genetic variation of the drug metabolizing enzymes. It undergoes metabolism by hepatic CYP2B6 enzyme and O -glucuronidation by UGT1A9.66 Polymorphisms of the genes coding for these enzymes affect elimination and clearance of propofol from the system resulting in discrepancies in the serum drug levels.67 For instance, patients with CYP2B6*4 alleles have been shown to have reduced drug clearance which increases their susceptibility to drug toxicity even with the regular doses.68 In another study, CYP2B6*6 has been demonstrated to be responsible for the differences in plasma drug levels and dose requirements.69 Additionally, propofol pharmacodynamics are affected by variations in the genes coding for GABA A target receptors (GABRE).70 Furthermore, another study suggests that the extensive variability of patient susceptibility could be attributed to a much greater range of genes including the dominant variations in GABAA1 rs2279020, GABAA2 rs11503014, and CHRM2 rs1824024.71 Cytochrome P450 family (CYP450), ATP-binding cassette (ABCB1), serine/threonine-protein kinase 3 (TAOK3), family with sequence similarity 53 member B (FAM53B), and the cannabinoid receptor (CNR1) are postulated to be involved in propofol pharmacokinetics; opioid receptors (OPRM1 and OPRD1), β-adrenoceptor (ADRB1), Catechol-O-methyltransferase (COMT), and ligand-gated ion channel (P2RX7) are postulated to be directly or indirectly involved in the pharmacodynamic response to propofol; nitric oxide synthase (NOS3), GABA type A (GABAA) receptor, NMDA receptors (GR1N3A and GR1N2B), Galanin (GAL), fatty acid amide hydrolase (FAAH), 5-hydroxytryptamine receptor (5HT2A), cholinergic receptors (CHRM2 and CHRNA5), dopamine transporters (DAT and DRD2), casein kinase (CSNK1E), calcium channels, potassium channels (KCNS1 and GIRK), and sodium channels (SCN9A) are also likely involved in the action of propofol. However, the gene variants so far studied have not shown any significant clinical differences.70…”