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.

Figure 1

Clinical characteristics of patients during anesthesia induction. Anesthesia was induced with propofol via target-controlled-infusion (TCI) at 4 µg/ml. At OAA/S scores of 5, 4, 3, 2, 1, and 0, the effect-site concentration (Cep), bispectral index (BIS), onset time and total propofol were recorded. (A,B,C and D), left, reflect the Cep, BIS, onset time and total propofol recorded at OAA/S scores of 5, 4, 3, 2, 1, and 0. (A,B,C and D), right, reflect the distribution of Cep, BIS, onset time and total propofol at the score of 0, when patients lost consciousness. The different colors in Fig. 1, right side, obviously reflect the wide distribution of Cep, BIS, onset time and total propofol values at the score of 0, when patients lost consciousness. Variance between different groups was analyzed by one-way ANOVA. *P < 0.05 vs. Cep and BIS at an OAA/S score of 5 in (A and B); *P < 0.05 vs. onset time and total propofol at an OAA/S score of 4 in (C and D).

Figure 2

High individual diversity of cardiovascular responses to propofol anesthesia under the condition of unconsciousness in patients. The MAP and HR values of 179 participants at OAA/S scores of 5, 4, 3, 2, 1, and 0 are shown in (A and B), left. (A and B), right, show the distribution of MAP and HR changes under the condition of unconsciousness. The different colors in Fig. 1, right side, obviously reflect the wide distribution of MAP and HR changes at the score of 0, when patients lost consciousness. The variance between different groups was analyzed by one-way ANOVA. *P < 0.05 vs. changes in MAP and HR at an OAA/S score of 4 in (A and B).

Figure 3

Flow chart. Among the 192 participants enrolled in our study, one participant showed hypertension at the induction of anesthesia, and the remaining 13 early terminations were due to other reasons (no continuous monitoring data, no blood provided, or lack of phenotypic data). Based on the SNP results, the patients were divided into two groups. By comparing the clinical characteristics between the two groups, susceptibility to propofol was determined.