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

Abstract

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.