Department of Anesthesiology, Intensive Care and Pain Medicine, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.
Department of Public Health, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.
Anesthesiology. 2024 Aug 1;141(2):300-312. doi: 10.1097/ALN.0000000000005036.
Propofol is a widely used intravenous hypnotic. Dosing is based mostly on weight, with great interindividual variation in consumption. Suggested factors affecting propofol requirements include age, sex, ethnicity, anxiety, alcohol consumption, smoking, and concomitant valproate use. Genetic factors have not been widely explored.
This study considered 1,000 women undergoing breast cancer surgery under propofol and remifentanil anesthesia. Depth of anesthesia was monitored with State Entropy (GE Healthcare, Finland). 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. 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.
Body mass index, smoking status, alcohol use, remifentanil dose (ln[mg · kg-1 · min-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 single-nucleotide polymorphisms 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 the Kir2.1 potassium channel showed suggestive association (P = 4.7 × 10-7). None of these single-nucleotide polymorphisms are coding variants but possibly affect the regulation of nearby genes. None of the single-nucleotide polymorphisms previously reported as affecting propofol pharmacokinetics or pharmacodynamics showed association in the data.
In this first genome-wide association study exploring propofol requirements, This study 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.
丙泊酚是一种广泛应用的静脉内催眠药。剂量主要基于体重，消耗存在很大的个体间差异。建议影响丙泊酚需求的因素包括年龄、性别、种族、焦虑、酒精摄入、吸烟和同时使用丙戊酸。遗传因素尚未得到广泛探讨。
本研究考虑了 1000 名接受丙泊酚和瑞芬太尼麻醉的乳腺癌手术女性。使用状态熵（GE Healthcare，芬兰）监测麻醉深度。记录手术期间丙泊酚的需求。使用全基因组阵列对血液中的 DNA 进行基因分型。使用多变量线性回归模型评估临床变量的相关性，并选择那些用于全基因组关联研究的协变量。使用推断的基因型数据进一步探索选定的基因座。通过计算机功能注释探索发现的遗传变异可能产生的后果。此外，还测试了来自候选基因研究的先前报道的遗传关联。
在多变量模型中，体重指数、吸烟状况、饮酒、瑞芬太尼剂量（ln[mg·kg-1·min-1]）和手术期间的平均状态熵仍然具有统计学意义。两个基因座达到全基因组显著性（P<5×10-8）。最显著的关联是单核苷酸多态性 rs997989（距离 ROBO3 30kb），可能影响附近基因 FEZ1 的表达，以及 rs9518419，靠近 NALCN（钠漏通道）；rs10512538 位于编码 Kir2.1 钾通道的 KCNJ2 附近，显示出提示性关联（P=4.7×10-7）。这些单核苷酸多态性都不是编码变异，但可能影响附近基因的调控。先前报道的影响丙泊酚药代动力学或药效学的单核苷酸多态性在数据中没有显示出关联。
在这项探索丙泊酚需求的全基因组关联研究中，本研究发现了新的遗传关联，提示了丙泊酚和全身麻醉的新的生物学相关途径。ROBO3/FEZ1、NALCN 和 KCNJ2 基因产物在丙泊酚麻醉中的作用值得进一步研究。
