Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.
Biostatistics Consulting, Department of Public Health, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland.
Br J Anaesth. 2021 May;126(5):949-957. doi: 10.1016/j.bja.2021.01.029. Epub 2021 Mar 4.
Rocuronium, a common neuromuscular blocking agent, is mainly excreted unchanged in urine (10-25%) and bile (>70%). Age, sex, liver blood flow, smoking, medical conditions, and ethnic background can affect its pharmacological actions. However, reasons for the wide variation in rocuronium requirements are mostly unknown. We hypothesised that pharmacogenetic factors might explain part of the variation.
One thousand women undergoing surgery for breast cancer were studied. Anaesthesia was maintained with propofol (50-100 μg kg min) and remifentanil (0.05-0.25 μg kg min). Neuromuscular block was maintained with rocuronium to keep the train-of-four ratio at 0-10%. DNA was extracted from peripheral blood and genotyped with a next-generation genotyping array. The genome-wide association study (GWAS) was conducted using an additive linear regression model with PLINK software. The FINEMAP tool and data from the Genotype-Tissue Expression project v8 were utilised to study the locus further.
The final patient population comprised 918 individuals. Of the clinical variables tested, age, BMI, ASA physical status, and total dose of propofol correlated significantly (all P<0.001) with the rocuronium dose in a linear regression model. The GWAS highlighted one genome-wide significant locus in chromosome 12. The single-nucleotide polymorphisms (SNPs) with the most significant evidence of association were located in or near SLCO1A2. The two top SNPs, rs7967354 (P=5.3e) and rs11045995 (P=1.4e), and the clinical variables accounted for 41% of the variability in rocuronium dosage.
Genetic variation in the gene SLCO1A2, encoding OATP1A2, an uptake transporter, accounted for 4% of the variability in rocuronium consumption. The underlying mechanism remains unknown.
罗库溴铵是一种常用的神经肌肉阻滞剂，主要以原形（10-25%）和胆汁（>70%）排泄。年龄、性别、肝血流量、吸烟、疾病状态和种族背景等因素均可影响其药理学作用。但是，罗库溴铵需求量存在广泛差异的原因大多未知。我们假设，药物遗传学因素可能可以解释部分差异。
研究了 1000 名接受乳腺癌手术的女性。麻醉维持使用丙泊酚（50-100μgkgmin）和瑞芬太尼（0.05-0.25μgkgmin）。使用罗库溴铵维持神经肌肉阻滞，使四个成串刺激（TOF）比值保持在 0-10%。从外周血中提取 DNA，并用下一代基因分型阵列进行基因分型。使用 PLINK 软件进行全基因组关联研究（GWAS），采用加性线性回归模型。利用 FINEMAP 工具和 Genotype-Tissue Expression 项目 v8 中的数据进一步研究该基因座。
最终的患者人群包括 918 名个体。在测试的临床变量中，年龄、BMI、ASA 身体状况和丙泊酚总剂量与罗库溴铵剂量呈显著线性相关（均 P<0.001）。GWAS 突出了染色体 12 上一个全基因组显著的基因座。与关联最显著的单核苷酸多态性（SNP）位于 SLCO1A2 内或附近。两个最重要的 SNP，rs7967354（P=5.3e）和 rs11045995（P=1.4e），以及临床变量，解释了罗库溴铵剂量变化的 41%。
基因 SLCO1A2 中的遗传变异，该基因编码 OATP1A2，是一种摄取转运体，解释了罗库溴铵消耗变化的 4%。其潜在机制尚不清楚。
