Department of Dental Anesthesiology, Tokyo Dental College, 2-9-18 Kanda- Misakicho, Chiyoda-Ku, Tokyo, 101-0061, Japan.
Department of Psychiatry and Behavioral Sciences, Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
Mol Brain. 2024 Sep 27;17(1):70. doi: 10.1186/s13041-024-01141-2.
Midazolam is widely used for intravenous sedation. However, wide interindividual variability is seen in the sensitivity to midazolam. The association between genetic factors and interindividual differences in midazolam sensitivity remains unclear. The present study explored the association between common genetic variants and sedative and amnesic effects of midazolam. This prospective study included patients who were scheduled to undergo dental procedures under intravenous sedation. The sedative effect was evaluated using the Ramsay sedation scale 5 min after midazolam (0.05 mg/kg) administration. We employed two parallel approaches in this study: genome-wide approach and candidate gene approach. The γ-aminobutyric acid type A receptor subunit genes were selected as candidate genes. Multivariate linear regression analyses were performed to investigate the association between the Ramsay sedation scale and genetic variants. We also analyzed the association between the presence of anterograde amnesia and genetic variants using multivariate binominal logistic regression analyses. The analyses were adjusted for potential confounding factors. A total of 191 patients were included in the analyses. In the genome-wide association analyses, no significant association was found between the genetic variants and Ramsay scores. In the candidate gene analyses, the rs73247636 (dominant model: β = 0.72 [95% confidence interval, 0.34 to 1.10], P < 0.001) and rs56278524 (dominant model: β = 0.73 [0.37 to 1.10], P < 0.001) polymorphisms of the GABRB1 gene were significantly associated with Ramsay scores. Additionally, the rs73247636 (dominant model: odds ratio [OR] = 8.39 [2.36 to 29.85], P = 0.001) and rs56278524 (dominant model: OR = 15.26 [3.42 to 68.07], P < 0.001) polymorphisms were also significantly associated with the presence of anterograde amnesia. The rs73247636 and rs56278524 single-nucleotide polymorphisms of GABRB1 were associated with the sedative and amnesic effects of midazolam.
咪达唑仑被广泛用于静脉镇静。然而，个体对咪达唑仑的敏感性存在广泛的个体差异。遗传因素与咪达唑仑敏感性个体差异之间的关系尚不清楚。本研究探讨了常见遗传变异与咪达唑仑镇静和遗忘作用之间的关系。这项前瞻性研究纳入了计划在静脉镇静下接受牙科手术的患者。镇静作用采用 Ramsay 镇静评分 5 分钟后（0.05mg/kg）评估咪达唑仑。我们在这项研究中采用了两种平行方法：全基因组方法和候选基因方法。γ-氨基丁酸 A 型受体亚基基因被选为候选基因。多变量线性回归分析用于研究 Ramsay 镇静评分与遗传变异之间的关系。我们还使用多变量二项逻辑回归分析研究了顺行性遗忘与遗传变异之间的关系。分析调整了潜在的混杂因素。共纳入 191 例患者进行分析。在全基因组关联分析中，遗传变异与 Ramsay 评分之间未发现显著相关性。在候选基因分析中，GABRB1 基因的 rs73247636（显性模型：β=0.72 [95%置信区间，0.34 至 1.10]，P<0.001）和 rs56278524（显性模型：β=0.73 [0.37 至 1.10]，P<0.001）多态性与 Ramsay 评分显著相关。此外，rs73247636（显性模型：比值比[OR] = 8.39 [2.36 至 29.85]，P=0.001）和 rs56278524（显性模型：OR=15.26 [3.42 至 68.07]，P<0.001）多态性与顺行性遗忘的发生也显著相关。GABRB1 的 rs73247636 和 rs56278524 单核苷酸多态性与咪达唑仑的镇静和遗忘作用有关。
