Lebreton Louis, Hennart Benjamin, Baklouti Sarah, Trimouille Aurélien, Boyer Jean-Christophe, Becquemont Laurent, Dhaenens Claire-Marie, Picard Nicolas
Département de biochimie, hôpital Pellegrin, centre hospitalier universitaire de Bordeaux, 33000 Bordeaux, France.
Unité fonctionnelle de toxicologie, CHU de Lille, 59037 Lille, France.
Therapie. 2024 Nov-Dec;79(6):709-717. doi: 10.1016/j.therap.2024.05.006. Epub 2024 Jun 5.
The administration of aminoglycosides can induce nephrotoxicity or ototoxicity, which can be monitored through pharmacological therapeutic drug monitoring. However, there are cases of genetic predisposition to ototoxicity related to the MT-RNR1 gene, which may occur from the first administrations. Pharmacogenetic analysis recommendations have recently been proposed by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The Francophone Pharmacogenetics Network (RNPGx) provides a bibliographic synthesis of this genetic predisposition, as well as professional recommendations. The MT-RNR1 gene codes for mitochondrial 12S rRNA, which constitutes the small subunit of the mitochondrial ribosome. Three variants can be identified: the variants m.1555A>G and m.1494C>T of the MT-RNR1 gene have a 'high' level of evidence regarding the risk of ototoxicity. The variant m.1095T>C has a 'moderate' level of evidence. The search for these variants can be performed in the laboratory if the administration of aminoglycosides can be delayed after obtaining the result. However, if the treatment is urgent, there is currently no rapid test available in France (a 'point-of-care' test is authorized in Great Britain). RNPGx considers: (1) the search for the m.1555A>G, m.1494C>T variants as 'highly recommended' and the m.1095T>C variant as 'moderately recommended' before the administration of an aminoglycoside (if compatible with the medical context). It should be noted that the level of heteroplasmy detected does not modify the recommendation; (2) pharmacogenetic analysis is currently not feasible in situations of short-term aminoglycoside administration, in the absence of an available analytical solution (rapid test to be evaluated in France); (3) the retrospective analysis in case of aminoglycoside-induced ototoxicity is 'recommended'; (4) analysis of relatives is 'recommended'. Through this summary, RNPGx proposes an updated review of the MT-RNR1-aminoglycoside gene-drug pair to serve as a basis for adapting practices regarding pharmacogenetic analysis related to aminoglycoside treatment.
氨基糖苷类药物的使用可诱发肾毒性或耳毒性，可通过药物治疗药物监测进行监测。然而，存在与MT-RNR1基因相关的耳毒性遗传易感性病例，可能在首次用药时就会出现。临床药物基因组学实施联盟（CPIC）最近提出了药物基因组学分析建议。法语国家药物基因组学网络（RNPGx）提供了这种遗传易感性的文献综述以及专业建议。MT-RNR1基因编码线粒体12S rRNA，它构成线粒体核糖体的小亚基。可以识别出三种变体：MT-RNR1基因的m.1555A>G和m.1494C>T变体在耳毒性风险方面有“高”水平的证据。m.1095T>C变体有“中等”水平的证据。如果在获得结果后可以推迟氨基糖苷类药物的使用，则可以在实验室进行这些变体的检测。然而，如果治疗紧急，法国目前没有快速检测方法（英国已批准“即时检验”）。RNPGx认为：（1）在使用氨基糖苷类药物之前（如果与医疗情况相符），强烈建议检测m.1555A>G、m.1494C>T变体，中等建议检测m.1095T>C变体。需要注意的是，检测到的异质性水平不会改变建议；（2）在没有可用分析解决方案（法国有待评估的快速检测）的情况下，目前在短期使用氨基糖苷类药物的情况下进行药物基因组学分析不可行；（3）建议对氨基糖苷类药物引起的耳毒性进行回顾性分析；（4）建议对亲属进行分析。通过本综述，RNPGx对MT-RNR1-氨基糖苷类基因-药物对进行了更新的综述，为调整与氨基糖苷类治疗相关的药物基因组学分析实践提供依据。
