Zerdazi El-Hadi, Vorspan Florence, Marees Andries T, Naccache François, Lepine Jean-Pierre, Laplanche Jean-Louis, Prince Nathalie, Marie-Claire Cynthia, Bellivier Frank, Mouly Stéphane, Bloch Vanessa
INSERM U1144 Variabilité de réponse aux psychotropes, Université Paris Descartes, Université Paris Diderot, Université Sorbonne Paris Cité, Faculté de Pharmacie, 4 avenue de l'observatoire -, 75006, Paris, France.
APHP, Service d'addictologie, DHU Pe-PSY, Pôle de Psychiatrie et d'Addictologie des Hôpitaux Universitaires, Henri Mondor, F94000, Créteil, France.
Fundam Clin Pharmacol. 2019 Feb;33(1):96-106. doi: 10.1111/fcp.12405.
Methadone is known to be a risk factor for sudden death by enlarging ECG QT corrected (QTc) interval. For other medical conditions, QTc lengthening has been described as the result of interactions between pharmacological treatments and genetic factors. Former heroin-dependent subjects under methadone maintenance treatment in remission for at last 3 months were recruited. We studied the association between QTc length (Bazett formula) and 126 SNPs located on five genes (KCNE1, KCNQ1, KCNH2, NOS1AP and SCN5A) previously associated with drug-induced QT prolongation. Both SNP-based and gene-based approaches were used, and we tested also the interaction of the top SNP with methadone dosage to predict the QTc length. In our sample of 154 patients, current methadone daily dose was associated with QTc length (r = 0.26; P = 10 ). Only one SNP, rs11911509 on KCNE1, remained significantly associated with QT length after correction for multiple testing (P = 3.84 × 10 ; p = 0.049). Using a gene-based approach, KCNE1 was also significantly associated with QTc length (p = 0.02). We found a significant interaction between methadone dosage and rs11911509 minor allele count (allele A vs. C; P = 0.01). Stratified analysis revealed that the correlation between QTc length and methadone dosage was restricted only to AA carriers of this top SNP. Patients' genetic background should be taken into account in the case of clinically relevant QT enlargement during methadone maintenance treatment.
众所周知，美沙酮可通过延长心电图校正QT间期（QTc）而成为猝死的一个风险因素。对于其他疾病，QTc延长被认为是药物治疗与遗传因素相互作用的结果。招募了至少已戒毒3个月且正在接受美沙酮维持治疗的既往海洛因依赖者。我们研究了QTc长度（采用Bazett公式）与位于五个基因（KCNE1、KCNQ1、KCNH2、NOS1AP和SCN5A）上的126个单核苷酸多态性（SNP）之间的关联，这些基因先前与药物诱导的QT延长有关。我们使用了基于SNP和基于基因的方法，并且还测试了最显著的SNP与美沙酮剂量之间的相互作用以预测QTc长度。在我们154例患者的样本中，当前美沙酮日剂量与QTc长度相关（r = 0.26；P = 0.01）。经过多重检验校正后，只有一个SNP，即KCNE1上的rs11911509，仍与QT长度显著相关（P = 3.84×10⁻⁵；P = 0.049）。采用基于基因的方法时，KCNE1也与QTc长度显著相关（P = 0.02）。我们发现美沙酮剂量与rs11911509的次要等位基因计数之间存在显著相互作用（等位基因A与C；P = 0.01）。分层分析显示，QTc长度与美沙酮剂量之间的相关性仅局限于该最显著SNP的AA携带者。在美沙酮维持治疗期间出现具有临床意义的QT延长的情况下，应考虑患者的遗传背景。
