KCNH2 polymorphism and methadone dosage interact to enhance QT duration

Hajj, Aline; Ksouda, Kamilia; Peoc’h, Katell; Curis, Emmanuel; Messali, A.; Deveaux, Laurence Labat; Bloch, Vanessa; Prince, Nathalie; Mouly, Stéphane; Scherrmann, Jean‐Michel; Lépine, Jean‐Pierre; Laplanche, Jean‐Louis; Drici, Milou‐Daniel; Vorspan, Florence

doi:10.1016/j.drugalcdep.2014.04.027

Cited by 19 publications

(20 citation statements)

References 33 publications

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“…Indeed, it was only significant among rs11911509 AA carriers. We conducted a previous study that did not find a significant association between QT length and other KCNE1 SNPs, but this could be due to lack of power, or because SNPs that were previously tested, that is KCNE1 rs1805127, rs1805128 and rs2236609 are not implicated in the interaction of the methadone molecule and the KCNE1 Potassium voltage‐gated channel protein. Those SNPs were not in linkage disequilibrium with the significant SNPs rs11911509 that we identified in the current study ( r 2 : 0.027 and 0.017, respectively).…”

Section: Discussionmentioning

confidence: 99%

“…and recruited additional patients (154 subjects vs. 82 subjects in Hajj et al.) , which allowed us to perform a gene‐based approach that was not available in our previous methodology.…”

Section: Discussionmentioning

confidence: 99%

“…We conducted a previous study [29] that did not find a significant association between QT length and other KCNE1 SNPs, but this could be due to lack of power, or because SNPs that were previously tested, that is KCNE1 rs1805127, rs1805128 and rs2236609 are not implicated in the interaction of the methadone molecule and the KCNE1 Potassium voltage-gated channel protein. Those SNPs were not in linkage disequilibrium with the significant SNPs rs11911509 that we identified in the current study (r 2 : 0.027 and 0.017, respectively [29], which allowed us to perform a gene-based approach that was not available in our previous methodology. The rs11911509 SNP that we identified here is an intronic variant of the KCNE1 gene with no known effect according to the Ensembl database [40], and no phenotype has been associated with this SNP to our knowledge.…”

Section: Discussionmentioning

confidence: 99%

“…Among identified genetic risk factors, DNA variants on KCNE1 , KCNQ1 , KCNH2 , NOS1AP and SCN5A have been shown to predispose to QT prolongation in case of drug exposure. Moreover, we previously observed a significant association of a KCNH2 single nucleotide variant with increased QT length in methadone‐treated patients .…”

Section: Introductionmentioning

confidence: 88%

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QT length during methadone maintenance treatment: gene × dose interaction

Zerdazi

Vorspan

Marees

et al. 2019

Fundamemntal Clinical Pharma

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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 5 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 x 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. This article is protected by copyright. All rights reserved.

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Section: Discussionmentioning

confidence: 99%

“…and recruited additional patients (154 subjects vs. 82 subjects in Hajj et al.) , which allowed us to perform a gene‐based approach that was not available in our previous methodology.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

See 2 more Smart Citations

QT length during methadone maintenance treatment: gene × dose interaction

Zerdazi

Vorspan

Marees

et al. 2019

Fundamemntal Clinical Pharma

Self Cite

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“…Whole exome sequencing may be a promising, time-and cost-effective technique for discovering the genetic basis of SCD in at-risk families and patients (Bagnall et al 2014;Hajj et al 2014;Narula et al 2015). Genetic mapping of at-risk families with a history of SCD or cardiomyopathy may also be used to predict the risk (Bulbanat et al 2014).…”

Section: Prevention and Treatmentmentioning

confidence: 99%

Role of risk stratification and genetics in sudden cardiac death

Rai

Agrawal

2017

Can. J. Physiol. Pharmacol.

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Keyword:Sudden cardiac death, coronary artery disease, heart failure, Arrhythmias, Atrial fibrillation https://mc06.manuscriptcentral.com/cjpp-pubs AbstractSudden cardiac death (SCD) is a major public health issue due to its increasing incidence in the general population and the difficulty in identifying high-risk individuals.Nearly 300,000-350,000 patients in the United States and 4-to 5 million patients in the world die from SCD. Coronary artery disease and advanced heart failure are the main etiology for SCD. Ischemia of any cause precipitates lethal arrhythmias, and ventricular tachycardia and ventricular fibrillation are the most common lethal arrhythmias precipitating SCD. Pulse-less electrical activity, brady-arrhythmia and electromechanical dissociation also result in SCD.Most sudden cardiac deaths occur out-of-the-hospital setting, so it is difficult to estimate the public burden, which results in overestimating the incidence of SCD. The insufficiency and limited predictive value of various indicators and criteria for SCD result in the increasing incidences. As a result, there is a need to develop better risk stratification criteria and find modifiable variables to decrease the incidence. Primary and secondary prevention and treatment of SCD need further research. This critical review is focused on the etiology, risk factors, prognostic factors and importance of risk stratification of SCD.Key words: Sudden cardiac death, Coronary artery disease, Heart failure, Arrhythmias, Atrial fibrillation, Ventricular fibrillation, Channelopathies, Risk stratification, Prevention

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Methadone‐associated QT interval prolongation in patients undergoing maintenance therapy in an urban opioid treatment program

et al. 2021

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Study Objective Methadone is associated with QT interval prolongation and torsades de pointes. The objective of this study was to (a) determine the incidence of QT interval prolongation among patients on maintenance methadone therapy in an urban opioid treatment program (OTP), (b) compare characteristics of patients who developed methadone‐associated QT prolongation with those who did not develop QT prolongation, and (c) investigate the relationship between QT interval prolongation and stereospecific serum methadone and metabolite [2‐ethylidene‐1,5‐dimethyl‐3,3‐diphenylpyrrolidine (EDDP)] concentrations. Design Prospective study. Setting Urban opioid treatment program (OTP). Patients n = 93 patients on maintenance methadone therapy in an urban OTP. Intervention Patients underwent a 12‐lead electrocardiogram (ECG) prior to initiating methadone and again during steady‐state maintenance methadone therapy. In a subset (n = 43), blood was obtained to determine serum (S)‐ and (R)‐methadone and (S)‐ and (R)‐EDDP concentrations, which were compared in patients who developed Bazett’s‐corrected QT (QTc) prolongation [≥470 ms (men) or ≥480 ms (women) and/or ≥60 ms lengthening from pretreatment value] with those who did not have QTc prolongation. Measurements and Main Results Mean [± standard deviation (SD)] age was 36 ± 12 years; 73% were female, and 74% were white. QTc prolongation occurred in 14 (15.1%) patients. Patients who developed QTc prolongation were older (41 ± 13 vs. 35 ± 9 years, p = 0.03) and had a longer pre‐methadone QTc compared with those who did not have QTc prolongation (429 ± 11 vs. 420 ± 20 ms, respectively, p = 0.02). Serum (S)‐methadone concentrations were higher in patients with QTc prolongation compared to patients without prolongation (199 ± 81 vs. 128 ± 68 ng/ml, respectively, p = 0.01), whereas the difference in serum (R)‐methadone concentrations between the groups did not reach significance (189 ± 68 vs. 125 ± 60 ng/ml, respectively, p = 0.08). Serum (R)‐methadone concentrations correlated with QTc intervals [R2 = 0.15 (95% confidence interval (CI) 0.11–0.62, p = 0.0009)]. The correlation between serum (S)‐methadone concentrations and QTc did not reach significance [R2 = 0.08 (95% CI −0.01 to 0.54, p = 0.06)]. Serum (S)‐and (R)‐EDDP concentrations were not significantly different between the groups and did not significantly correlate with QTc intervals. Conclusions Approximately 15% of patients taking maintenance methadone therapy developed QT interval prolongation. Both serum (S)‐ and (R)‐methadone concentrations, but not (S)‐ or (R)‐EDDP, contribute to methadone‐associated QT prolongation.

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KCNH2 polymorphism and methadone dosage interact to enhance QT duration

Cited by 19 publications

References 33 publications

QT length during methadone maintenance treatment: gene × dose interaction

QT length during methadone maintenance treatment: gene × dose interaction

Role of risk stratification and genetics in sudden cardiac death

Methadone‐associated QT interval prolongation in patients undergoing maintenance therapy in an urban opioid treatment program

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