Population-specific variations in KCNH2 predispose patients to delayed ventricular repolarization upon dihydroartemisinin-piperaquine therapy
Rattachement africain : se, Mali, br, pt, de. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
ABSTRACT Dihydroartemisinin-piperaquine is efficacious for the treatment of uncomplicated malaria and its use is increasing globally. Despite the positive results in fighting malaria, inhibition of the Kv11.1 channel (hERG; encoded by the KCNH2 gene) by piperaquine has raised concerns about cardiac safety. Whether genetic factors could modulate the risk of piperaquine-mediated QT prolongations remained unclear. Here, we first profiled the genetic landscape of KCNH2 variability using data from 141,614 individuals. Overall, we found 1,007 exonic variants distributed over the entire gene body, 555 of which were missense. By optimizing the gene-specific parametrization of 16 partly orthogonal computational algorithms, we developed a KCNH2 -specific ensemble classifier that identified a total of 116 putatively deleterious missense variations. To evaluate the clinical relevance of KCNH2 variability, we then sequenced 293 Malian patients with uncomplicated malaria and identified 13 variations within the voltage sensing and pore domains of Kv11.1 that directly interact with channel blockers. Cross-referencing of genetic and electrocardiographic data before and after piperaquine exposure revealed that carriers of two common variants, rs1805121 and rs41314375, experienced significantly higher QT prolongations (ΔQTc of 41.8 ms and 61 ms, respectively, vs 14.4 ms in controls) with more than 50% of carriers having increases in QTc >30 ms. Furthermore, we identified three carriers of rare population-specific variations who experienced clinically relevant delayed ventricular repolarization. Combined, our results map population-scale genetic variability of KCNH2 and identify genetic biomarkers for piperaquine-induced QT prolongation that could help to flag at-risk patients and optimize efficacy and adherence to antimalarial therapy.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Population-specific variations in <i>KCNH2</i> predispose patients to delayed ventricular repolarization upon dihydroartemisinin-piperaquine therapy
- Date Crossref
- 02/05/2024
- Éditeur
- American Society for Microbiology
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Karolinska Institutet Department of Physiology and Pharmacology pays non établi dans la noticeUniversité ou école supérieure
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University of Bamako University of Bamako, Mali (code pays fourni par la source)Université ou école supérieure
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Malaria Research and Training Center Mali (code pays fourni par la source)Structure de recherche
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Fundação Oswaldo Cruz pays non établi dans la noticeStructure de recherche
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University of Lisbon Institute of Hygiene and Tropical Medicine pays non établi dans la noticeUniversité ou école supérieure
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Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology pays non établi dans la noticeStructure de recherche
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University of Tübingen pays non établi dans la noticeUniversité ou école supérieure
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Faculty of Pharmacy Department of Epidemiology of Parasitic Diseases Bamako, Mali (pays nommé en fin d’affiliation)Université ou école supérieure
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Instituto René Rachou Molecular Biology and Malaria Immunology Research Group pays non établi dans la noticeStructure de recherche
Department of Physiology and Pharmacology — Karolinska Institutet, University of Bamako (University of Bamako, Mali) et Malaria Research and Training Center (Mali), avec 6 autres affiliations. Pays d’affiliation : Mali.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.