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Despite the positive results in fighting malaria, inhibition of the Kv11.1 channel (hERG; encoded by the\n              <jats:italic>KCNH2<\/jats:italic>\n              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\n              <jats:italic>KCNH2<\/jats:italic>\n              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\n              <jats:italic>KCNH2<\/jats:italic>\n              -specific ensemble classifier that identified a total of 116 putatively deleterious missense variations. To evaluate the clinical relevance of\n              <jats:italic>KCNH2<\/jats:italic>\n              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 (\u0394QTc of 41.8 ms and 61 ms, respectively, vs 14.4 ms in controls) with more than 50% of carriers having increases in QTc &gt;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\n              <jats:italic>KCNH2<\/jats:italic>\n              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.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/aac.01390-23","type":"journal-article","created":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T13:00:39Z","timestamp":1711630839000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Population-specific variations in\n            <i>KCNH2<\/i>\n            predispose patients to delayed ventricular repolarization upon dihydroartemisinin-piperaquine therapy"],"prefix":"10.1128","volume":"68","author":[{"given":"Mahamadou D.","family":"Camara","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden"},{"name":"Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3066-5444","authenticated-orcid":false,"given":"Yitian","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antoine","family":"Dara","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mamadou M.","family":"T\u00e9k\u00e9t\u00e9","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ta\u00eds","family":"N\u00f3brega de Sousa","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Tumour Cell Biology, Karolinska Institutet, Stockholm, Sweden"},{"name":"Molecular Biology and Malaria Immunology Research Group, Instituto Ren\u00e9 Rachou, Funda\u00e7\u00e3o Oswaldo Cruz (FIOCRUZ), Belo Horizonte, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S\u00e9kou","family":"Sissoko","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9087-8439","authenticated-orcid":false,"given":"Laurent","family":"Demb\u00e9l\u00e9","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nouhoun","family":"Ouologuem","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amadou","family":"Hamidou Togo","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed L.","family":"Alhousseini","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bakary","family":"Fofana","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Issaka","family":"Sagara","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdoulaye A.","family":"Djimde","sequence":"additional","affiliation":[{"name":"Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Pharmacy, University of Science, Techniques and Technologies, Bamako, Mali"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro J.","family":"Gil","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Tumour Cell Biology, Karolinska Institutet, Stockholm, Sweden"},{"name":"Global Health and Tropical Medicine, Institute of Hygiene and Tropical Medicine, Nova University of Lisbon, Lisbon, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1140-6204","authenticated-orcid":false,"given":"Volker M.","family":"Lauschke","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, 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