{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T04:22:02Z","timestamp":1772166122463,"version":"3.50.1"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T00:00:00Z","timestamp":1594771200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T00:00:00Z","timestamp":1594771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Malar J"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Artemisinin-based combination therapy (ACT) partner drugs, currently used in Ghana are lumefantrine, amodiaquine and piperaquine.\n                      <jats:italic>Plasmodium falciparum<\/jats:italic>\n                      isolates with reduced susceptibility to these partner drugs may affect treatment outcome. Mutations in\n                      <jats:italic>pfmdr1<\/jats:italic>\n                      gene is linked to reduced parasite susceptibility to amodiaquine and lumefantrine. In addition, the potency of the partner drugs in vivo depends on the metabolism by the cytochrome P450 (CYP) enzyme in the host. Mutations in the\n                      <jats:italic>CYP2C8<\/jats:italic>\n                      and\n                      <jats:italic>CYP3A4<\/jats:italic>\n                      genes are linked to reduced metabolism of amodiaquine and lumefantrine in vitro\n                      <jats:italic>,<\/jats:italic>\n                      respectively. This study investigated the host and parasite genetic factors affecting the susceptibility of the malaria parasite to ACT partner drugs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Archived samples from 240 patients age\u2009\u2264\u20099\u00a0years participating in anti-malarial drug resistance survey in Ghana, and given artemether with lumefantrine (AL) or artesunate with amodiaquine (AA), were selected and analysed. Polymerase chain reaction (PCR) followed by Sanger sequencing was used to determine the polymorphisms in\n                      <jats:italic>CYP2C8, CYP3A4<\/jats:italic>\n                      and\n                      <jats:italic>pfmdr1<\/jats:italic>\n                      genes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      For\n                      <jats:italic>CYP3A4<\/jats:italic>\n                      , all had wild type alleles, suggesting that the hosts are good metabolizers of lumefantrine. For\n                      <jats:italic>CYP2C8<\/jats:italic>\n                      60% had wild type alleles, 35% heterozygous and 5% homozygous recessive alleles suggesting efficient metabolism of amodiaquine by the hosts. For\n                      <jats:italic>pfmdr1<\/jats:italic>\n                      gene, at codon 86, 95% were wild type (N86) and 5% mutant (Y86). For codon 184, 36% were wild type (Y184) and 64% mutant (F184) while for codons 1034, 1042 and 1246, 100% (all) were wild type. The high prevalence of N86-F184-D1246 haplotype (NFD) suggest presence of parasites with reduced susceptibility to lumefantrine and not amodiaquine. Delayed clearance was observed in individuals with mutations in the\n                      <jats:italic>pfmdr<\/jats:italic>\n                      1 gene and not cytochrome 450 gene. Both synonymous and non-synonymous mutations were observed in the\n                      <jats:italic>pfmdr<\/jats:italic>\n                      1 at low prevalence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The outcome of this study indicates that the parasite's genetic factors rather than the host\u2019s are likely to drive resistance to ACT in Ghana.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12936-020-03320-7","type":"journal-article","created":{"date-parts":[[2020,7,15]],"date-time":"2020-07-15T06:04:38Z","timestamp":1594793078000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Plasmodium falciparum genetic factors rather than host factors are likely to drive resistance to ACT in Ghana"],"prefix":"10.1186","volume":"19","author":[{"given":"Peter","family":"Hodoameda","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy Odurowah","family":"Duah-Quashie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles Oheneba","family":"Hagan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sena","family":"Matrevi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Abuaku","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kwadwo","family":"Koram","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neils Ben","family":"Quashie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,7,15]]},"reference":[{"key":"3320_CR1","unstructured":"WHO. World malaria report 2018. Geneva: World Health Organization; 2018. www.who.int\/malaria. Accessed 15 Nov 2019"},{"key":"3320_CR2","unstructured":"WHO. World malaria report 2014. Geneva: World Health Organization; 2014. https:\/\/www.who.int\/malaria\/publications\/world_malaria_report_2014\/wmr-2014-no-profiles.pdf. Accessed 23 Apr 2019"},{"key":"3320_CR3","volume-title":"Antimalarial drug policy for Ghana","author":"Ministry of Health","year":"2009","unstructured":"Ministry of Health. Antimalarial drug policy for Ghana. Accra: Ministry of Health; 2009."},{"issue":"6 Suppl","key":"3320_CR4","first-page":"181","volume":"77","author":"NJ White","year":"2007","unstructured":"White NJ, Nosten F. Artemisinin-based combination treatment of falciparum malaria. Am J Trop Med Hyg. 2007;77(6 Suppl):181\u201392.","journal-title":"Am J Trop Med Hyg."},{"key":"3320_CR5","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1051\/parasite\/2018021","volume":"25","author":"M Ouji","year":"2018","unstructured":"Ouji M, Augereau J-M, Paloque L, Benoit-Vical F. Plasmodium falciparum resistance to artemisinin-based combination therapies: a sword of Damocles in the path toward malaria elimination. Parasite. 2018;25:24.","journal-title":"Parasite"},{"key":"3320_CR6","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","volume":"138","author":"UM Zanger","year":"2013","unstructured":"Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138:103\u201341.","journal-title":"Pharmacol Ther"},{"key":"3320_CR7","doi-asserted-by":"publisher","first-page":"18883","DOI":"10.1073\/pnas.0911317106","volume":"106","author":"JM S\u00e1","year":"2009","unstructured":"S\u00e1 JM, Twu O, Hayton K, Reyes S, Fay MP, Ringwald P, et al. Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine. Proc Natl Acad Sci USA. 2009;106:18883\u20139.","journal-title":"Proc Natl Acad Sci USA"},{"key":"3320_CR8","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1111\/j.1365-3156.2007.01843.x","volume":"12","author":"C Sisowath","year":"2007","unstructured":"Sisowath C, Ferreira PE, Bustamante LY, Dahlstr\u00f6m S, M\u00e5rtensson A, Bj\u00f6rkman A, et al. The role of pfmdr1 in Plasmodium falciparum tolerance to artemether-lumefantrine in Africa. Trop Med Int Health. 2007;12:736\u201342.","journal-title":"Trop Med Int Health"},{"key":"3320_CR9","doi-asserted-by":"publisher","first-page":"3395","DOI":"10.1128\/AAC.01421-09","volume":"54","author":"N Chen","year":"2010","unstructured":"Chen N, Chavchich M, Peters JM, Kyle DE, Gatton ML, Cheng Q. Deamplification of pfmdr1-containing amplicon on chromosome 5 in Plasmodium falciparum is associated with reduced resistance to artelinic acid in vitro. Antimicrob Agents Chemother. 2010;54:3395\u2013401.","journal-title":"Antimicrob Agents Chemother"},{"key":"3320_CR10","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1016\/j.meegid.2007.03.005","volume":"7","author":"G Holmgren","year":"2007","unstructured":"Holmgren G, Hamrin J, Sv\u00e4rd J, M\u00e5rtensson A, Gil JP, Bj\u00f6rkman A. Selection of pfmdr1 mutations after amodiaquine monotherapy and amodiaquine plus artemisinin combination therapy in East Africa. Infect Genet Evol. 2007;7:562\u20139.","journal-title":"Infect Genet Evol"},{"key":"3320_CR11","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/sj.clpt.6100122","volume":"82","author":"S Parikh","year":"2007","unstructured":"Parikh S, Ouedraogo JB, Goldstein JA, Rosenthal PJ, Kroetz DL. Amodiaquine metabolism is impaired by common polymorphisms in CYP2C8: implications for malaria treatment in Africa. Clin Pharmacol Ther. 2007;82:197\u2013203.","journal-title":"Clin Pharmacol Ther"},{"key":"3320_CR12","doi-asserted-by":"publisher","first-page":"467","DOI":"10.2165\/00044011-199918060-00006","volume":"18","author":"G Lefevre","year":"1999","unstructured":"Lefevre G, Thomsen MS. Clinical pharmacokinetics of artemether and lumefantrine (Riamet). Clin Drug Investig. 1999;18:467\u201380.","journal-title":"Clin Drug Investig"},{"key":"3320_CR13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1559-0275-8-12","volume":"8","author":"AHB Wu","year":"2011","unstructured":"Wu AHB. Drug metabolizing enzyme activities versus genetic variances for drug of clinical pharmacogenomic relevance. Clin Proteomics. 2011;8:1\u20139.","journal-title":"Clin Proteomics"},{"key":"3320_CR14","doi-asserted-by":"publisher","first-page":"1563","DOI":"10.1098\/rstb.2005.1685","volume":"360","author":"M Ingelman-Sundberg","year":"2005","unstructured":"Ingelman-Sundberg M, Rodriguez-Antona C. Pharmacogenetics of drug-metabolizing enzymes: implications for a safer and more effective drug therapy. Philos Trans R Soc B Biol Sci. 2005;360:1563\u201370.","journal-title":"Philos Trans R Soc B Biol Sci"},{"key":"3320_CR15","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s12936-015-1080-x","volume":"15","author":"B Abuaku","year":"2016","unstructured":"Abuaku B, Duah N, Quaye L, Quashie N, Malm K, Plange CB. Therapeutic efficacy of artesunate\u2014amodiaquine and artemether\u2014lumefantrine combinations in the treatment of uncomplicated malaria in two ecological zones in Ghana. Malar J. 2016;15:6.","journal-title":"Malar J"},{"key":"3320_CR16","first-page":"1","volume":"63","author":"TC Lorenz","year":"2012","unstructured":"Lorenz TC. Polymerase chain reaction: basic protocol plus troubleshooting and optimization strategies. J Vis Exp. 2012;63:1\u201314.","journal-title":"J Vis Exp"},{"key":"3320_CR17","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.1086\/651949","volume":"201","author":"S Vinayak","year":"2010","unstructured":"Vinayak S, Alam T, Sem R, Shah NK, Susanti AI, Lim P, et al. Multiple genetic backgrounds of the amplified Plasmodium falciparum multidrug resistance (pfmdr1) gene and selective sweep of 184F mutation in Cambodia. J Infect Dis. 2010;201:1551\u2013600.","journal-title":"J Infect Dis"},{"key":"3320_CR18","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1007\/s00228-004-0871-8","volume":"61","author":"I Cavaco","year":"2005","unstructured":"Cavaco I, Stromberg-Norklit J, Kaneko A, Msellem MI, Dahoma M, Ribeiro VL, et al. CYP2C8 polymorphism frequencies among malaria patients in Zanzibar. Eur J Clin Pharmacol. 2005;61:15\u20138.","journal-title":"Eur J Clin Pharmacol"},{"key":"3320_CR19","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1186\/1475-2875-8-285","volume":"8","author":"EM Hodel","year":"2009","unstructured":"Hodel EM, Ley SD, Qi W, Ariey F, Genton B, Beck H. A microarray-based system for the simultaneous analysis of single nucleotide polymorphisms in human genes involved in the metabolism of anti-malarial drugs. Malar J. 2009;8:285.","journal-title":"Malar J"},{"key":"3320_CR20","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1086\/429864","volume":"76","author":"JE Wigginton","year":"2005","unstructured":"Wigginton JE, Cutler DJ, Abecasis GR. A note on exact tests of Hardy-Weinberg equilibrium. Am J Hum Genet. 2005;76:887\u201393.","journal-title":"Am J Hum Genet"},{"key":"3320_CR21","doi-asserted-by":"publisher","first-page":"e23875","DOI":"10.1371\/journal.pone.0023875","volume":"6","author":"PE Ferreira","year":"2011","unstructured":"Ferreira PE, Holmgren G, Veiga MI, Uhl\u00e9n P, Kaneko A, Gil JP. PfMDR1: Mechanisms of transport modulation by functional polymorphisms. PLoS ONE. 2011;6:e23875.","journal-title":"PLoS ONE"},{"key":"3320_CR22","doi-asserted-by":"publisher","first-page":"1769","DOI":"10.1038\/s41467-018-04104-z","volume":"9","author":"S Bopp","year":"2018","unstructured":"Bopp S, Magistrado P, Wong W, Schaffner SF, Mukherjee A, Lim P, et al. Plasmepsin II-III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum. Nat Commun. 2018;9:1769.","journal-title":"Nat Commun"},{"key":"3320_CR23","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1186\/1475-2875-12-377","volume":"12","author":"NO Duah","year":"2013","unstructured":"Duah NO, Matrevi SA, De Souza DK, Binnah DD, Tamakloe MM, Opoku VS, et al. Increased pfmdr1 gene copy number and the decline in pfcrt and pfmdr1 resistance alleles in Ghanaian Plasmodium falciparum isolates after the change of anti-malarial drug treatment policy. Malar J. 2013;12:377.","journal-title":"Malar J"},{"key":"3320_CR24","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1016\/S0169-409X(02)00066-2","volume":"54","author":"JK Lamba","year":"2012","unstructured":"Lamba JK, Lin YS, Schuetz EG, Thummel KE. Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev. 2012;54:1271\u201394.","journal-title":"Adv Drug Deliv Rev"},{"key":"3320_CR25","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1186\/s12936-017-1914-9","volume":"16","author":"RF Mutagonda","year":"2017","unstructured":"Mutagonda RF, Kamuhabwa AAR, Minzi OMS, Massawe SN, Asghar M, Homann MV, et al. Effect of pharmacogenetics on plasma lumefantrine pharmacokinetics and malaria treatment outcome in pregnant women. Malar J. 2017;16:267.","journal-title":"Malar J"},{"key":"3320_CR26","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1186\/s12936-017-2006-6","volume":"16","author":"K Kiaco","year":"2017","unstructured":"Kiaco K, Rodrigues AS, Ros\u00e1rio V, Gil JP, Lopes D. The drug transporter ABCB1 c.3435C> T SNP influences artemether-lumefantrine treatment outcome. Malar J. 2017;16:383.","journal-title":"Malar J."},{"key":"3320_CR27","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1124\/jpet.300.2.399","volume":"300","author":"X-Q Li","year":"2002","unstructured":"Li X-Q, Bj\u00f6rkman A, Andersson TB, Ridderstr\u00f6m M, Masimirembwa CM. Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. J Pharmacol Exp Ther. 2002;300:399\u2013407.","journal-title":"J Pharmacol Exp Ther"},{"key":"3320_CR28","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1186\/1471-2350-10-124","volume":"10","author":"W Kudzi","year":"2009","unstructured":"Kudzi W, Dodoo ANO, Mills JJ. Characterisation of CYP2C8, CYP2C9 and CYP2C19 polymorphisms in a Ghanaian population. BMC Med Genet. 2009;10:124.","journal-title":"BMC Med Genet"}],"container-title":["Malaria Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12936-020-03320-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12936-020-03320-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12936-020-03320-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T19:21:18Z","timestamp":1626290478000},"score":1,"resource":{"primary":{"URL":"https:\/\/malariajournal.biomedcentral.com\/articles\/10.1186\/s12936-020-03320-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,15]]},"references-count":28,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["3320"],"URL":"https:\/\/doi.org\/10.1186\/s12936-020-03320-7","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-25966\/v2","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.3.rs-25966\/v1","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.2.21377\/v1","asserted-by":"object"},{"id-type":"doi","id":"10.21203\/rs.3.rs-25966\/v3","asserted-by":"object"}]},"ISSN":["1475-2875"],"issn-type":[{"value":"1475-2875","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,15]]},"assertion":[{"value":"27 April 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 July 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 July 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Ethical clearance was obtained from the Noguchi Memorial Institute for Medical Research (NMIMR) Institutional Review Board (IRB) and the Ghana Health Service IRB number IRB00001276. Informed consent was obtained from the guardians of the participants. This was after the purpose of the study has been explained to them in their native language and given an opportunity to ask questions that is of concern to them.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"255"}}