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Molecular markers of anti-malarial drug resistance in Central, West and East African children with severe malaria.

Nguetse, CN; Adegnika, AA; Agbenyega, T; Ogutu, BR; Krishna, S; Kremsner, PG; Velavan, TP (2017) Molecular markers of anti-malarial drug resistance in Central, West and East African children with severe malaria. Malar J, 16 (1). p. 217. ISSN 1475-2875 https://doi.org/10.1186/s12936-017-1868-y
SGUL Authors: Krishna, Sanjeev

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Abstract

BACKGROUND: The Plasmodium falciparum multidrug resistance 1 (PfMDR1), P. falciparum Ca(2+)-ATPase (PfATP6) and Kelch-13 propeller domain (PfK13) loci are molecular markers of parasite susceptibility to anti-malarial drugs. Their frequency distributions were determined in the isolates collected from children with severe malaria originating from three African countries. METHODS: Samples from 287 children with severe malaria [(Gabon: n = 114); (Ghana: n = 89); (Kenya: n = 84)] were genotyped for pfmdr1, pfatp6 and pfk13 loci by DNA sequencing and assessing pfmdr1 copy number variation (CNV) by real-time PCR. RESULTS: Pfmdr1-N86Y mutation was detected in 48, 10 and 10% in Lambaréné, Kumasi and Kisumu, respectively. At codon 184, the prevalence of the mutation was 73% in Lambaréné, 63% in Kumasi and 49% Kisumu. The S1034C and N1042D variants were absent at all three sites, while the frequency of the D1246Y mutation was 1, 3 and 13% in Lambaréné, Kumasi and Kisumu, respectively. Isolates with two pfmdr1 gene copy number predominantly harboured the N86Y wild-type allele and were mostly found in Kumasi (10%) (P < 0.0001). Among the main pfmdr1 haplotypes (NFD, NYD and YFD), NYD was associated with highest parasitaemia (P = 0.04). At the pfatp6 locus, H243Y and A623E mutations were observed at very low frequency at all three sites. The prevalence of the pfatp6 E431K variant was 6, 18 and 17% in Lambaréné, Kumasi and Kisumu, respectively. The L263E and S769N mutations were absent in all isolates. The pfk13 variants associated with artemisinin resistance in Southeast Asia were not observed. Eleven novel substitutions in the pfk13 locus occurring at low frequency were observed. CONCLUSIONS: Artemisinins are still highly efficacious in large malaria-endemic regions though declining efficacy has occurred in Southeast Asia. The return of chloroquine-sensitive strains following the removal of drug pressure is observed. However, selection of wild-type alleles in the multidrug-resistance gene and the increased gene copy number is associated with reduced lumefantrine sensitivity. This study indicates a need to constantly monitor drug resistance to artemisinin in field isolates from malaria-endemic countries.

Item Type: Article
Additional Information: © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Keywords: Africa, Anti-malarial drugs, Malaria, P. falciparum, Pfatp6, Pfk13, Pfmdr1, Resistance, Tropical Medicine, 1108 Medical Microbiology
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Malar J
ISSN: 1475-2875
Language: eng
Dates:
DateEvent
23 May 2017Published
17 May 2017Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
DFG-KU775/17-1Deutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100001659
CT.2004.31070.001European and Developing Countries Clinical Trials Partnershiphttp://dx.doi.org/10.13039/501100001713
PubMed ID: 28535801
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/108888
Publisher's version: https://doi.org/10.1186/s12936-017-1868-y

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