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      Polymorphisms in K13, pfcrt, pfmdr1, pfdhfr, and pfdhps in parasites isolated from symptomatic malaria patients in Burkina Faso Translated title: Polymorphismes de K13, pfcrt, pfmdr1, pfdhfr et pfdhps chez des parasites isolés de patients symptomatiques de paludisme au Burkina Faso

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          Abstract

          Background: The emergence of resistance to artemisinin derivatives in western Cambodia is threatening to revert the recent advances made toward global malaria control and elimination. Known resistance-mediating polymorphisms in the K13, pfcrt, pfmdr1, pfdhfr, and pfdhps genes are of greatest importance for monitoring the spread of antimalarial drug resistance. Methods: Samples for the present study were collected from 244 patients with uncomplicated malaria in health centers of Bobo-Dioulasso, Burkina Faso. Blood sample was collected on filter paper before the subject received any treatment. The parasite DNA was then extracted and amplified by Polymerase Chain Reaction (PCR) to evaluate the prevalence of polymorphism of pfcrtK76T, pfmdr1 (N86Y, Y184F), and pfdhps (A437G, K540E). The K13 gene polymorphism was analyzed by nested PCR followed by sequencing. Results: The overall results showed 2.26% (5/221) of K13 synonymous mutant alleles (two C469C, one Y493Y, one G496G, and one V589V), 24.78%, 19.58%, 68.75%, 60.9%, 53.7%, 63.8%, and 64.28%, respectively, for mutant pfcrt 76T, pfmdr1-86Y, pfmdr1-184F, pfdhfr51I, pfdhfr59R, pfdhfr108N, and pfdhps 437G. We did not report any mutation at codon 540 of pfdhps. Conclusion: These results provide baseline prevalence of known drug resistance polymorphisms and suggest that artemisinin combination therapies may retain good efficacy in the treatment of uncomplicated malaria in Burkina Faso.

          Translated abstract

          Contexte : L’émergence de la résistance aux dérivés de l’artémisinine dans l’ouest du Cambodge menace d’annuler les avancées récentes en matière de lutte et d’élimination du paludisme à l’échelle mondiale. Les polymorphismes de médiation de résistance connus dans les gènes K13, pfcrt, pfmdr1, pfdhfr et pfdhps sont de la plus grande importance pour surveiller la propagation de la résistance aux antipaludiques. Méthodes : Les échantillons de cette étude ont été prélevés sur 244 patients atteints de paludisme non compliqué dans les centres de santé de Bobo-Dioulasso, au Burkina Faso. Les échantillons de sang ont été prélevés sur du papier filtre avant que le sujet ne reçoive aucun traitement. L’ADN du parasite a ensuite été extrait et amplifié par PCR pour évaluer la prévalence du polymorphisme de pfcrtK76T, pfmdr1 (N86Y, Y184F) et pfdhps (A437G, K540E). Le polymorphisme du gène K13 a été analysé par PCR imbriquée suivie d’un séquençage. Résultats : Les résultats globaux ont montré 2.26 % d’allèles mutants (5/221) pour K13 (deux C469C, un Y493Y, un G496G et un V589V), et 24.78 %, 19.58 %, 68.75 %, 60.9 %, 53.7 %, 63.8 % et 64.28 %, respectivement, pour les mutants pfcrt 76T, pfmdr1-86Y, pfmdr1-184F, pfdhfr51I, pfdhfr59R, pfdhfr108N et pfdhps 437G. Nous n’avons signalé aucune mutation au codon 540 de pfdhps. Conclusion : Ces résultats montrent une prévalence très faible des polymorphismes de pharmacorésistance connus et suggèrent que les thérapies combinées à base d’artémisinine pourraient conserver une bonne efficacité dans le traitement du paludisme non compliqué au Burkina Faso.

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          Most cited references 32

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          A molecular marker for chloroquine-resistant falciparum malaria.

          Chloroquine-resistant Plasmodium falciparum malaria is a major health problem, particularly in sub-Saharan Africa. Chloroquine resistance has been associated in vitro with point mutations in two genes, pfcrt and pfmdr 1, which encode the P. falciparum digestive-vacuole transmembrane proteins PfCRT and Pgh1, respectively. To assess the value of these mutations as markers for clinical chloroquine resistance, we measured the association between the mutations and the response to chloroquine treatment in patients with uncomplicated falciparum malaria in Mali. The frequencies of the mutations in patients before and after treatment were compared for evidence of selection of resistance factors as a result of exposure to chloroquine. The pfcrt mutation resulting in the substitution of threonine (T76) for lysine at position 76 was present in all 60 samples from patients with chloroquine-resistant infections (those that persisted or recurred after treatment), as compared with a base-line prevalence of 41 percent in samples obtained before treatment from 116 randomly selected patients (P<0.001), indicating absolute selection for this mutation. The pfmdr 1 mutation resulting in the substitution of tyrosine for asparagine at position 86 was also selected for, since it was present in 48 of 56 post-treatment samples from patients with chloroquine-resistant infections (86 percent), as compared with a base-line prevalence of 50 percent in 115 samples obtained before treatment (P<0.001). The presence of pfcrt T76 was more strongly associated with the development of chloroquine resistance (odds ratio, 18.8; 95 percent confidence interval, 6.5 to 58.3) than was the presence of pfmdr 1 Y86 (odds ratio, 3.2; 95 percent confidence interval, 1.5 to 6.8) or the presence of both mutations (odds ratio, 9.8; 95 percent confidence interval, 4.4 to 22.1). This study shows an association between the pfcrt T76 mutation in P. falciparum and the development of chloroquine resistance during the treatment of malaria. This mutation can be used as a marker in surveillance for chloroquine-resistant falciparum malaria.
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            Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum.

            Widespread use of antimalarial agents can profoundly influence the evolution of the human malaria parasite Plasmodium falciparum. Recent selective sweeps for drug-resistant genotypes may have restricted the genetic diversity of this parasite, resembling effects attributed in current debates to a historic population bottleneck. Chloroquine-resistant (CQR) parasites were initially reported about 45 years ago from two foci in southeast Asia and South America, but the number of CQR founder mutations and the impact of chlorquine on parasite genomes worldwide have been difficult to evaluate. Using 342 highly polymorphic microsatellite markers from a genetic map, here we show that the level of genetic diversity varies substantially among different regions of the parasite genome, revealing extensive linkage disequilibrium surrounding the key CQR gene pfcrt and at least four CQR founder events. This disequilibrium and its decay rate in the pfcrt-flanking region are consistent with strong directional selective sweeps occurring over only approximately 20-80 sexual generations, especially a single resistant pfcrt haplotype spreading to very high frequencies throughout most of Asia and Africa. The presence of linkage disequilibrium provides a basis for mapping genes under drug selection in P. falciparum.
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              Reemergence of chloroquine-sensitive Plasmodium falciparum malaria after cessation of chloroquine use in Malawi.

              In 1993, Malawi became the first African country to replace chloroquine with sulfadoxine-pyrimethamine nationwide in response to high rates of chloroquine-resistant falciparum malaria. To determine whether withdrawal of chloroquine can lead to the reemergence of chloroquine sensitivity, the prevalence of the pfcrt 76T molecular marker for chloroquine-resistant Plasmodium falciparum malaria was retrospectively measured in Blantyre, Malawi. The prevalence of the chloroquine-resistant pfcrt genotype decreased from 85% in 1992 to 13% in 2000. In 2001, chloroquine cleared 100% of 63 asymptomatic P. falciparum infections, no isolates were resistant to chloroquine in vitro, and no infections with the chloroquine-resistant pfcrt genotype were detected. A concerted national effort to withdraw chloroquine from use has been followed by a return of chloroquine-sensitive falciparum malaria in Malawi. The reintroduction of chloroquine, ideally in combination with another antimalarial drug, should be considered in areas where chloroquine resistance has declined and safe and affordable alternatives remain unavailable.
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                Author and article information

                Journal
                Parasite
                Parasite
                parasite
                Parasite
                EDP Sciences
                1252-607X
                1776-1042
                2016
                22 December 2016
                : 23
                : ( publisher-idID: parasite/2016/01 )
                Affiliations
                [1 ] Institut de Recherche en Sciences de la Santé, Direction Régionale de l’Ouest 399 Avenue de la liberté 01 BP 545 Bobo-Dioulasso 01 Burkina Faso
                [2 ] Institut de Recherche en Sciences de la Santé, Unité de Recherche Clinique de Nanoro BP 218 Ouaga CMS 11 Burkina Faso
                Author notes
                [* ]Corresponding authors: afabricesome@ 123456yahoo.fr (AF Somé), hsorgho@ 123456hotmail.com (H Sorgho)
                Article
                parasite160069 10.1051/parasite/2016069
                10.1051/parasite/2016069
                5178381
                28004634
                © A.F. Somé et al., published by EDP Sciences, 2016

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 38, Pages: 7
                Categories
                Research Article

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