Sequence Polymorphisms in<i>pfcrt</i>Are Strongly Associated with Chloroquine Resistance in<i>Plasmodium falciparum</i>

Chen, Nanhua; Russell, Bruce; Staley, John; Kotecka, Barbara; Nasveld, Peter; Cheng, Qin

doi:10.1086/320206

Cited by 56 publications

(54 citation statements)

References 7 publications

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“…This observation supports the view that the pfcrt polymorphism at position 76 is in fact a significant factor of CQ resistance, as shown in previous studies from Cameroon, 13 Mali, 8 Mozambique, 10 Nigeria, 20 Sudan, 12 Uganda, 9,21 Madagascar, 22 Laos, 11,23 Papua New Guinea, 14,24 and Thailand. 14,23 The proportion of children infected with parasite clones carrying the pfcrt T76 variant decreased significantly with age and correlated with the age-associated decrease in CQ levels. The higher levels of CQ in younger children might result from the fact that these children are more frequently given CQ when they are febrile during an assumed malaria attack.…”

Section: Discussionsupporting

confidence: 91%

“…6,7 Evidence that pfcrt T76 is a key marker of CQ resistance has been demonstrated in several studies on the selection of this mutation after treatment with CQ [8][9][10][11] and by varying in vivo and in vitro responses to CQ in different parasite isolates. [12][13][14] Findings on the relationship between blood levels of CQ and the occurrence of pfcrt 76 variants have not been reported.…”

Section: Introductionmentioning

confidence: 99%

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Association of Plasmodium Falciparum Chloroquine Resistance Transporter Variant T76 With Age-Related Plasma Chloroquine Levels

May

Meyer²

2003

The American Journal of Tropical Medicine and Hygiene

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Abstract. The mutation leading to the substitution of a threonine (T76) for a lysine at position 76 of the Plasmodium falciparum chloroquine resistance transporter (PfCRT) was genotyped in 100 Nigerian children with asymptomatic parasitemia. Isolates containing both pfcrt variants were found to harbor higher numbers of parasite clones (P < 0.002). The prevalence of the pfcrt T76 variant decreased with age (P < 0.0001) and increased with blood levels of chloroquine (CQ) (P < 0.0001). Whereas the K76 allele was more frequent in individuals without detectable plasma CQ levels (79.7%), only the pfcrt T76 variant was observed in children with CQ levels > 150 nmol/L. In individuals without detectable plasma CQ, the proportion of those with pfcrt T76 decreased from 60% in children < 2 years old to 23.5% in children Ն 6 years old (P < 0.01). The association of actual blood levels of CQ and the occurrence of pfcrt T76 underlines that the pfcrt T76 variant is in fact the mediator of CQ resistance.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Association of Plasmodium Falciparum Chloroquine Resistance Transporter Variant T76 With Age-Related Plasma Chloroquine Levels

May

Meyer²

2003

The American Journal of Tropical Medicine and Hygiene

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“…This approach was also predicted to generate a downstream, disrupted remnant pfcrt sequence that lacked a promoter and the first seven exons of the endogenous gene. For this experiment, we transfected the 7G8 line to test whether expression levels of the 7G8-type pfcrt allele (which appears to have originated independently in South America and Oceania (19,20,25,46)) had a direct impact on the P. falciparum CQR phenotype.…”

Section: Effect Of Truncation Of Pfcrt 3ј-utr Determined Usingmentioning

confidence: 99%

Chloroquine Resistance Modulated in Vitro by Expression Levels of the Plasmodium falciparum Chloroquine Resistance Transporter

Waller

Muhle

Ursos

et al. 2003

Journal of Biological Chemistry

112

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Plasmodium falciparum malaria is increasingly difficult to treat and control due to the emergence of parasite resistance to the major antimalarials, notably chloroquine. Recent work has shown that the chloroquine resistance phenotype can be conferred by multiple amino acid mutations in the parasite digestive vacuole transmembrane protein PfCRT. Here, we have addressed whether chloroquine resistance can also be affected by changes in expression levels of this protein.Transient transfection reporter assays revealed that truncation of the pfcrt 3-untranslated region just prior to putative polyadenylation sites resulted in a 10-fold decrease in luciferase expression levels. Using allelic exchange on a chloroquine-resistant line (7G8 from Brazil), this truncated 3-untranslated region was inserted downstream of the pfcrt coding sequence, in the place of the endogenous 3-untranslated region. The resulting pfcrt-modified "knockdown" clones displayed a marked decrease in pfcrt transcription and an estimated 30 -40% decrease in PfCRT protein expression levels. [ 3 H]hypoxanthine incorporation assays demonstrated up to a 40% decrease in chloroquine with or without verapamil IC 50 levels of pfcrt knockdown clones, relative to the 7G8 parent. Single-cell photometric analyses were consistent with an altered intracellular pH in the knockdown clones, providing further evidence for a relationship between PfCRT, pH regulation, and chloroquine resistance. Genetic truncation of 3-untranslated regions provides a useful approach for assessing the impact of candidate genes on drug resistance or other quantifiable phenotypes in P. falciparum.

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“…5 Occurrence of mutations at additional polymorphic sites in the pfcrt gene is completely linked to the K76T allele. 6 In contrast to resistance to CQ, sulfadoxine, and pyrimethamine, there is not yet unequivocal identification of genetic traits responsible for resistance to mefloquine (MQ) and artemisinin, but various in vitro resistance studies report a positive predictive value for polymorphisms in the P. falciparum multidrug resistance gene (pfmdr1) encoding the P-glycoprotein homologue Pgh-1. 7,8 Several implications exist that single nucleotide polymorphisms (SNPs) in codons 86(N86Y), 184(Y184F), 1034(S1034C), 1042(N1042D), and 1246(D1246Y) of the pfmdr1 gene may modulate sensitivity for not only MQ but also lumefantrine and even artemisinin by influencing parasite response to these drugs.…”

Section: Introductionmentioning

confidence: 99%

Molecular Surveillance as Monitoring Tool for Drug-Resistant Plasmodium falciparum in Suriname

Adhin

Labadie-Bracho²,

Bretas³

2013

The American Society of Tropical Medicine and Hygiene

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Abstract. The aim of this translational study was to show the use of molecular surveillance for polymorphisms and copy number as a monitoring tool to track the emergence and dynamics of Plasmodium falciparum drug resistance. A molecular baseline for Suriname was established in 2005, with P. falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance (pfmdr1) markers and copy number in 40 samples. The baseline results revealed the existence of a uniformly distributed mutated genotype corresponding with the fully mefloquine-sensitive 7G8-like genotype (Y184F, S1034C, N1042D, and D1246Y) and a fixed pfmdr1 N86 haplotype. All samples harbored the pivotal pfcrtK76T mutation, showing that chloroquine reintroduction should not yet be contemplated in Suriname. After 5 years, 40 samples were assessed to trace temporal changes in the status of pfmdr1 polymorphisms and copy number and showed minor genetic alterations in the pfmdr1 gene and no significant changes in copy number, thus providing scientific support for prolongation of the current drug policy in Suriname.

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Sequence Polymorphisms inpfcrtAre Strongly Associated with Chloroquine Resistance inPlasmodium falciparum

Cited by 56 publications

References 7 publications

Association of Plasmodium Falciparum Chloroquine Resistance Transporter Variant T76 With Age-Related Plasma Chloroquine Levels

Association of Plasmodium Falciparum Chloroquine Resistance Transporter Variant T76 With Age-Related Plasma Chloroquine Levels

Chloroquine Resistance Modulated in Vitro by Expression Levels of the Plasmodium falciparum Chloroquine Resistance Transporter

Molecular Surveillance as Monitoring Tool for Drug-Resistant Plasmodium falciparum in Suriname

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