Plasmodium vivax: allele variants of the mdr1 gene do not associate with chloroquine resistance among isolates from Brazil, Papua, and monkey-adapted strains

Sá, Juliana M.; Nomura, Takashi; Neves, J.; Baird, J. Kevin; Wellems, Thomas E.; Portillo, Hernando A. del

doi:10.1016/j.exppara.2004.12.005

Cited by 73 publications

(61 citation statements)

References 22 publications

(23 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The finding of parasites with wild-type pvmdr-1 alleles that are CQ-resistant [22,24] suggests that other polymorphisms may contribute to this phenotype. Similar to P. falciparum [25], in vitro susceptibility to CQ in P. vivax appears to be modulated by pvmdr-1 copy number.…”

Section: Resultsmentioning

confidence: 99%

“…K76T mutant alleles of the P. falciparum orthologue of pvcrt-o , which encodes the protein chloroquine resistance transporter (PfCRT), confer CQ resistance to this species [46], but the limited data available to date fail to support associations between mutations in pvcrt-o alleles and CQ resistance in P. vivax [44,45]. We also typed one synonymous (at codon 4065) and five nonsynonymous (N89 S, N500 D, M908L, Y976F, and F1076L) SNPs previously described at the multidrug resistance 1 gene of P. vivax ( pvmdr-1 ) [21,22,24,45], which encodes a P-glycoprotein of the family of ATP binding cassette (ABC) transporters. The Y976F mutation (TAC→TTC) has been associated with CQ resistance in Southeast Asia [22] and Papua New Guinea [23].…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Single-nucleotide polymorphism, linkage disequilibrium and geographic structure in the malaria parasite Plasmodium vivax: prospects for genome-wide association studies

et al. 2010

View full text Add to dashboard Cite

BackgroundThe ideal malaria parasite populations for initial mapping of genomic regions contributing to phenotypes such as drug resistance and virulence, through genome-wide association studies, are those with high genetic diversity, allowing for numerous informative markers, and rare meiotic recombination, allowing for strong linkage disequilibrium (LD) between markers and phenotype-determining loci. However, levels of genetic diversity and LD in field populations of the major human malaria parasite P. vivax remain little characterized.ResultsWe examined single-nucleotide polymorphisms (SNPs) and LD patterns across a 100-kb chromosome segment of P. vivax in 238 field isolates from areas of low to moderate malaria endemicity in South America and Asia, where LD tends to be more extensive than in holoendemic populations, and in two monkey-adapted strains (Salvador-I, from El Salvador, and Belem, from Brazil). We found varying levels of SNP diversity and LD across populations, with the highest diversity and strongest LD in the area of lowest malaria transmission. We found several clusters of contiguous markers with rare meiotic recombination and characterized a relatively conserved haplotype structure among populations, suggesting the existence of recombination hotspots in the genome region analyzed. Both silent and nonsynonymous SNPs revealed substantial between-population differentiation, which accounted for ~40% of the overall genetic diversity observed. Although parasites clustered according to their continental origin, we found evidence for substructure within the Brazilian population of P. vivax. We also explored between-population differentiation patterns revealed by loci putatively affected by natural selection and found marked geographic variation in frequencies of nucleotide substitutions at the pvmdr-1 locus, putatively associated with drug resistance.ConclusionThese findings support the feasibility of genome-wide association studies in carefully selected populations of P. vivax, using relatively low densities of markers, but underscore the risk of false positives caused by population structure at both local and regional levels.See commentary: http://www.biomedcentral.com/1741-7007/8/90

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Single-nucleotide polymorphism, linkage disequilibrium and geographic structure in the malaria parasite Plasmodium vivax: prospects for genome-wide association studies

et al. 2010

View full text Add to dashboard Cite

show abstract

“…The Y976F mutation (TAC!TTC) in pvmdr-1 has been associated with CQ resistance in Southeast Asia 8 and Papua New Guinea, 9 but whether this polymorphism can be used as a molecular marker of CQ resistance in parasites collected worldwide remains unclear. 3,[10][11][12] Interestingly, the Y976F change has been reported to be rare in alleles that do not carry the F1076L (TTT!CTT) change, consistent with a two-step mutation pathway (F1076L followed by Y976F) putatively leading to CQ resistance. 13,14 Similar to P. falciparum, 15 susceptibility to CQ in P. vivax appears to be also modulated by pvmdr-1 copy number.…”

Section: 2mentioning

confidence: 86%

“…19 Analysis of single-nucleotide polymorphism in P. vivax mdr-1. We typed five common nonsynonymous SNPs (A266G, A1498G, A2722C, A2927T, and T3226C) described in the pvmdr-1 gene of field isolates collected worldwide, 8,10,12,13 which correspond to the amino acid changes N89S, N500D, M908L, Y976F, and F1076L. These polymorphisms were genotyped under contract by K-Biosciences (Cambridge, United Kingdom) with an amplifluor assay.…”

Section: Methodsmentioning

confidence: 99%

Single-Nucleotide Polymorphism and Copy Number Variation of the Multidrug Resistance-1 Locus of Plasmodium vivax: Local and Global Patterns

Vargas-Rodríguez

Bastos²,

Menezes³

et al. 2012

The American Journal of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

Abstract. Emerging resistance to chloroquine (CQ) poses a major challenge for Plasmodium vivax malaria control, and nucleotide substitutions and copy number variation in the P. vivax multidrug resistance 1 ( pvmdr-1) locus, which encodes a digestive vacuole membrane transporter, may modulate this phenotype. We describe patterns of genetic variation in pvmdr-1 alleles from Acre and Amazonas in northwestern Brazil, and compare then with those reported in other malaria-endemic regions. The pvmdr-1 mutation Y976F, which is associated with CQ resistance in Southeast Asia and Oceania, remains rare in northwestern Brazil (1.8%) and its prevalence mirrors that of CQ resistance worldwide. Gene amplification of pvmdr-1, which is associated with mefloquine resistance but increased susceptibility to CQ, remains relatively rare in northwestern Brazil (0.9%) and globally ( 4%), but became common ( 10%) in Tak Province, Thailand, possibly because of drug-mediated selection. The global database we have assembled provides a baseline for further studies of genetic variation in pvmdr-1 and drug resistance in P. vivax malaria.

show abstract

“…The diversity of P. vivax has been reported in terms of relapse patterns, morphology, and biochemistry (Figtree et al 2000). Ortholog genes of P. falciparum associated to drug resistance, such as PvDHFR related to pyrimethamine resistance (de Pecoulas et al 1998), PvCG10 to chloroquine resistance (Nomura et al 2001), and PvMDR1 to multiple drug resistance (Sá et al 2005) have been characterized for P. vivax. However, analysis does not confirm if these polymorphic genes are really related to resistant phenotypes.…”

Section: Polymorphic Molecular Markers and Genetic Diversitymentioning

confidence: 99%

The genetic diversity of Plasmodium vivax: a review

Souza-Neiras

Melo

Machado

2007

Mem. Inst. Oswaldo Cruz

View full text Add to dashboard Cite

Plasmodium vivax: allele variants of the mdr1 gene do not associate with chloroquine resistance among isolates from Brazil, Papua, and monkey-adapted strains

Cited by 73 publications

References 22 publications

Single-nucleotide polymorphism, linkage disequilibrium and geographic structure in the malaria parasite Plasmodium vivax: prospects for genome-wide association studies

Single-nucleotide polymorphism, linkage disequilibrium and geographic structure in the malaria parasite Plasmodium vivax: prospects for genome-wide association studies

Single-Nucleotide Polymorphism and Copy Number Variation of the Multidrug Resistance-1 Locus of Plasmodium vivax: Local and Global Patterns

The genetic diversity of Plasmodium vivax: a review

Contact Info

Product

Resources

About