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01.12.2012 | Research | Ausgabe 1/2012 Open Access

Malaria Journal 1/2012

Large-scale survey for novel genotypes of Plasmodium falciparum chloroquine-resistance gene pfcrt

Zeitschrift:
Malaria Journal > Ausgabe 1/2012
Autoren:
Nobuyuki Takahashi, Kazuyuki Tanabe, Takahiro Tsukahara, Mawuli Dzodzomenyo, Lek Dysoley, Boualam Khamlome, Jetsumon Sattabongkot, Masatoshi Nakamura, Miki Sakurai, Jun Kobayashi, Akira Kaneko, Hiroyoshi Endo, Francis Hombhanje, Takafumi Tsuboi, Toshihiro Mita
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1475-2875-11-92) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

NT performed experiments, data analysis and paper writing. TT1, MD, LD, BK, JS, MN, MS, JK, FH, TT2 and AK coordination of sampling. KT critically reviewed the manuscript. KT, HE and TM participated in acquisition of funding. TM made substantial contributions to study design, coordination of sampling, data analysis, paper writing and reviewing. All authors have read and approved the final manuscript.

Abstract

Background

In Plasmodium falciparum, resistance to chloroquine (CQ) is conferred by a K to T mutation at amino acid position 76 (K76T) in the P. falciparum CQ transporter (PfCRT). To date, at least 15 pfcrt genotypes, which are represented by combinations of five amino acids at positions 72-76, have been described in field isolates from various endemic regions. To identify novel mutant pfcrt genotypes and to reveal the genetic relatedness of pfcrt genotypes, a large-scale survey over a wide geographic area was performed.

Methods

Sequences for exon 2 in pfcrt, including known polymorphic sites at amino acid positions 72, 74, 75 and 76, were obtained from 256 P. falciparum isolates collected from eight endemic countries in Asia (Bangladesh, Cambodia, Lao P.D.R., the Philippines and Thailand), Melanesia (Papua New Guinea and Vanuatu) and Africa (Ghana). A haplotype network was constructed based on six microsatellite markers located -29 kb to 24 kb from pfcrt in order to examine the genetic relatedness among mutant pfcrt genotypes.

Results

In addition to wild type (CVMNK at positions 72-76), four mutant pfcrt were identified; CVIET, CVIDT, S VMNT and CVMNT (mutated amino acids underlined). Haplotype network revealed that there were only three mutant pfcrt lineages, originating in Indochina, Philippines and Melanesia. Importantly, the Indochina lineage contained two mutant pfcrt genotypes, CVIET (n = 95) and CVIDT (n = 14), indicating that CVIDT shares a common origin with CVIET. Similarly, one major haplotype in the Melanesian lineage contained two pfcrt genotypes; S VMNT (n = 71) and CVMNT (n = 3). In Africa, all mutant pfcrt genotypes were the CVIET of the Indochina lineage, probably resulting from the intercontinental migration of CQ resistance from Southeast Asia.

Conclusions

The number of CQ-mutant lineages observed in this study was identical to that found in previous studies. This supports the hypothesis that the emergence of novel CQ resistance is rare. However, in the mutant pfcrt genotypes, amino acid changes at positions 72, 74 and 75 appear to have recently been generated at least several times, producing distinct pfcrt mutant genotypes. The occurrence of new mutations flanking K76T may yield stronger resistance to CQ and/or a higher fitness than the original pfcrt mutant.
Zusatzmaterial
Additional file 1: PCR conditions for genotyping of pfcrt. (XLS 20 KB)
12936_2011_2094_MOESM1_ESM.XLS
Additional file 2: PCR conditions for determining variations of six microsatellite loci flanking pfcrt. (XLS 22 KB)
12936_2011_2094_MOESM2_ESM.XLS
Authors’ original file for figure 1
12936_2011_2094_MOESM3_ESM.pdf
Authors’ original file for figure 2
12936_2011_2094_MOESM4_ESM.pdf
Authors’ original file for figure 3
12936_2011_2094_MOESM5_ESM.pdf
Authors’ original file for figure 4
12936_2011_2094_MOESM6_ESM.pdf
Literatur
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