pfmdr1 amplification and fixation of pfcrt chloroquine resistance alleles in Plasmodium falciparum in Venezuela.
Molecular tools are valuable for determining evolutionary history and the prevalence of drug-resistant malaria parasites. These tools have helped to predict decreased sensitivity to antimalarials and fixation of multidrug resistance genotypes in some regions. In order to assess how historical drug policies impacted Plasmodium falciparum in Venezuela, we examined molecular changes in genes associated with drug resistance. We examined pfmdr1 and pfcrt in samples from Sifontes, Venezuela, and integrated our findings with earlier work describing dhfr and dhps in these samples. We characterized pfmdr1 genotypes and copy number variation, pfcrt genotypes, and proximal microsatellites in 93 samples originating from surveillance from 2003 to 2004. Multicopy pfmdr1 was found in 12% of the samples. Two pfmdr1 alleles, Y184F/N1042D/D1246Y (37%) and Y184F/S1034C/N1042D/D1246Y (63%), were found. These alleles share ancestry, and no evidence of strong selective pressure on mutations was found. pfcrt chloroquine resistance alleles are fixed with two alleles: S(tct)VMNT (91%) and S(agt)VMNT (9%). These alleles are associated with strong selection. There was also an association between pfcrt, pfmdr1, dhfr, and dhps genotypes/haplotypes. Duplication of pfmdr1 suggests a potential shift in mefloquine sensitivity in this region, which warrants further study. A bottleneck occurred in P. falciparum in Sifontes, Venezuela, and multidrug resistance genotypes are present. This population could be targeted for malaria elimination programs to prevent the possible spread of multidrug-resistant parasites.
Emory University, Atlanta, Georgia, USA.
Sean
S
Griffing
Luke
L
Syphard
Sankar
S
Sridaran
Andrea M
AM
McCollum
Tonya
T
Mixson-Hayden
Sumiti
S
Vinayak
Leopoldo
L
Villegas
John W
JW
Barnwell
Ananias A
AA
Escalante
Venkatachalam
V
Udhayakumar
D000483:Alleles; D000962:Antimalarials / Q000494:pharmacology*; D001483:Base Sequence; D002738:Chloroquine / Q000494:pharmacology*; D017931:DNA Primers / Q000235:genetics; D016054:DNA, Protozoan / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics; D019143:Evolution, Molecular; D005784:Gene Amplification; D018628:Gene Dosage; D017125:Genes, Protozoan; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D026901:Membrane Transport Proteins / Q000235:genetics*; D018895:Microsatellite Repeats; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D015800:Protozoan Proteins / Q000235:genetics*; D014687:Venezuela
D000962:Antimalarials; D002738:Chloroquine; D017931:DNA Primers; D016054:DNA, Protozoan; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; C513498:Mdr1 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum