Genetic polymorphisms of candidate markers and in vitro susceptibility of Plasmodium falciparum isolates from Thai-Myanmar border in relation to clinical response to artesunate–mefloquine combination

• Published in: Acta tropica 2014-11, Vol.139, p.77-83
• Main Authors: Phompradit, Papichaya, Muhamad, Poonuch, Chaijaroenkul, Wanna, Na-Bangchang, Kesara
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Antimalarials - pharmacology; Artemisinins - pharmacology; Drug Resistance - genetics; Drug Therapy, Combination; Female; Gene amplification; Gene Dosage; Haplotypes; Humans; Malaria, Falciparum - drug therapy; Male; Mefloquine - pharmacology; Middle Aged; Multidrug resistance; Multidrug Resistance-Associated Proteins - genetics; Mutation; Myanmar; Parasitic Sensitivity Tests; pfmdr1; pfmrp1; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - genetics; Polymorphism, Genetic; Protozoan Proteins - genetics; Single nucleotide polymorphism; Thailand; Young Adult
• ISSN: 0001-706X; 1873-6254
• DOI: 10.1016/j.actatropica.2014.06.015

Genetic polymorphisms of the candidate markers of antimalarial drug resistance in relationship with in vitro susceptibility of Plasmodium falciparum and clinical response following artesunate–mefloquine. •The genetic markers of P. falciparum resistance to AS and MQ were studied.•Pfmdr1 gene copy number was found to be the key predictor of drug resistance.•The presence of pfmrp1 mutation modulated the level of resistance. The genetic polymorphisms of the candidate markers of antimalarial drug resistance pfcrt, pfmdr1, pfatp6, and pfmrp1 were investigated in relationship with in vitro susceptibility of Plasmodium falciparum isolates and clinical response following artesunate (AS)–mefloquine (MQ) combination in 21 and 27 samples obtained from patients with recrudescence and adequate clinical response, respectively. MQ (21.0 vs. 49.9nM) and AS (1.6 vs. 2.8nM) IC50 values (concentrations that inhibit parasite growth by 50%) were significantly higher in isolates collected from patients with recrudescence. Furthermore, a significantly higher MQ IC50 was found in isolates from patients with recrudescence that carried pfmrp1 mutations at amino acid residues 191Y, 437A, and 876V. For AS sensitivity, a significant association was also detected in isolates from patients with recrudescence that carried gene mutations at amino acid residues 437A and 876V. MQ IC50 of the isolates with recrudescence which carried ≥4 pfmdr1 gene copies was significantly higher than that carrying only one gene copy. In addition, a significantly higher proportion of isolates carrying one gene copy was detected in the group with adequate clinical response compared with recrudescence. Results from this limited sample size suggested the potential link between pfmdr1 gene copy number and pfmrp1 gene mutation, in vitro parasite susceptibility, and AS–MQ treatment response.