The role of pfmdr1 in Plasmodium falciparum tolerance to artemether-lumefantrine in Africa.
OBJECTIVE
Artemether-lumefantrine (AL), presently the most favoured combination therapy against uncomplicated Plasmodium falciparum malaria in Africa, has recently shown to select for the pfmdr1 86N allele. The objective of this study was to search for the selection of other mutations potentially involved in artemether-lumefantrine tolerance and/or resistance, i.e. pfmdr1 gene amplification, pfmdr1 Y184F, S1034C, N1042D, D1246Y, pfcrt S163R and PfATP6 S769N.


METHODS
The above mentioned SNPs were analysed by PCR-restriction fragment length polymorphism and pfmdr1 gene amplification by real-time PCR based protocols in parasites from 200 children treated with AL for uncomplicated P. falciparum malaria in Zanzibar.


RESULTS
A statistically significant selection of pfmdr1 184F mostly in combination with 86N was seen in reinfections after treatment. No pfmdr1 gene amplification was found.


CONCLUSIONS
The results suggest that different pfmdr1 alleles are involved in the development of tolerance/resistance to lumefantrine.
Sisowath
Christin
C
Malaria Research Unit, Division of Infectious Diseases, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. christin.sisowath@ki.se
Ferreira
Pedro E
PE
Bustamante
Leyla Y
LY
Dahlström
Sabina
S
Mårtensson
Andreas
A
Björkman
Anders
A
Krishna
Sanjeev
S
Gil
José P
JP
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins / Q000627:therapeutic use*; D002648:Child; D004338:Drug Combinations; D004351:Drug Resistance / Q000235:genetics; D004983:Ethanolamines / Q000627:therapeutic use*; D005449:Fluorenes / Q000627:therapeutic use*; D005784:Gene Amplification / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D019450:Genes, MDR / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D015800:Protozoan Proteins / Q000235:genetics*; D012008:Recurrence; D013636:Tanzania / Q000453:epidemiology
D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium