Dissecting the loci of low-level quinine resistance in malaria parasites.
Quinine (QN) remains effective against Plasmodium falciparum, but its decreasing efficacy is documented from different continents. Multiple genes are likely to contribute to the evolution of QN resistance. To locate genes contributing to QN response variation, we have searched a P. falciparum genetic cross for quantitative trait loci (QTL). Results identify additive QTL in segments of chromosomes (Chrs) 13, 7 and 5, and pairwise effects from two additional loci of Chrs 9 and 6 that interact, respectively, with the QTL of Chrs 13 and 7. The mapped segments of Chrs 7 and 5 contain pfcrt, the determinant of chloroquine resistance (CQR), and pfmdr1, a gene known to affect QN responses. Association of pfcrt with a QTL of QN resistance supports anecdotal evidence for an evolutionary relationship between CQR and reduced QN sensitivity. The Chr 13 segment contains several candidate genes, one of which (pfnhe-1) encodes a putative Na(+)/H(+) exchanger. A repeat polymorphism in pfnhe-1 shows significant association with low QN response in a collection of P. falciparum strains from Asia, Africa and Central and South America. Dissection of the genes and modifiers involved in QN response will require experimental strategies that can evaluate multiple genes from different chromosomes in combination.
Ferdig
Michael T
MT
Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 4, Room 126, NIH Campus, Bethesda, MD 20892-0425, USA.
Cooper
Roland A
RA
Mu
Jianbing
J
Deng
Bingbing
B
Joy
Deirdre A
DA
Su
Xin-zhuan
XZ
Wellems
Thomas E
TE
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D002874:Chromosome Mapping; D004351:Drug Resistance / Q000235:genetics*; D017125:Genes, Protozoan; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D026901:Membrane Transport Proteins; D008969:Molecular Sequence Data; D020412:Multifactorial Inheritance; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics*; D011110:Polymorphism, Genetic; D015800:Protozoan Proteins / Q000235:genetics / Q000502:physiology; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D011803:Quinine / Q000494:pharmacology*; D012091:Repetitive Sequences, Nucleic Acid; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000502:physiology
D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D017923:Sodium-Hydrogen Exchangers; C059987:mdr gene protein, Plasmodium; D002738:Chloroquine; D011803:Quinine