title: Polymorphism of antimalaria drug metabolizing, nuclear receptor, and drug transport genes among malaria patients in Zanzibar, East Africa.
abstract: Artemisinin-based combination therapy is a main strategy for malaria control in Africa. Zanzibar introduced this new treatment policy in 2003. The authors have studied the prevalence of a number of functional single nucleotide polymorphisms (SNPs) in genes associated with the elimination of the artemisinin-based combination therapy compounds in use in Zanzibar to investigate the frequencies of subgroups potentially at higher drug exposure and therefore possible higher risk of toxicity. One hundred three unrelated children with uncomplicated malaria from the Unguja and Pemba islands of Zanzibar were enrolled. With use of polymerase chain reaction (PCR)-restriction fragment length polymorphism and real-time PCR-based allele discrimination methods, the CYP2B6 (G15631T), CYP3A4 (A-392G), CYP3A5 (A6986G, G14690A, 27131-132 insT, C3699T) SNPs and MDR1 SNPs C3435T, G2677T/A, and T-129C were analyzed. PCR product sequencing was applied to regulatory regions of MDR1, the CYP3A4 proximal promoter, and to exons 2 and 5 of PXR, a gene coding for a nuclear factor activated by artemisinin antimalarials and associated with the transcription induction of most of the studied genes. Homozygous subjects for alleles coding for low activity proteins were found at the following frequencies: 1) MDR1: 2.9%; 2) CYP2B6: 9.7%; 3) CYP3A5: 14.1%; and 4) CYP3A4: 49.5%. No functionally relevant allele was found in the analyzed regions of PXR. A new MDR1 SNP was found (T-158C), located in a putative antigen recognition element. Ten (10.1%) subjects were predicted to be low metabolizers simultaneously for CYP3A4 and CYP3A5. This fraction of the population is suggested to be under higher exposure to certain antimalarials, including lumefantrine and quinine.
authors.affiliation: Malaria Research Laboratory, Unit of Infectious Diseases, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
authors.forename: Pedro Eduardo
authors.initials: PE
authors.lastname: Ferreira
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Veiga
authors.forename: Isa
authors.initials: I
authors.lastname: Cavaco
authors.forename: J Paulo
authors.initials: JP
authors.lastname: Martins
authors.forename: Björn
authors.initials: B
authors.lastname: Andersson
authors.forename: Shaliya
authors.initials: S
authors.lastname: Mushin
authors.forename: Abullah S
authors.initials: AS
authors.lastname: Ali
authors.forename: Achuyt
authors.initials: A
authors.lastname: Bhattarai
authors.forename: Vera
authors.initials: V
authors.lastname: Ribeiro
authors.forename: Anders
authors.initials: A
authors.lastname: Björkman
authors.forename: José Pedro
authors.initials: JP
authors.lastname: Gil
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000962:Antimalarials / Q000493:pharmacokinetics*; D037621:Artemisinins / Q000493:pharmacokinetics; D002675:Child, Preschool; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000235:genetics*; D013636:Tanzania
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000962:Antimalarials; D037621:Artemisinins; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System; C031327:artemisinin