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Antimicrobial Agents and Chemotherapy, June 2005, p. 2180-2188, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2180-2188.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Are Transporter Genes Other than the Chloroquine Resistance Locus (pfcrt) and Multidrug Resistance Gene (pfmdr) Associated with Antimalarial Drug Resistance?

Timothy J. C. Anderson,^1* Shalini Nair,¹ Huang Qin,¹ Sittaporn Singlam,² Alan Brockman,² Lucy Paiphun,² and François Nosten^2,3,4

Southwest Foundation for Biomedical Research, P.O. Box 760549, San Antonio, Texas 78245,¹ Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand,² Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand,³ Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, United Kingdom⁴

Received 16 December 2004/ Returned for modification 24 January 2005/ Accepted 14 February 2005

Mu et al. (Mu, J., M. T. Ferdig, X. Feng, D. A. Joy, J. Duan, T. Furuya, G. Subramanian, L. Aravind, R. A. Cooper, J. C. Wootton, M. Xiong, and X. Z. Su, Mol. Microbiol. 49:977-989, 2003) recently reported exciting associations between nine new candidate transporter genes and in vitro resistance to chloroquine (CQ) and quinine (QN), with six of these loci showing association with CQ or QN in a southeast Asian population sample. We replicated and extended this work by examining polymorphisms in these genes and in vitro resistance to eight drugs in parasites collected from the Thailand-Burma border. To minimize problems of multiple testing, we used a two-phase study design, while to minimize problems caused by population structure, we analyzed parasite isolates collected from a single clinic. We first examined associations between genotype and drug response in 108 unique single-clone parasite isolates. We found strong associations between single nucleotide polymorphisms in pfmdr and mefloquine (MFQ), artesunate (AS), and lumefantrine (LUM) response. We also observed associations between an ABC transporter (G7) and response to QN and AS and between another ABC transporter (G49) and response to dihydro-artemisinin (DHA). We reexamined significant associations in an independent sample of 199 unique single-clone infections from the same location. The significant associations with pfmdr-1042 detected in the first survey remained. However, with the exception of the G7-artesunate association, all other associations observed with the nine new candidate transporters disappeared. We also examined linkage disequilibrium (LD) between markers and phenotypic correlations between drug responses. We found minimal LD between genes. Furthermore, we found no correlation between chloroquine and quinine responses, although we did find expected strong correlations between MFQ, QN, AS, DHA, and LUM. To conclude, we found no evidence for an association between 8/9 candidate genes and response to eight different antimalarial drugs. However, the consistent association observed between a 3-bp indel in G7 and AS response merits further investigation.

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* Corresponding author. Mailing address: Southwest Foundation for Biomedical Research, P.O. Box 760549, San Antonio, TX 78245. Phone: (210) 258 9596. Fax: (210) 670 3344. E-mail: tanderso{at}darwin.sfbr.org.

Supplemental material for this article may be found at http://aac.asm.org/.

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Antimicrobial Agents and Chemotherapy, June 2005, p. 2180-2188, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2180-2188.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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