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JAC Advance Access published online on November 25, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn482
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
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Original research

Indigenous evolution of Plasmodium falciparum pyrimethamine resistance multiple times in Africa

Toshihiro Mita1,*, Kazuyuki Tanabe2, Nobuyuki Takahashi1, Richard Culleton2,3, Mathieu Ndounga4, Mawuli Dzodzomenyo1,5, Willis S. Akhwale6, Akira Kaneko7 and Takatoshi Kobayakawa1

1 Department of International Affairs and Tropical Medicine, Tokyo Women's Medical University, 9-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan 2 Laboratory of Malariology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan 3 Department of Protozoology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto-cho, Nagasaki 852-8523, Japan 4 Laboratoire de Pharmacologie, Centre d'Etudes sur les des Resources Vegetales, Brazzaville, Republic of Congo 5 Department of Biological, Environmental and Occupational Health Sciences, School of Public Health, University of Ghana, PO Box LG 13, Legon, Ghana 6 Department of Disease Prevention and Control, Ministry of Public Health and Sanitation, PO Box 19982-00202, Nairobi, Kenya 7 Department of Medicine, Malaria Research Laboratory, Karolinska Institutet, 171-77 Stockholm, Sweden

Received 16 July 2008; returned 18 September 2008; revised 7 October 2008; accepted 31 October 2008

* Corresponding author. Tel: +81-3-5269-7422; Fax: +81-3-5269-7422; E-mail: hiro-tm{at}research.twmu.ac.jp

Objectives: Resistance to pyrimethamine in Plasmodium falciparum is conferred by mutations in the gene encoding dihydrofolate reductase (DHFR). It is known that DHFR double mutants have evolved independently in multiple geographic areas, whereas the triple mutant prevalent in Africa appears to have originated in south-east Asia. In this study, we investigated whether other triple mutants may have evolved independently in Africa.

Methods: We determined the DHFR genotypes and haplotypes of five microsatellite loci flanking the DHFR locus between 4.49 kb upstream and 1.48 kb downstream of 159 isolates collected from three African countries (Republic of Congo, Ghana and Kenya).

Results: The CIRNI type of DHFR triple mutant (with mutations underlined at amino acid positions 51, 59 and 108) was predominant in the Republic of Congo (82%) and Ghana (81%) and was the second most prevalent in Kenya (27%), where the CICNI type of DHFR double mutant was dominant. Three distinct microsatellite haplotypes were identified in the DHFR triple mutant. One haplotype was identical to that originating in south-east Asia. The other two haplotypes occurred in Ghana and Kenya, which were unique, previously undescribed and identical to those of the two DHFR double mutants found in the same locations.

Conclusions: This study presents strong evidence for the unique, multiple independent evolution of pyrimethamine resistance in Africa. Indigenous evolution of the triple mutant from the double mutant appears to have occurred in a step-wise manner in Kenya and Ghana or in nearby countries in east and west Africa.

Key Words: malaria , dhfr , microsatellite


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