Mutations in the Antifolate-Resistance-Associated Genes Dihydrofolate Reductase and Dihydropteroate Synthase in Plasmodium vivax Isolates from Malaria-Endemic Countries

Feng Lu Department of Parasitology, Kangwon National University College of Medicine, Chuncheon, Republic of Korea; Jiangsu Institute of Parasitic Diseases, Wuxi, People's Republic of China; Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, Republic of Korea; Department of Internal Medicine, Gachon University Cheorwon Gil Hospital, Cheorwon, Republic of Korea; Vector-Borne Diseases Control Project, Department of Health, Ministry of Health, Mandalay, Myanmar; Department of Parasitology, Inha University School of Medicine, Incheon, Republic of Korea; Department of Malaria and Parasite Disease, National Institute of Health, Korea Centers for Disease Control and Prevention, Seoul, Republic of Korea; Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China; Department of Entomology, Armed Forces Research Institute of Medical Science, Bangkok, Thailand

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Chae Seung Lim Department of Parasitology, Kangwon National University College of Medicine, Chuncheon, Republic of Korea; Jiangsu Institute of Parasitic Diseases, Wuxi, People's Republic of China; Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, Republic of Korea; Department of Internal Medicine, Gachon University Cheorwon Gil Hospital, Cheorwon, Republic of Korea; Vector-Borne Diseases Control Project, Department of Health, Ministry of Health, Mandalay, Myanmar; Department of Parasitology, Inha University School of Medicine, Incheon, Republic of Korea; Department of Malaria and Parasite Disease, National Institute of Health, Korea Centers for Disease Control and Prevention, Seoul, Republic of Korea; Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China; Department of Entomology, Armed Forces Research Institute of Medical Science, Bangkok, Thailand

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Deok Hwa Nam Department of Parasitology, Kangwon National University College of Medicine, Chuncheon, Republic of Korea; Jiangsu Institute of Parasitic Diseases, Wuxi, People's Republic of China; Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, Republic of Korea; Department of Internal Medicine, Gachon University Cheorwon Gil Hospital, Cheorwon, Republic of Korea; Vector-Borne Diseases Control Project, Department of Health, Ministry of Health, Mandalay, Myanmar; Department of Parasitology, Inha University School of Medicine, Incheon, Republic of Korea; Department of Malaria and Parasite Disease, National Institute of Health, Korea Centers for Disease Control and Prevention, Seoul, Republic of Korea; Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China; Department of Entomology, Armed Forces Research Institute of Medical Science, Bangkok, Thailand

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Kwonkee Kim Department of Parasitology, Kangwon National University College of Medicine, Chuncheon, Republic of Korea; Jiangsu Institute of Parasitic Diseases, Wuxi, People's Republic of China; Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, Republic of Korea; Department of Internal Medicine, Gachon University Cheorwon Gil Hospital, Cheorwon, Republic of Korea; Vector-Borne Diseases Control Project, Department of Health, Ministry of Health, Mandalay, Myanmar; Department of Parasitology, Inha University School of Medicine, Incheon, Republic of Korea; Department of Malaria and Parasite Disease, National Institute of Health, Korea Centers for Disease Control and Prevention, Seoul, Republic of Korea; Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China; Department of Entomology, Armed Forces Research Institute of Medical Science, Bangkok, Thailand

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Khin Lin Department of Parasitology, Kangwon National University College of Medicine, Chuncheon, Republic of Korea; Jiangsu Institute of Parasitic Diseases, Wuxi, People's Republic of China; Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, Republic of Korea; Department of Internal Medicine, Gachon University Cheorwon Gil Hospital, Cheorwon, Republic of Korea; Vector-Borne Diseases Control Project, Department of Health, Ministry of Health, Mandalay, Myanmar; Department of Parasitology, Inha University School of Medicine, Incheon, Republic of Korea; Department of Malaria and Parasite Disease, National Institute of Health, Korea Centers for Disease Control and Prevention, Seoul, Republic of Korea; Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China; Department of Entomology, Armed Forces Research Institute of Medical Science, Bangkok, Thailand

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Tong-Soo Kim Department of Parasitology, Kangwon National University College of Medicine, Chuncheon, Republic of Korea; Jiangsu Institute of Parasitic Diseases, Wuxi, People's Republic of China; Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, Republic of Korea; Department of Internal Medicine, Gachon University Cheorwon Gil Hospital, Cheorwon, Republic of Korea; Vector-Borne Diseases Control Project, Department of Health, Ministry of Health, Mandalay, Myanmar; Department of Parasitology, Inha University School of Medicine, Incheon, Republic of Korea; Department of Malaria and Parasite Disease, National Institute of Health, Korea Centers for Disease Control and Prevention, Seoul, Republic of Korea; Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China; Department of Entomology, Armed Forces Research Institute of Medical Science, Bangkok, Thailand

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Hyeong-Woo Lee Department of Parasitology, Kangwon National University College of Medicine, Chuncheon, Republic of Korea; Jiangsu Institute of Parasitic Diseases, Wuxi, People's Republic of China; Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, Republic of Korea; Department of Internal Medicine, Gachon University Cheorwon Gil Hospital, Cheorwon, Republic of Korea; Vector-Borne Diseases Control Project, Department of Health, Ministry of Health, Mandalay, Myanmar; Department of Parasitology, Inha University School of Medicine, Incheon, Republic of Korea; Department of Malaria and Parasite Disease, National Institute of Health, Korea Centers for Disease Control and Prevention, Seoul, Republic of Korea; Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China; Department of Entomology, Armed Forces Research Institute of Medical Science, Bangkok, Thailand

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Jun-Hu Chen Department of Parasitology, Kangwon National University College of Medicine, Chuncheon, Republic of Korea; Jiangsu Institute of Parasitic Diseases, Wuxi, People's Republic of China; Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, Republic of Korea; Department of Internal Medicine, Gachon University Cheorwon Gil Hospital, Cheorwon, Republic of Korea; Vector-Borne Diseases Control Project, Department of Health, Ministry of Health, Mandalay, Myanmar; Department of Parasitology, Inha University School of Medicine, Incheon, Republic of Korea; Department of Malaria and Parasite Disease, National Institute of Health, Korea Centers for Disease Control and Prevention, Seoul, Republic of Korea; Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China; Department of Entomology, Armed Forces Research Institute of Medical Science, Bangkok, Thailand

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Yue Wang Department of Parasitology, Kangwon National University College of Medicine, Chuncheon, Republic of Korea; Jiangsu Institute of Parasitic Diseases, Wuxi, People's Republic of China; Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, Republic of Korea; Department of Internal Medicine, Gachon University Cheorwon Gil Hospital, Cheorwon, Republic of Korea; Vector-Borne Diseases Control Project, Department of Health, Ministry of Health, Mandalay, Myanmar; Department of Parasitology, Inha University School of Medicine, Incheon, Republic of Korea; Department of Malaria and Parasite Disease, National Institute of Health, Korea Centers for Disease Control and Prevention, Seoul, Republic of Korea; Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China; Department of Entomology, Armed Forces Research Institute of Medical Science, Bangkok, Thailand

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Jetsumon Sattabongkot Department of Parasitology, Kangwon National University College of Medicine, Chuncheon, Republic of Korea; Jiangsu Institute of Parasitic Diseases, Wuxi, People's Republic of China; Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, Republic of Korea; Department of Internal Medicine, Gachon University Cheorwon Gil Hospital, Cheorwon, Republic of Korea; Vector-Borne Diseases Control Project, Department of Health, Ministry of Health, Mandalay, Myanmar; Department of Parasitology, Inha University School of Medicine, Incheon, Republic of Korea; Department of Malaria and Parasite Disease, National Institute of Health, Korea Centers for Disease Control and Prevention, Seoul, Republic of Korea; Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China; Department of Entomology, Armed Forces Research Institute of Medical Science, Bangkok, Thailand

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Eun-Taek Han Department of Parasitology, Kangwon National University College of Medicine, Chuncheon, Republic of Korea; Jiangsu Institute of Parasitic Diseases, Wuxi, People's Republic of China; Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, Republic of Korea; Department of Internal Medicine, Gachon University Cheorwon Gil Hospital, Cheorwon, Republic of Korea; Vector-Borne Diseases Control Project, Department of Health, Ministry of Health, Mandalay, Myanmar; Department of Parasitology, Inha University School of Medicine, Incheon, Republic of Korea; Department of Malaria and Parasite Disease, National Institute of Health, Korea Centers for Disease Control and Prevention, Seoul, Republic of Korea; Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China; Department of Entomology, Armed Forces Research Institute of Medical Science, Bangkok, Thailand

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DOI:
https://doi.org/10.4269/ajtmh.2010.10-0004
Volume/Issue:
Volume 83: Issue 3
Page(s):
474–479
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Parasite dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) are known target enzymes of antifolate drugs used for the treatment and prophylaxis of persons with malaria. We sequenced the Plasmodium vivax dihydrofolate reductase (pvdhfr) and dihydropteroate synthase (pvdhps) genes to examine the prevalence and extent of point mutations in isolates from malaria-endemic countries. Double mutations (S58R and S117N) or quadruple mutations (F57L/I, S58R, T61M, and S117T) in the pvdhfr gene were found in isolates from Thailand (96.4%) and Myanmar (71.4%), but in only one isolate (1.0%) from Korea, where sulfadoxine-pyrimethamine has never been used. The pvdhfr point mutations correlated strongly with the pvdhps point mutations and ranged from single to triple mutations (S382A, A383G, and A553G), among isolates from Thailand, Myanmar, and Korea. These findings suggests that the prevalence of mutations in pvdhfr and pvdhps in P. vivax isolates from different malaria-endemic countries is associated with selection pressure imposed by sulfadoxine-pyrimethamine.

Author Notes

*Address correspondence to Eun-Taek Han, Department of Parasitology, Kangwon National University College of Medicine, Hyoja2-dong, Chunchon, Gangwon-do 200-701, Republic of Korea. E-mail: ethan@kangwon.ac.kr

Financial support: This study was supported by a National Research Foundation of Korea grant funded by the Korean Government (KRF-2008-314-E00075).

Disclosure: The view of the authors do not purport to reflect the position of the U.S. Department of the Army or Department of Defense.

Authors' addresses: Feng Lu, Department of Parasitology, Kangwon National University College of Medicine, Chuncheon, Gangwon-do, Republic of Korea and Jiangsu Institute of Parasitic Diseases, Wuxi, People's Republic of China, E-mail: lufeng981@hotmail.com. Chae Seung Lim and Deok-Hwa Nam, Department of Laboratory Medicine, College of Medicine, Korea University, Seoul, Republic of Korea, E-mails: malarim@korea.ac.kr and deokhwanam@korea.ac.kr. Kwonkee Kim, Department of Internal Medicine, Gachon University Cheorwon Gil Hospital, Cheorwon, Gangwon-do, Republic of Korea, E-mail: gibango1224@nate.com. Khin Lin, Vector-Borne Diseases Control Project, Department of Health, Ministry of Health, Mandalay, Myanmar. Tong-Soo Kim, Department of Parasitology, Inha University School of Medicine, Incheon, Republic of Korea, E-mail: tongsookim@inha.ac.kr. Hyeong-Woo Lee, Department of Malaria and Parasite Disease, National Institute of Health, Korea Centers for Disease Control and Prevention, Seoul, Republic of Korea and Department of Pathology, University of Florida, Gainesville, FL, E-mail: rainlee67@yahoo.co.kr. Jun-Hu Chen and Yue Wang, Department of Parasitology, Kangwon National University College of Medicine, Chuncheon, Gangwon-do, Republic of Korea and Institute of Parasitic Diseases, Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China, E-mails: hzjunhuchen@yahoo.com.cn and wangyuerr@yahoo.com.cn. Jetsumon Sattabongkot, Department of Entomology, Armed Forces Research Institute of Medical Science, Bangkok, Thailand, E-mail: jetsumonp@afrims.org. Eun-Taek Han, Department of Parasitology, Kangwon National University College of Medicine, Chuncheon, Gangwon-do, Republic of Korea, E-mail: ethan@kangwon.ac.kr.

Copyright:
©The American Society of Tropical Medicine and Hygiene 2010
Received:
03 Jan 2010
|
Accepted:
15 May 2010
|
Published Online:
07 Sep 2010
Cover The American Journal of Tropical Medicine and Hygiene
The American Journal of Tropical Medicine and Hygiene
Print ISSN:
0002-9637
Online ISSN:
1476-1645
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