Association of molecular markers in Plasmodium falciparum crt and mdr1 with in vitro chloroquine resistance: A Philippine study |
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| Authors: | Toshimitsu Hatabu Moritoshi Iwagami Shin-ichiro Kawazu Nao Taguchi Aleyla D. Escueta Elena A. Villacorte Pilarita T. Rivera Shigeyuki Kano |
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| Affiliation: | 1. Gunma University School of Health Sciences, 3-39-15 Showa-machi, Maebashi 371-8514, Japan;2. Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan;3. College of Public Health, University of the Philippines Manila, Manila, Philippines;1. Fondation Congolaise pour la Recherche Médicale, Faculté des Sciences de la Santé (University Marien Ngouabi), Brazzaville, People’s Republic of Congo;2. Faculté des Sciences et Techniques, University Marien Ngouabi, Brazzaville, People’s Republic of Congo;3. Institute for Tropical Medicine, University of Tübingen, Tübingen, Germany;1. Evolutionary Genomics and Bioinformatics Laboratory, Division of Genomics and Bioinformatics, National Institute of Malaria Research, Sector 8, Dwarka, New Delhi 110077, India;2. Department of Biotechnology, Kumaun University, Nainital 263001, Uttarakhand, India;1. Research Institute for Tropical Medicine-Department of Health, Muntinlupa City, Philippines;2. Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Pathumthani 12121, Thailand;1. Wellcome Trust Sanger Institute, Hinxton, UK;2. Centre for Genomics and Global Health, Wellcome Trust Centre for Human Genetics, Oxford, UK;3. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA;4. National Center for Parasitology, Entomology, and Malaria Control, Phnom Penh, Cambodia;5. Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand;1. Malaria Molecular Epidemiology Unit, Institut Pasteur in Cambodia, Phnom Penh, Cambodia;2. Malaria Translational Research Unit, Institut Pasteur, Paris, France;3. Institut Pasteur in Cambodia, Phnom Penh, Cambodia;4. Department of Parasites and Insect Vectors, Institut Pasteur, Paris, France;5. Plate-forme Génomique, Département Génomes et Génétique, Institut Pasteur, Paris, France;6. Structural Microbiology Unit, Biology of Malaria Targets Group, Department of Structural Biology and Chemistry and CNRS, UMR3528, Institut Pasteur, Paris, France;7. Institut Cochin Inserm U1016, Université Paris-Descartes, Sorbonne Paris Cité, and Laboratoire de Parasitologie-Mycologie, Hôpital Cochin, Paris, France;8. National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia;9. Laboratoire de Mathématiques Appliquées (MAP5) UMR CNRS 8145, Université Paris Descartes, Paris, France;10. Department of Microbiology and Immunology and Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA;11. Global Malaria Programme, World Health Organization, Geneva, Switzerland;1. Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand;2. Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand;3. Oxford University Clinical Research Unit – Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam;4. Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK |
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| Abstract: | Specific mutations in the pfcrt and pfmdr1 genes have been reported to be associated with chloroquine-resistant falciparum malaria parasites worldwide. These genetic markers are considered to be useful tools for the elucidation of several aspects of the epidemiology of drug resistant malaria. In this study, Plasmodium falciparum isolates from three distinct areas of the Philippines were analyzed for drug-resistance-associated genetic mutations, and their association with the in vitro chloroquine (CQ) response. Two novel pfcrt 72–76 allelic types, CVMDT and SVMDT, were detected. The frequency of the pfcrt K76T mutation in the isolates that were successfully tested for in vitro CQ susceptibility was found to be 100% in Kalinga, 80% in Palawan, and 87% in Mindanao. The frequency of the pfmdr1 N86Y mutation was 39% in Kalinga, 35% in Palawan, and 93% in Mindanao isolates. No mutations were found at positions 1042 and 1246 of pfmdr1. However, there were no significant associations found between polymorphisms in these genes and in vitro CQ susceptibility. The results of this study indicate that mutations in pfcrt and pfmdr1 are not predictive of in vitro CQ resistance in Philippine isolates and may therefore not be suitable as molecular markers for surveillance. |
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