Irina Tatiana Jovel1, Pedro Eduardo Ferreira2, Maria Isabel Veiga3, Maja Malmberg4, Andreas Mårtensson5, Akira Kaneko6, Sedigheh Zakeri7, Claribel Murillo8, Francois Nosten9, Anders Björkman10, Johan Ursing11. 1. Malaria Research, Infectious Diseases Unit, Department of Medicine Solna, Karolinska University Hospital/Karolinska Institutet, Retzius väg 10, 171 77 Stockholm, Sweden; Departamento de Parasitología, Escuela de Microbiología, Facultad de Ciencias, Universidad Nacional Autónoma de Honduras (UNAH), Tegucigalpa, Honduras. Electronic address: irina.jovel@ki.se. 2. Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden; School of Biological Sciences, Nanyang Technological University, Singapore. Electronic address: pedroemferreira@gmail.com. 3. Malaria Research, Infectious Diseases Unit, Department of Medicine Solna, Karolinska University Hospital/Karolinska Institutet, Retzius väg 10, 171 77 Stockholm, Sweden; Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal. Electronic address: maria.isabel.veiga@gmail.com. 4. Malaria Research, Infectious Diseases Unit, Department of Medicine Solna, Karolinska University Hospital/Karolinska Institutet, Retzius väg 10, 171 77 Stockholm, Sweden; Department of Biomedical Sciences and Veterinary Public Health, Section of Virology, Swedish University of Agricultural Sciences, Uppsala, Sweden. Electronic address: malmberg.maja@gmail.com. 5. Malaria Research, Infectious Diseases Unit, Department of Medicine Solna, Karolinska University Hospital/Karolinska Institutet, Retzius väg 10, 171 77 Stockholm, Sweden; Global Health, Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden. Electronic address: andreas.martensson@ki.se. 6. Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden. Electronic address: akira.kaneko@ki.se. 7. Malaria and Vector Research Group, Biotechnology Research Center, Pasteur Institute of Iran, Iran. Electronic address: zakeris@yahoo.com. 8. Centro Internacional de Entrenamiento e Investigaciones Médicas, Cali, Colombia. Electronic address: claribel_murillo@cideim.org.co. 9. Shoklo Malaria Research Unit, Mae Sot Tak, Thailand; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Nuffield Department of Clinical Medicine, Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, United Kingdom. Electronic address: francois@tropmedres.ac. 10. Malaria Research, Infectious Diseases Unit, Department of Medicine Solna, Karolinska University Hospital/Karolinska Institutet, Retzius väg 10, 171 77 Stockholm, Sweden. Electronic address: anders.bjorkman@karolinska.se. 11. Malaria Research, Infectious Diseases Unit, Department of Medicine Solna, Karolinska University Hospital/Karolinska Institutet, Retzius väg 10, 171 77 Stockholm, Sweden. Electronic address: johan.ursing@karolinska.se.
Abstract
BACKGROUND: Chloroquine resistance in Plasmodium falciparum malaria has been associated with pfcrt 76T (chloroquine resistance transporter gene) and pfmdr1 86Y (multidrug resistance gene 1) alleles. Pfcrt 76T enables transport of protonated chloroquine out of the parasites digestive vacuole resulting in a loss of hydrogen ions (H(+)). V type H(+) pyrophosphatase (PfVP2) is thought to pump H(+) into the digestive vacuole. This study aimed to describe the geographic distribution of single nucleotide polymorphisms in pfvp2 and their possible associations with pfcrt and pfmdr1 polymorphisms. METHODS: Blood samples from 384 patients collected (1981-2009) in Honduras (n=35), Colombia (n=50), Liberia (n=50), Guinea Bissau (n=50), Tanzania (n=50), Iran (n=50), Thailand (n=49) and Vanuatu (n=50) were analysed. The pfcrt 72-76 haplotype, pfmdr1 copy numbers, pfmdr1 N86Y and pfvp2 V405I, K582R and P711S alleles were identified using PCR based methods. RESULTS: Pfvp2 was amplified in 344 samples. The pfvp2 allele proportions were V405 (97%), 405I (3%), K582 (99%), 582R (1%), P711 (97%) and 711S (3%). The number of patients with any of pfvp2 405I, 582R and/or 711S were as follows: Honduras (2/30), Colombia (0/46), Liberia (7/48), Guinea-Bissau (4/50), Tanzania (3/48), Iran (3/50), Thailand (1/49) and Vanuatu (0/31). The alleles were most common in Liberia (P=0.01) and Liberia+Guinea-Bissau (P=0.01). The VKP haplotype was found in 189/194 (97%) and 131/145 (90%) samples harbouring pfcrt 76T and pfcrt K76 respectively (P=0.007). CONCLUSIONS: The VKP haplotype was dominant. Most pfvp2 405I, 582R and 711S SNPs were seen where CQ resistance was not highly prevalent at the time of blood sampling possibly due to greater genetic variation prior to the bottle neck event of spreading CQ resistance. The association between the pfvp2 VKP haplotype and pfcrt 76T, which may indicate that pfvp2 is involved in CQ resistance, should therefore be interpreted with caution.
BACKGROUND:Chloroquine resistance in Plasmodium falciparum malaria has been associated with pfcrt 76T (chloroquine resistance transporter gene) and pfmdr1 86Y (multidrug resistance gene 1) alleles. Pfcrt 76T enables transport of protonated chloroquine out of the parasites digestive vacuole resulting in a loss of hydrogen ions (H(+)). V type H(+) pyrophosphatase (PfVP2) is thought to pump H(+) into the digestive vacuole. This study aimed to describe the geographic distribution of single nucleotide polymorphisms in pfvp2 and their possible associations with pfcrt and pfmdr1 polymorphisms. METHODS: Blood samples from 384 patients collected (1981-2009) in Honduras (n=35), Colombia (n=50), Liberia (n=50), Guinea Bissau (n=50), Tanzania (n=50), Iran (n=50), Thailand (n=49) and Vanuatu (n=50) were analysed. The pfcrt 72-76 haplotype, pfmdr1 copy numbers, pfmdr1 N86Y and pfvp2 V405I, K582R and P711S alleles were identified using PCR based methods. RESULTS: Pfvp2 was amplified in 344 samples. The pfvp2 allele proportions were V405 (97%), 405I (3%), K582 (99%), 582R (1%), P711 (97%) and 711S (3%). The number of patients with any of pfvp2 405I, 582R and/or 711S were as follows: Honduras (2/30), Colombia (0/46), Liberia (7/48), Guinea-Bissau (4/50), Tanzania (3/48), Iran (3/50), Thailand (1/49) and Vanuatu (0/31). The alleles were most common in Liberia (P=0.01) and Liberia+Guinea-Bissau (P=0.01). The VKP haplotype was found in 189/194 (97%) and 131/145 (90%) samples harbouring pfcrt 76T and pfcrt K76 respectively (P=0.007). CONCLUSIONS: The VKP haplotype was dominant. Most pfvp2 405I, 582R and 711S SNPs were seen where CQ resistance was not highly prevalent at the time of blood sampling possibly due to greater genetic variation prior to the bottle neck event of spreading CQ resistance. The association between the pfvp2 VKP haplotype and pfcrt 76T, which may indicate that pfvp2 is involved in CQ resistance, should therefore be interpreted with caution.
Authors: Sabina Dahlström Otienoburu; Oumou Maïga-Ascofaré; Birgit Schramm; Vincent Jullien; Joel J Jones; Yah M Zolia; Pascal Houzé; Elizabeth A Ashley; Jean-René Kiechel; Philippe J Guérin; Jacques Le Bras; Sandrine Houzé Journal: Malar J Date: 2016-09-05 Impact factor: 2.979