title: Global distribution of polymorphisms associated with delayed Plasmodium falciparum parasite clearance following artemisinin treatment: genotyping of archive blood samples.
abstract: The recent emergence and spread of artemisinin-resistant Plasmodium falciparum isolates is a growing concern for global malaria-control efforts. A recent genome-wide analysis study identified two SNPs at genomic positions MAL10-688956 and MAL13-1718319, which are linked to delayed clearance of parasites following artemisinin combination therapy (ACT). It is expected that continuous artemisinin pressure will affect the distribution of these SNPs. Here, we investigate the worldwide distribution of these SNPs using a large number of archived samples in order to generate baseline data from the period before the emergence of ACT resistance. The presence of SNPs in MAL10-688956 and MAL13-1718319 was assessed by nested PCR RFLP and direct DNA sequencing using 653 global P. falciparum samples obtained before the reported emergence of ACT resistance. SNPs at MAL10-688956 and MAL13-1718319 associated with delayed parasite clearance following ACT administration were observed in 8% and 3% of parasites, respectively, mostly in Cambodia and Thailand. Parasites harbouring both SNPs were found in only eight (1%) isolates, all of which were from Cambodia and Thailand. Linkage disequilibrium was detected between MAL10-688956 and MAL13-1718319, suggesting that this SNP combination may have been selected by ACT drug pressure. Neither of the SNPs associated with delayed parasite clearance were observed in samples from Africa or South America. Baseline information of the geographical difference of MAL10-688956 and MAL13-1718319 SNPs provides a solid basis for assessing whether these SNPs are selected by artemisinin-based combination therapies.
authors.affiliation: Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Department of General Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Murai
authors.affiliation: Malaria Unit, Department of Pathology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
authors.forename: Richard
authors.initials: R
authors.lastname: Culleton
authors.affiliation: Department of General Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Hisaoka
authors.affiliation: Department of International Affairs and Tropical Medicine, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Endo
authors.affiliation: Department of Molecular and Cellular Parasitology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Department of International Affairs and Tropical Medicine, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. Electronic address: tmita@juntendo.ac.jp.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Mita
mesh_terms: D000349:Africa / Q000453:epidemiology; D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins / Q000627:therapeutic use*; D001769:Blood / Q000469:parasitology*; D002160:Cambodia / Q000453:epidemiology; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology*; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D013020:South America / Q000453:epidemiology; D013785:Thailand / Q000453:epidemiology
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C031327:artemisinin
keywords: Artemisinin combination therapy; Drug resistance; MAL10-688956; MAL13-1718319; Plasmodium falciparum