title: Absence of putative artemisinin resistance mutations among Plasmodium falciparum in Sub-Saharan Africa: a molecular epidemiologic study.
abstract: Plasmodium falciparum parasites that are resistant to artemisinins have been detected in Southeast Asia. Resistance is associated with several polymorphisms in the parasite's K13-propeller gene. The molecular epidemiology of these artemisinin resistance genotypes in African parasite populations is unknown. We developed an assay to quantify rare polymorphisms in parasite populations that uses a pooled deep-sequencing approach to score allele frequencies, validated it by evaluating mixtures of laboratory parasite strains, and then used it to screen P. falciparum parasites from >1100 African infections collected since 2002 from 14 sites across sub-Saharan Africa. We found no mutations in African parasite populations that are associated with artemisinin resistance in Southeast Asian parasites. However, we observed 15 coding mutations, including 12 novel mutations, and limited allele sharing between parasite populations, consistent with a large reservoir of naturally occurring K13-propeller variation. Although polymorphisms associated with artemisinin resistance in P. falciparum in Southeast Asia are not prevalent in sub-Saharan Africa, numerous K13-propeller coding polymorphisms circulate in Africa. Although their distributions do not support a widespread selective sweep for an artemisinin-resistant phenotype, the impact of these mutations on artemisinin susceptibility is unknown and will require further characterization. Rapid, scalable molecular surveillance offers a useful adjunct in tracking and containing artemisinin resistance.
authors.affiliation: Division of Infectious Diseases, Department of Medicine Duke Global Health Institute, Duke University Medical Center, Durham Department of Epidemiology, Gillings School of Global Public Health.
authors.forename: Steve M
authors.initials: SM
authors.lastname: Taylor
authors.affiliation: Curriculum in Genetics and Molecular Biology.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Parobek
authors.affiliation: Graduate School of Biomedical Sciences.
authors.forename: Derrick K
authors.initials: DK
authors.lastname: DeConti
authors.affiliation: Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Medicine, Pharmacy, and Odontostomatology, University of Science, Techniques, and Technologies of Bamako, Mali Department of Clinical Sciences, Liverpool School of Tropical Medicine.
authors.forename: Kassoum
authors.initials: K
authors.lastname: Kayentao
authors.affiliation: Faculty of Health Sciences, University of Ouagadougou, Burkina Faso.
authors.forename: Sheick Oumar
authors.initials: SO
authors.lastname: Coulibaly
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Greenwood
authors.affiliation: Department of Community Health, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi.
authors.forename: Harry
authors.initials: H
authors.lastname: Tagbor
authors.affiliation: Navrongo Health Research Centre, Ghana Health Service, Navrongo.
authors.forename: John
authors.initials: J
authors.lastname: Williams
authors.affiliation: Medical Research Council Laboratories, Banjul, Gambia.
authors.forename: Kalifa
authors.initials: K
authors.lastname: Bojang
authors.affiliation: Medical Research Council Laboratories, Banjul, Gambia.
authors.forename: Fanta
authors.initials: F
authors.lastname: Njie
authors.affiliation: Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia CDC-Kenya.
authors.forename: Meghna
authors.initials: M
authors.lastname: Desai
authors.affiliation: KEMRI-CDC.
authors.forename: Simon
authors.initials: S
authors.lastname: Kariuki
authors.affiliation: Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia.
authors.forename: Julie
authors.initials: J
authors.lastname: Gutman
authors.affiliation: Malaria Alert Center, University of Malawi College of Medicine, Blantyre Department of Community Health, College of Medicine, Lilongwe, Malawi.
authors.forename: Don P
authors.initials: DP
authors.lastname: Mathanga
authors.affiliation: Malaria Research, Department of Medicine Solna Global Health, Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mårtensson
authors.affiliation: Department of Parasitology, Muhumbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
authors.forename: Billy
authors.initials: B
authors.lastname: Ngasala
authors.affiliation: Department of Medicine, University of California, San Francisco.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Conrad
authors.affiliation: Department of Medicine, University of California, San Francisco.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.affiliation: Ecole de Sante Publique, Faculte de Medicine, University of Kinshasa, Democratic Republic of the Congo.
authors.forename: Antoinette K
authors.initials: AK
authors.lastname: Tshefu
authors.affiliation: Department of Pediatrics.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Moormann
authors.affiliation: Center for Global Health Research, KEMRI, Kisumu, Kenya.
authors.forename: John M
authors.initials: JM
authors.lastname: Vulule
authors.affiliation: Department of Epidemiology of Parasitic Diseases, Malaria Research and Training Center, Faculty of Medicine, Pharmacy, and Odontostomatology, University of Science, Techniques, and Technologies of Bamako, Mali.
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
authors.affiliation: Department of Clinical Sciences, Liverpool School of Tropical Medicine Center for Global Health Research, KEMRI, Kisumu, Kenya.
authors.forename: Feiko O
authors.initials: FO
authors.lastname: Ter Kuile
authors.affiliation: Department of Epidemiology, Gillings School of Global Public Health.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Meshnick
authors.affiliation: Division of Transfusion Medicine Program in Bioinformatics and Integrative Biology, University of Massachusetts School of Medicine, Worcester.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bailey
authors.affiliation: Curriculum in Genetics and Molecular Biology Divison of Infectious Diseases, School of Medicine, University of North Carolina, Chapel Hill.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Juliano
mesh_terms: D000328:Adult; D017954:Africa South of the Sahara / Q000453:epidemiology; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology*; D008297:Male; D017720:Molecular Epidemiology; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000302:isolation & purification; D011110:Polymorphism, Genetic; D011247:Pregnancy; D015995:Prevalence
chemical_list: D000962:Antimalarials; D037621:Artemisinins; C031327:artemisinin
keywords: artemisinin resistance; drug resistance; falciparum malaria; molecular epidemiology