Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia

Shannon Takala-Harrison, Christopher G. Jacob, Cesar Arze, Michael P. Cummings, Joana C. Silva, Arjen M. Dondorp, Mark M. Fukuda, Tran Tinh Hien, Mayfong Mayxay, Harald Noedl, Francois Nosten, Myat P. Kyaw, Nguyen Thanh Thuy Nhien, Mallika Imwong, Delia Bethell, Youry Se, Chanthap Lon, Stuart D. Tyner, David L. Saunders, Frederic ArieyOdile Mercereau-Puijalon, Didier Menard, Paul N. Newton, Maniphone Khanthavong, Bouasy Hongvanthong, Peter Starzengruber, Hans Peter Fuehrer, Paul Swoboda, Wasif A. Khan, Aung Pyae Phyo, Myaing M. Nyunt, Myat H. Nyunt, Tyler S. Brown, Matthew Adams, Christopher S. Pepin, Jason Bailey, John C. Tan, Michael T. Ferdig, Taane G. Clark, Olivo Miotto, Bronwyn MacInnis, Dominic P. Kwiatkowski, Nicholas J. White, Pascal Ringwald, Christopher V. Plowe

Research output: Contribution to journalArticle

Abstract

Background: The emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia threatens malaria treatment efficacy. Mutations in a kelch protein encoded on P. falciparum chromosome 13 (K13) have been associated with resistance in vitro and in field samples from Cambodia. Methods: P. falciparum infections from artesunate efficacy trials in Bangladesh, Cambodia, Laos, Myanmar, and Vietnam were genotyped at 33 716 genome-wide single-nucleotide polymorphisms (SNPs). Linear mixed models were used to test associations between parasite genotypes and parasite clearance half-lives following artesunate treatment. K13 mutations were tested for association with artemisinin resistance, and extended haplotypes on chromosome 13 were examined to determine whether mutations arose focally and spread or whether they emerged independently. Results: The presence of nonreference K13 alleles was associated with prolonged parasite clearance half-life (P = 1.97 × 10-12). Parasites with a mutation in any of the K13 kelch domains displayed longer parasite clearance half-lives than parasites with wild-type alleles. Haplotype analysis revealed both population-specific emergence of mutations and independent emergence of the same mutation in different geographic areas. Conclusions: K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia. While we found some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar.

Original languageEnglish (US)
Pages (from-to)670-679
Number of pages10
JournalJournal of Infectious Diseases
Volume211
Issue number5
DOIs
StatePublished - 2015
Externally publishedYes

Fingerprint

Southeastern Asia
Plasmodium falciparum
Parasites
Cambodia
Mutation
Myanmar
Chromosomes, Human, Pair 13
Haplotypes
Malaria
Alleles
Laos
Bangladesh
Vietnam
Single Nucleotide Polymorphism
Half-Life
artemisinine
Linear Models
Genotype
Genome
Population

Keywords

  • Artemisinin resistance
  • Kelch
  • Malaria
  • Plasmodium falciparum
  • Southeast Asia

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology and Allergy

Cite this

Takala-Harrison, S., Jacob, C. G., Arze, C., Cummings, M. P., Silva, J. C., Dondorp, A. M., ... Plowe, C. V. (2015). Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia. Journal of Infectious Diseases, 211(5), 670-679. https://doi.org/10.1093/infdis/jiu491

Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia. / Takala-Harrison, Shannon; Jacob, Christopher G.; Arze, Cesar; Cummings, Michael P.; Silva, Joana C.; Dondorp, Arjen M.; Fukuda, Mark M.; Hien, Tran Tinh; Mayxay, Mayfong; Noedl, Harald; Nosten, Francois; Kyaw, Myat P.; Nhien, Nguyen Thanh Thuy; Imwong, Mallika; Bethell, Delia; Se, Youry; Lon, Chanthap; Tyner, Stuart D.; Saunders, David L.; Ariey, Frederic; Mercereau-Puijalon, Odile; Menard, Didier; Newton, Paul N.; Khanthavong, Maniphone; Hongvanthong, Bouasy; Starzengruber, Peter; Fuehrer, Hans Peter; Swoboda, Paul; Khan, Wasif A.; Phyo, Aung Pyae; Nyunt, Myaing M.; Nyunt, Myat H.; Brown, Tyler S.; Adams, Matthew; Pepin, Christopher S.; Bailey, Jason; Tan, John C.; Ferdig, Michael T.; Clark, Taane G.; Miotto, Olivo; MacInnis, Bronwyn; Kwiatkowski, Dominic P.; White, Nicholas J.; Ringwald, Pascal; Plowe, Christopher V.

In: Journal of Infectious Diseases, Vol. 211, No. 5, 2015, p. 670-679.

Research output: Contribution to journalArticle

Takala-Harrison, S, Jacob, CG, Arze, C, Cummings, MP, Silva, JC, Dondorp, AM, Fukuda, MM, Hien, TT, Mayxay, M, Noedl, H, Nosten, F, Kyaw, MP, Nhien, NTT, Imwong, M, Bethell, D, Se, Y, Lon, C, Tyner, SD, Saunders, DL, Ariey, F, Mercereau-Puijalon, O, Menard, D, Newton, PN, Khanthavong, M, Hongvanthong, B, Starzengruber, P, Fuehrer, HP, Swoboda, P, Khan, WA, Phyo, AP, Nyunt, MM, Nyunt, MH, Brown, TS, Adams, M, Pepin, CS, Bailey, J, Tan, JC, Ferdig, MT, Clark, TG, Miotto, O, MacInnis, B, Kwiatkowski, DP, White, NJ, Ringwald, P & Plowe, CV 2015, 'Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia', Journal of Infectious Diseases, vol. 211, no. 5, pp. 670-679. https://doi.org/10.1093/infdis/jiu491
Takala-Harrison, Shannon ; Jacob, Christopher G. ; Arze, Cesar ; Cummings, Michael P. ; Silva, Joana C. ; Dondorp, Arjen M. ; Fukuda, Mark M. ; Hien, Tran Tinh ; Mayxay, Mayfong ; Noedl, Harald ; Nosten, Francois ; Kyaw, Myat P. ; Nhien, Nguyen Thanh Thuy ; Imwong, Mallika ; Bethell, Delia ; Se, Youry ; Lon, Chanthap ; Tyner, Stuart D. ; Saunders, David L. ; Ariey, Frederic ; Mercereau-Puijalon, Odile ; Menard, Didier ; Newton, Paul N. ; Khanthavong, Maniphone ; Hongvanthong, Bouasy ; Starzengruber, Peter ; Fuehrer, Hans Peter ; Swoboda, Paul ; Khan, Wasif A. ; Phyo, Aung Pyae ; Nyunt, Myaing M. ; Nyunt, Myat H. ; Brown, Tyler S. ; Adams, Matthew ; Pepin, Christopher S. ; Bailey, Jason ; Tan, John C. ; Ferdig, Michael T. ; Clark, Taane G. ; Miotto, Olivo ; MacInnis, Bronwyn ; Kwiatkowski, Dominic P. ; White, Nicholas J. ; Ringwald, Pascal ; Plowe, Christopher V. / Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia. In: Journal of Infectious Diseases. 2015 ; Vol. 211, No. 5. pp. 670-679.
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abstract = "Background: The emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia threatens malaria treatment efficacy. Mutations in a kelch protein encoded on P. falciparum chromosome 13 (K13) have been associated with resistance in vitro and in field samples from Cambodia. Methods: P. falciparum infections from artesunate efficacy trials in Bangladesh, Cambodia, Laos, Myanmar, and Vietnam were genotyped at 33 716 genome-wide single-nucleotide polymorphisms (SNPs). Linear mixed models were used to test associations between parasite genotypes and parasite clearance half-lives following artesunate treatment. K13 mutations were tested for association with artemisinin resistance, and extended haplotypes on chromosome 13 were examined to determine whether mutations arose focally and spread or whether they emerged independently. Results: The presence of nonreference K13 alleles was associated with prolonged parasite clearance half-life (P = 1.97 × 10-12). Parasites with a mutation in any of the K13 kelch domains displayed longer parasite clearance half-lives than parasites with wild-type alleles. Haplotype analysis revealed both population-specific emergence of mutations and independent emergence of the same mutation in different geographic areas. Conclusions: K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia. While we found some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar.",
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AU - Jacob, Christopher G.

AU - Arze, Cesar

AU - Cummings, Michael P.

AU - Silva, Joana C.

AU - Dondorp, Arjen M.

AU - Fukuda, Mark M.

AU - Hien, Tran Tinh

AU - Mayxay, Mayfong

AU - Noedl, Harald

AU - Nosten, Francois

AU - Kyaw, Myat P.

AU - Nhien, Nguyen Thanh Thuy

AU - Imwong, Mallika

AU - Bethell, Delia

AU - Se, Youry

AU - Lon, Chanthap

AU - Tyner, Stuart D.

AU - Saunders, David L.

AU - Ariey, Frederic

AU - Mercereau-Puijalon, Odile

AU - Menard, Didier

AU - Newton, Paul N.

AU - Khanthavong, Maniphone

AU - Hongvanthong, Bouasy

AU - Starzengruber, Peter

AU - Fuehrer, Hans Peter

AU - Swoboda, Paul

AU - Khan, Wasif A.

AU - Phyo, Aung Pyae

AU - Nyunt, Myaing M.

AU - Nyunt, Myat H.

AU - Brown, Tyler S.

AU - Adams, Matthew

AU - Pepin, Christopher S.

AU - Bailey, Jason

AU - Tan, John C.

AU - Ferdig, Michael T.

AU - Clark, Taane G.

AU - Miotto, Olivo

AU - MacInnis, Bronwyn

AU - Kwiatkowski, Dominic P.

AU - White, Nicholas J.

AU - Ringwald, Pascal

AU - Plowe, Christopher V.

PY - 2015

Y1 - 2015

N2 - Background: The emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia threatens malaria treatment efficacy. Mutations in a kelch protein encoded on P. falciparum chromosome 13 (K13) have been associated with resistance in vitro and in field samples from Cambodia. Methods: P. falciparum infections from artesunate efficacy trials in Bangladesh, Cambodia, Laos, Myanmar, and Vietnam were genotyped at 33 716 genome-wide single-nucleotide polymorphisms (SNPs). Linear mixed models were used to test associations between parasite genotypes and parasite clearance half-lives following artesunate treatment. K13 mutations were tested for association with artemisinin resistance, and extended haplotypes on chromosome 13 were examined to determine whether mutations arose focally and spread or whether they emerged independently. Results: The presence of nonreference K13 alleles was associated with prolonged parasite clearance half-life (P = 1.97 × 10-12). Parasites with a mutation in any of the K13 kelch domains displayed longer parasite clearance half-lives than parasites with wild-type alleles. Haplotype analysis revealed both population-specific emergence of mutations and independent emergence of the same mutation in different geographic areas. Conclusions: K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia. While we found some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar.

AB - Background: The emergence of artemisinin-resistant Plasmodium falciparum in Southeast Asia threatens malaria treatment efficacy. Mutations in a kelch protein encoded on P. falciparum chromosome 13 (K13) have been associated with resistance in vitro and in field samples from Cambodia. Methods: P. falciparum infections from artesunate efficacy trials in Bangladesh, Cambodia, Laos, Myanmar, and Vietnam were genotyped at 33 716 genome-wide single-nucleotide polymorphisms (SNPs). Linear mixed models were used to test associations between parasite genotypes and parasite clearance half-lives following artesunate treatment. K13 mutations were tested for association with artemisinin resistance, and extended haplotypes on chromosome 13 were examined to determine whether mutations arose focally and spread or whether they emerged independently. Results: The presence of nonreference K13 alleles was associated with prolonged parasite clearance half-life (P = 1.97 × 10-12). Parasites with a mutation in any of the K13 kelch domains displayed longer parasite clearance half-lives than parasites with wild-type alleles. Haplotype analysis revealed both population-specific emergence of mutations and independent emergence of the same mutation in different geographic areas. Conclusions: K13 appears to be a major determinant of artemisinin resistance throughout Southeast Asia. While we found some evidence of spreading resistance, there was no evidence of resistance moving westward from Cambodia into Myanmar.

KW - Artemisinin resistance

KW - Kelch

KW - Malaria

KW - Plasmodium falciparum

KW - Southeast Asia

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