Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7-1343700) with parasite clearance rates after artemisinin-based treatments - A WWARN individual patient data meta-analysis

Chanaki Amaratunga, Voahangy Hanitriniaina Andrianaranjaka, Elizabeth Ashley, Delia Bethell, Anders Björkman, Craig A. Bonnington, Roland A. Cooper, Mehul Dhorda, Arjen Dondorp, Annette Erhart, Rick M. Fairhurst, Abul Faiz, Caterina Fanello, Mark M. Fukuda, Philippe Guérin, Rob Hooft Van Huijsduijnen, Tran Tinh Hien, N. V. Hong, Ye Htut, Fang Huang & 35 others Georgina Humphreys, Mallika Imwong, Kalynn Kennon, Pharath Lim, Khin Lin, Chanthap Lon, Andreas Mårtensson, Mayfong Mayxay, Olugbenga Mokuolu, Ulrika Morris, Billy E. Ngasala, Alfred Amambua-Ngwa, Harald Noedl, François Nosten, Marie Onyamboko, Aung Pyae Phyo, Christopher V. Plowe, Sasithon Pukrittayakamee, Milijaona Randrianarivelojosia, Philip J. Rosenthal, David L. Saunders, Carol Hopkins Sibley, Frank Smithuis, Michele D. Spring, Paul Sondo, Sokunthea Sreng, Peter Starzengruber, Kasia Stepniewska, Seila Suon, Shannon Takala-Harrison, Kamala Thriemer, Nguyen Thuy-Nhien, Kyaw Myo Tun, Nicholas J. White, Charles Woodrow

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Background: Plasmodium falciparum infections with slow parasite clearance following artemisinin-based therapies are widespread in the Greater Mekong Subregion. A molecular marker of the slow clearance phenotype has been identified: single genetic changes within the propeller region of the Kelch13 protein (pfk13; Pf3D7-1343700). Global searches have identified almost 200 different non-synonymous mutant pfk13 genotypes. Most mutations occur at low prevalence and have uncertain functional significance. To characterize the impact of different pfk13 mutations on parasite clearance, we conducted an individual patient data meta-analysis of the associations between parasite clearance half-life (PC 1/2 ) and pfk13 genotype based on a large set of individual patient records from Asia and Africa. 

    Methods: A systematic literature review following the PRISMA protocol was conducted to identify studies published between 2000 and 2017 which included frequent parasite counts and pfk13 genotyping. Four databases (Ovid Medline, PubMed, Ovid Embase, and Web of Science Core Collection) were searched. Eighteen studies (15 from Asia, 2 from Africa, and one multicenter study with sites on both continents) met inclusion criteria and were shared. Associations between the log transformed PC 1/2 values and pfk13 genotype were assessed using multivariable regression models with random effects for study site. 

    Results: Both the pfk13 genotypes and the PC 1/2 were available from 3250 (95%) patients (n = 3012 from Asia (93%), n = 238 from Africa (7%)). Among Asian isolates, all pfk13 propeller region mutant alleles observed in five or more specific isolates were associated with a 1.5- to 2.7-fold longer geometric mean PC 1/2 compared to the PC 1/2 of wild type isolates (all p ≤ 0.002). In addition, mutant allele E252Q located in the P. falciparum region of pfk13 was associated with 1.5-fold (95%CI 1.4-1.6) longer PC 1/2 . None of the isolates from four countries in Africa showed a significant difference between the PC 1/2 of parasites with or without pfk13 propeller region mutations. Previously, the association of six pfk13 propeller mutant alleles with delayed parasite clearance had been confirmed. This analysis demonstrates that 15 additional pfk13 alleles are associated strongly with the slow-clearing phenotype in Southeast Asia. 

    Conclusion: Pooled analysis associated 20 pfk13 propeller region mutant alleles with the slow clearance phenotype, including 15 mutations not confirmed previously.

    Original languageEnglish
    Article number1
    Pages (from-to)1-20
    Number of pages20
    JournalBMC Medicine
    Volume17
    DOIs
    Publication statusPublished - 17 Jan 2019

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    Plasmodium falciparum
    Meta-Analysis
    Parasites
    Alleles
    Mutation
    Genotype
    Genes
    Phenotype
    Therapeutics
    Southeastern Asia
    PubMed
    Malaria
    Multicenter Studies
    Half-Life
    artemisinine
    Databases
    Proteins

    Cite this

    Amaratunga, Chanaki ; Andrianaranjaka, Voahangy Hanitriniaina ; Ashley, Elizabeth ; Bethell, Delia ; Björkman, Anders ; Bonnington, Craig A. ; Cooper, Roland A. ; Dhorda, Mehul ; Dondorp, Arjen ; Erhart, Annette ; Fairhurst, Rick M. ; Faiz, Abul ; Fanello, Caterina ; Fukuda, Mark M. ; Guérin, Philippe ; Van Huijsduijnen, Rob Hooft ; Hien, Tran Tinh ; Hong, N. V. ; Htut, Ye ; Huang, Fang ; Humphreys, Georgina ; Imwong, Mallika ; Kennon, Kalynn ; Lim, Pharath ; Lin, Khin ; Lon, Chanthap ; Mårtensson, Andreas ; Mayxay, Mayfong ; Mokuolu, Olugbenga ; Morris, Ulrika ; Ngasala, Billy E. ; Amambua-Ngwa, Alfred ; Noedl, Harald ; Nosten, François ; Onyamboko, Marie ; Phyo, Aung Pyae ; Plowe, Christopher V. ; Pukrittayakamee, Sasithon ; Randrianarivelojosia, Milijaona ; Rosenthal, Philip J. ; Saunders, David L. ; Sibley, Carol Hopkins ; Smithuis, Frank ; Spring, Michele D. ; Sondo, Paul ; Sreng, Sokunthea ; Starzengruber, Peter ; Stepniewska, Kasia ; Suon, Seila ; Takala-Harrison, Shannon ; Thriemer, Kamala ; Thuy-Nhien, Nguyen ; Tun, Kyaw Myo ; White, Nicholas J. ; Woodrow, Charles. / Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7-1343700) with parasite clearance rates after artemisinin-based treatments - A WWARN individual patient data meta-analysis. In: BMC Medicine. 2019 ; Vol. 17. pp. 1-20.
    @article{d412952b672148a4bd0d27f0e0fed546,
    title = "Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7-1343700) with parasite clearance rates after artemisinin-based treatments - A WWARN individual patient data meta-analysis",
    abstract = "Background: Plasmodium falciparum infections with slow parasite clearance following artemisinin-based therapies are widespread in the Greater Mekong Subregion. A molecular marker of the slow clearance phenotype has been identified: single genetic changes within the propeller region of the Kelch13 protein (pfk13; Pf3D7-1343700). Global searches have identified almost 200 different non-synonymous mutant pfk13 genotypes. Most mutations occur at low prevalence and have uncertain functional significance. To characterize the impact of different pfk13 mutations on parasite clearance, we conducted an individual patient data meta-analysis of the associations between parasite clearance half-life (PC 1/2 ) and pfk13 genotype based on a large set of individual patient records from Asia and Africa. Methods: A systematic literature review following the PRISMA protocol was conducted to identify studies published between 2000 and 2017 which included frequent parasite counts and pfk13 genotyping. Four databases (Ovid Medline, PubMed, Ovid Embase, and Web of Science Core Collection) were searched. Eighteen studies (15 from Asia, 2 from Africa, and one multicenter study with sites on both continents) met inclusion criteria and were shared. Associations between the log transformed PC 1/2 values and pfk13 genotype were assessed using multivariable regression models with random effects for study site. Results: Both the pfk13 genotypes and the PC 1/2 were available from 3250 (95{\%}) patients (n = 3012 from Asia (93{\%}), n = 238 from Africa (7{\%})). Among Asian isolates, all pfk13 propeller region mutant alleles observed in five or more specific isolates were associated with a 1.5- to 2.7-fold longer geometric mean PC 1/2 compared to the PC 1/2 of wild type isolates (all p ≤ 0.002). In addition, mutant allele E252Q located in the P. falciparum region of pfk13 was associated with 1.5-fold (95{\%}CI 1.4-1.6) longer PC 1/2 . None of the isolates from four countries in Africa showed a significant difference between the PC 1/2 of parasites with or without pfk13 propeller region mutations. Previously, the association of six pfk13 propeller mutant alleles with delayed parasite clearance had been confirmed. This analysis demonstrates that 15 additional pfk13 alleles are associated strongly with the slow-clearing phenotype in Southeast Asia. Conclusion: Pooled analysis associated 20 pfk13 propeller region mutant alleles with the slow clearance phenotype, including 15 mutations not confirmed previously.",
    author = "Chanaki Amaratunga and Andrianaranjaka, {Voahangy Hanitriniaina} and Elizabeth Ashley and Delia Bethell and Anders Bj{\"o}rkman and Bonnington, {Craig A.} and Cooper, {Roland A.} and Mehul Dhorda and Arjen Dondorp and Annette Erhart and Fairhurst, {Rick M.} and Abul Faiz and Caterina Fanello and Fukuda, {Mark M.} and Philippe Gu{\'e}rin and {Van Huijsduijnen}, {Rob Hooft} and Hien, {Tran Tinh} and Hong, {N. V.} and Ye Htut and Fang Huang and Georgina Humphreys and Mallika Imwong and Kalynn Kennon and Pharath Lim and Khin Lin and Chanthap Lon and Andreas M{\aa}rtensson and Mayfong Mayxay and Olugbenga Mokuolu and Ulrika Morris and Ngasala, {Billy E.} and Alfred Amambua-Ngwa and Harald Noedl and Fran{\cc}ois Nosten and Marie Onyamboko and Phyo, {Aung Pyae} and Plowe, {Christopher V.} and Sasithon Pukrittayakamee and Milijaona Randrianarivelojosia and Rosenthal, {Philip J.} and Saunders, {David L.} and Sibley, {Carol Hopkins} and Frank Smithuis and Spring, {Michele D.} and Paul Sondo and Sokunthea Sreng and Peter Starzengruber and Kasia Stepniewska and Seila Suon and Shannon Takala-Harrison and Kamala Thriemer and Nguyen Thuy-Nhien and Tun, {Kyaw Myo} and White, {Nicholas J.} and Charles Woodrow",
    year = "2019",
    month = "1",
    day = "17",
    doi = "10.1186/s12916-018-1207-3",
    language = "English",
    volume = "17",
    pages = "1--20",
    journal = "BMC Medicine",
    issn = "1741-7015",
    publisher = "BioMed Central",

    }

    Amaratunga, C, Andrianaranjaka, VH, Ashley, E, Bethell, D, Björkman, A, Bonnington, CA, Cooper, RA, Dhorda, M, Dondorp, A, Erhart, A, Fairhurst, RM, Faiz, A, Fanello, C, Fukuda, MM, Guérin, P, Van Huijsduijnen, RH, Hien, TT, Hong, NV, Htut, Y, Huang, F, Humphreys, G, Imwong, M, Kennon, K, Lim, P, Lin, K, Lon, C, Mårtensson, A, Mayxay, M, Mokuolu, O, Morris, U, Ngasala, BE, Amambua-Ngwa, A, Noedl, H, Nosten, F, Onyamboko, M, Phyo, AP, Plowe, CV, Pukrittayakamee, S, Randrianarivelojosia, M, Rosenthal, PJ, Saunders, DL, Sibley, CH, Smithuis, F, Spring, MD, Sondo, P, Sreng, S, Starzengruber, P, Stepniewska, K, Suon, S, Takala-Harrison, S, Thriemer, K, Thuy-Nhien, N, Tun, KM, White, NJ & Woodrow, C 2019, 'Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7-1343700) with parasite clearance rates after artemisinin-based treatments - A WWARN individual patient data meta-analysis', BMC Medicine, vol. 17, 1, pp. 1-20. https://doi.org/10.1186/s12916-018-1207-3

    Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7-1343700) with parasite clearance rates after artemisinin-based treatments - A WWARN individual patient data meta-analysis. / Amaratunga, Chanaki; Andrianaranjaka, Voahangy Hanitriniaina; Ashley, Elizabeth; Bethell, Delia; Björkman, Anders; Bonnington, Craig A.; Cooper, Roland A.; Dhorda, Mehul; Dondorp, Arjen; Erhart, Annette; Fairhurst, Rick M.; Faiz, Abul; Fanello, Caterina; Fukuda, Mark M.; Guérin, Philippe; Van Huijsduijnen, Rob Hooft; Hien, Tran Tinh; Hong, N. V.; Htut, Ye; Huang, Fang; Humphreys, Georgina; Imwong, Mallika; Kennon, Kalynn; Lim, Pharath; Lin, Khin; Lon, Chanthap; Mårtensson, Andreas; Mayxay, Mayfong; Mokuolu, Olugbenga; Morris, Ulrika; Ngasala, Billy E.; Amambua-Ngwa, Alfred; Noedl, Harald; Nosten, François; Onyamboko, Marie; Phyo, Aung Pyae; Plowe, Christopher V.; Pukrittayakamee, Sasithon; Randrianarivelojosia, Milijaona; Rosenthal, Philip J.; Saunders, David L.; Sibley, Carol Hopkins; Smithuis, Frank; Spring, Michele D.; Sondo, Paul; Sreng, Sokunthea; Starzengruber, Peter; Stepniewska, Kasia; Suon, Seila; Takala-Harrison, Shannon; Thriemer, Kamala; Thuy-Nhien, Nguyen; Tun, Kyaw Myo; White, Nicholas J.; Woodrow, Charles.

    In: BMC Medicine, Vol. 17, 1, 17.01.2019, p. 1-20.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7-1343700) with parasite clearance rates after artemisinin-based treatments - A WWARN individual patient data meta-analysis

    AU - Amaratunga, Chanaki

    AU - Andrianaranjaka, Voahangy Hanitriniaina

    AU - Ashley, Elizabeth

    AU - Bethell, Delia

    AU - Björkman, Anders

    AU - Bonnington, Craig A.

    AU - Cooper, Roland A.

    AU - Dhorda, Mehul

    AU - Dondorp, Arjen

    AU - Erhart, Annette

    AU - Fairhurst, Rick M.

    AU - Faiz, Abul

    AU - Fanello, Caterina

    AU - Fukuda, Mark M.

    AU - Guérin, Philippe

    AU - Van Huijsduijnen, Rob Hooft

    AU - Hien, Tran Tinh

    AU - Hong, N. V.

    AU - Htut, Ye

    AU - Huang, Fang

    AU - Humphreys, Georgina

    AU - Imwong, Mallika

    AU - Kennon, Kalynn

    AU - Lim, Pharath

    AU - Lin, Khin

    AU - Lon, Chanthap

    AU - Mårtensson, Andreas

    AU - Mayxay, Mayfong

    AU - Mokuolu, Olugbenga

    AU - Morris, Ulrika

    AU - Ngasala, Billy E.

    AU - Amambua-Ngwa, Alfred

    AU - Noedl, Harald

    AU - Nosten, François

    AU - Onyamboko, Marie

    AU - Phyo, Aung Pyae

    AU - Plowe, Christopher V.

    AU - Pukrittayakamee, Sasithon

    AU - Randrianarivelojosia, Milijaona

    AU - Rosenthal, Philip J.

    AU - Saunders, David L.

    AU - Sibley, Carol Hopkins

    AU - Smithuis, Frank

    AU - Spring, Michele D.

    AU - Sondo, Paul

    AU - Sreng, Sokunthea

    AU - Starzengruber, Peter

    AU - Stepniewska, Kasia

    AU - Suon, Seila

    AU - Takala-Harrison, Shannon

    AU - Thriemer, Kamala

    AU - Thuy-Nhien, Nguyen

    AU - Tun, Kyaw Myo

    AU - White, Nicholas J.

    AU - Woodrow, Charles

    PY - 2019/1/17

    Y1 - 2019/1/17

    N2 - Background: Plasmodium falciparum infections with slow parasite clearance following artemisinin-based therapies are widespread in the Greater Mekong Subregion. A molecular marker of the slow clearance phenotype has been identified: single genetic changes within the propeller region of the Kelch13 protein (pfk13; Pf3D7-1343700). Global searches have identified almost 200 different non-synonymous mutant pfk13 genotypes. Most mutations occur at low prevalence and have uncertain functional significance. To characterize the impact of different pfk13 mutations on parasite clearance, we conducted an individual patient data meta-analysis of the associations between parasite clearance half-life (PC 1/2 ) and pfk13 genotype based on a large set of individual patient records from Asia and Africa. Methods: A systematic literature review following the PRISMA protocol was conducted to identify studies published between 2000 and 2017 which included frequent parasite counts and pfk13 genotyping. Four databases (Ovid Medline, PubMed, Ovid Embase, and Web of Science Core Collection) were searched. Eighteen studies (15 from Asia, 2 from Africa, and one multicenter study with sites on both continents) met inclusion criteria and were shared. Associations between the log transformed PC 1/2 values and pfk13 genotype were assessed using multivariable regression models with random effects for study site. Results: Both the pfk13 genotypes and the PC 1/2 were available from 3250 (95%) patients (n = 3012 from Asia (93%), n = 238 from Africa (7%)). Among Asian isolates, all pfk13 propeller region mutant alleles observed in five or more specific isolates were associated with a 1.5- to 2.7-fold longer geometric mean PC 1/2 compared to the PC 1/2 of wild type isolates (all p ≤ 0.002). In addition, mutant allele E252Q located in the P. falciparum region of pfk13 was associated with 1.5-fold (95%CI 1.4-1.6) longer PC 1/2 . None of the isolates from four countries in Africa showed a significant difference between the PC 1/2 of parasites with or without pfk13 propeller region mutations. Previously, the association of six pfk13 propeller mutant alleles with delayed parasite clearance had been confirmed. This analysis demonstrates that 15 additional pfk13 alleles are associated strongly with the slow-clearing phenotype in Southeast Asia. Conclusion: Pooled analysis associated 20 pfk13 propeller region mutant alleles with the slow clearance phenotype, including 15 mutations not confirmed previously.

    AB - Background: Plasmodium falciparum infections with slow parasite clearance following artemisinin-based therapies are widespread in the Greater Mekong Subregion. A molecular marker of the slow clearance phenotype has been identified: single genetic changes within the propeller region of the Kelch13 protein (pfk13; Pf3D7-1343700). Global searches have identified almost 200 different non-synonymous mutant pfk13 genotypes. Most mutations occur at low prevalence and have uncertain functional significance. To characterize the impact of different pfk13 mutations on parasite clearance, we conducted an individual patient data meta-analysis of the associations between parasite clearance half-life (PC 1/2 ) and pfk13 genotype based on a large set of individual patient records from Asia and Africa. Methods: A systematic literature review following the PRISMA protocol was conducted to identify studies published between 2000 and 2017 which included frequent parasite counts and pfk13 genotyping. Four databases (Ovid Medline, PubMed, Ovid Embase, and Web of Science Core Collection) were searched. Eighteen studies (15 from Asia, 2 from Africa, and one multicenter study with sites on both continents) met inclusion criteria and were shared. Associations between the log transformed PC 1/2 values and pfk13 genotype were assessed using multivariable regression models with random effects for study site. Results: Both the pfk13 genotypes and the PC 1/2 were available from 3250 (95%) patients (n = 3012 from Asia (93%), n = 238 from Africa (7%)). Among Asian isolates, all pfk13 propeller region mutant alleles observed in five or more specific isolates were associated with a 1.5- to 2.7-fold longer geometric mean PC 1/2 compared to the PC 1/2 of wild type isolates (all p ≤ 0.002). In addition, mutant allele E252Q located in the P. falciparum region of pfk13 was associated with 1.5-fold (95%CI 1.4-1.6) longer PC 1/2 . None of the isolates from four countries in Africa showed a significant difference between the PC 1/2 of parasites with or without pfk13 propeller region mutations. Previously, the association of six pfk13 propeller mutant alleles with delayed parasite clearance had been confirmed. This analysis demonstrates that 15 additional pfk13 alleles are associated strongly with the slow-clearing phenotype in Southeast Asia. Conclusion: Pooled analysis associated 20 pfk13 propeller region mutant alleles with the slow clearance phenotype, including 15 mutations not confirmed previously.

    UR - http://www.scopus.com/inward/record.url?scp=85060148168&partnerID=8YFLogxK

    U2 - 10.1186/s12916-018-1207-3

    DO - 10.1186/s12916-018-1207-3

    M3 - Article

    VL - 17

    SP - 1

    EP - 20

    JO - BMC Medicine

    JF - BMC Medicine

    SN - 1741-7015

    M1 - 1

    ER -