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; 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

doi: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

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 HuangGeorgina 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 journal › Article › peer-review

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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 language	English
Article number	1
Journal	BMC Medicine
Volume	17
Issue number	1
DOIs	https://doi.org/10.1186/s12916-018-1207-3
State	Published - 17 Jan 2019
Externally published	Yes

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10.1186/s12916-018-1207-3

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Amaratunga, C., Andrianaranjaka, V. H., Ashley, E., Bethell, D., Björkman, A., Bonnington, C. A., Cooper, R. A., Dhorda, M., Dondorp, A., Erhart, A., Fairhurst, R. M., Faiz, A., Fanello, C., Fukuda, M. M., Guérin, P., Van Huijsduijnen, R. H., Hien, T. T., Hong, N. V., Htut, Y., ... 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, 17(1), Article 1. https://doi.org/10.1186/s12916-018-1207-3

@article{df5495e7ff334474aab261273ea71cdf,

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{\c c}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",

note = "Publisher Copyright: {\textcopyright} 2019 The Author(s).",

year = "2019",

month = jan,

day = "17",

doi = "10.1186/s12916-018-1207-3",

language = "English",

volume = "17",

journal = "BMC Medicine",

issn = "1741-7015",

number = "1",

}

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, no. 1, 1. 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 et al.
In: BMC Medicine, Vol. 17, No. 1, 1, 17.01.2019.

Research output: Contribution to journal › Article › peer-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

AN - SCOPUS:85060148168

SN - 1741-7015

VL - 17

JO - BMC Medicine

JF - BMC Medicine

IS - 1

M1 - 1

ER -

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

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