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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
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, Volume 17, No. 1, Article 1, Year 2019
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Description
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. © 2019 The Author(s).
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC6335805/bin/12916_2018_1207_MOESM1_ESM.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC6335805/bin/12916_2018_1207_MOESM2_ESM.xlsx
https://efashare.b-cdn.net/share/pmc/articles/PMC6335805/bin/12916_2018_1207_MOESM3_ESM.pdf
Authors & Co-Authors
Amaratunga, Chanaki
United Kingdom, Oxford
Oxford
Andrianaranjaka, Voahangy Hanitriniaina Isabelle
United Kingdom, Oxford
Oxford
Ashley, Elizabeth A.
United Kingdom, Oxford
Oxford
Bethell, Delia B.
United Kingdom, Oxford
Oxford
Bjǒrkman, Anders B.
United Kingdom, Oxford
Oxford
Bonnington, Craig A.
United Kingdom, Oxford
Oxford
Cooper, Roland A.
United Kingdom, Oxford
Oxford
Dhorda, M. J.
United Kingdom, Oxford
Oxford
Dondorp, A. M.
United Kingdom, Oxford
Oxford
Erhart, Annette
United Kingdom, Oxford
Oxford
Fairhurst, Rick M.
United Kingdom, Oxford
Oxford
Faiz, Mohammad Abul
United Kingdom, Oxford
Oxford
Fanello, Caterina I.
United Kingdom, Oxford
Oxford
Fukuda, Mark M.
United Kingdom, Oxford
Oxford
Guérin, Philippe Jean Jean
United Kingdom, Oxford
Oxford
Hooft Van Huijsduijnen, Rob A.M.
United Kingdom, Oxford
Oxford
Hien, Tran Tinh
United Kingdom, Oxford
Oxford
Hong, Nguyenvan
United Kingdom, Oxford
Oxford
Htut, Ye
United Kingdom, Oxford
Oxford
Huang, Fang
United Kingdom, Oxford
Oxford
Humphreys, Georgina S.
United Kingdom, Oxford
Oxford
Imwong, Mallika
United Kingdom, Oxford
Oxford
Kennon, Kalynn
United Kingdom, Oxford
Oxford
Lim, Pharath
United Kingdom, Oxford
Oxford
Lin, Khin
United Kingdom, Oxford
Oxford
Lon, Chanthap
United Kingdom, Oxford
Oxford
Mårtensson, Andreas A.
United Kingdom, Oxford
Oxford
Mayxay, Mayfong
United Kingdom, Oxford
Oxford
Mokuolu, Olugbenga Ayodeji
United Kingdom, Oxford
Oxford
Morris, Ulrika
United Kingdom, Oxford
Oxford
Ngasala, Billy E.
United Kingdom, Oxford
Oxford
Amambua-Ngwa, Alfred
United Kingdom, Oxford
Oxford
Noedl, Harald
United Kingdom, Oxford
Oxford
Nosten, François Henry
United Kingdom, Oxford
Oxford
Onyamboko, Marie A.
United Kingdom, Oxford
Oxford
Pyae Phyo, Aung Pyae P.
United Kingdom, Oxford
Oxford
Plowe, Christopher Vv
United Kingdom, Oxford
Oxford
Pukrittayakamee, Sasithon
United Kingdom, Oxford
Oxford
Randrianarivelojosia, Milijaona
United Kingdom, Oxford
Oxford
Rosenthal, Philip Jon
United Kingdom, Oxford
Oxford
Saunders, David L.
United Kingdom, Oxford
Oxford
Sibley, Carol Hopkins
United Kingdom, Oxford
Oxford
Smithuis, Frank M.
United Kingdom, Oxford
Oxford
Spring, Michele Donna
United Kingdom, Oxford
Oxford
Sondo, Paul
United Kingdom, Oxford
Oxford
Sreng, Sokunthea
United Kingdom, Oxford
Oxford
Starzengrüber, Peter
United Kingdom, Oxford
Oxford
Stepniewska, Kasia
United Kingdom, Oxford
Oxford
Suon, Seila
United Kingdom, Oxford
Oxford
Takala-Harrison, Shannon L.
United Kingdom, Oxford
Oxford
Thriemer, Kamala L.
United Kingdom, Oxford
Oxford
Thuy-Nhien, Nguyen Thanh
United Kingdom, Oxford
Oxford
Tun, Kyaw Myo
United Kingdom, Oxford
Oxford
White, Nicholas J.
United Kingdom, Oxford
Oxford
Woodrow, Charles Jonathan
United Kingdom, Oxford
Oxford
Statistics
Citations: 80
Authors: 55
Affiliations: 1
Identifiers
Doi:
10.1186/s12916-018-1207-3
ISSN:
17417015
Research Areas
Genetics And Genomics
Health System And Policy
Study Design
Cross Sectional Study
Study Approach
Systematic review