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Malar J. 2019 Mar 7;18(1):60. doi: 10.1186/s12936-019-2701-6.

K13-propeller gene polymorphisms in Plasmodium falciparum parasite population in malaria affected countries: a systematic review of prevalence and risk factors.

Author information

1
Department of Pharmacology & Therapeutics, Makerere University, P.O. Box 7072, Kampala, Uganda. ocanmoses@gmail.com.
2
Africa Centre for Systematic Reviews and Knowledge Translation, Makerere University College of Health Sciences, P.O. Box 7072, Kampala, Uganda. ocanmoses@gmail.com.
3
Department of Psychiatry, Makerere University, P.O. Box 7072, Kampala, Uganda.
4
Department of Medical Microbiology, Makerere University, P.O. Box 7072, Kampala, Uganda.
5
Department of Medicine, Makerere University, P.O. Box 7072, Kampala, Uganda.
6
Infectious Disease Institute, Makerere University, P. O. Box 22418, Kampala, Uganda.
7
Albert Cook Library, Makerere University, P.O. Box 7072, Kampala, Uganda.
8
Clinical Epidemiology Unit, Department of Medicine, Makerere University, P.O. Box 7072, Kampala, Uganda.
9
Africa Centre for Systematic Reviews and Knowledge Translation, Makerere University College of Health Sciences, P.O. Box 7072, Kampala, Uganda.
10
Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

Abstract

BACKGROUND:

Efficacy of artemisinin (ART) agents, a critical element of current malaria control efforts is threatened by emergence and spread of resistance. Mutations in pfkelch13 gene associated with ART-resistance evolved in Southeast Asia (SEA). k13 mutations whose role in ART-resistance remains unknown, have subsequently emerged independently across all malaria-affected regions. The aim of this systematic review was to determine the prevalence and identify risk factors of Plasmodium falciparum k13 mutations in malaria-endemic countries.

METHODS:

An electronic search of studies from 2014 to date was done in MEDLINE via PubMED, SCOPUS, EMBASE and LILACS/VHL databases. Mesh terms and Boolean operators (AND, OR) were used. Two librarians independently conducted this search (RS and AK). The articles were screened for inclusion using a priori criteria set following PRISMA-P and STREGA guidelines. Three independent reviewers (NL, BB, and OM) extracted the data. Data analysis was performed in Open Meta Analyst software. Random effects analysis (DL) was used and heterogeneity established using I2-statistic.

RESULTS:

A total of 482 articles were retrieved from Pubmed = 302, Lilacs/Vhl = 50, Embase = 80, and Scopus = 37; Bibliography/other searches = 13, of which 374 did not meet the inclusion criteria. The aggregate prevalence of single nucleotide polymorphisms (SNPs) in pfkelch13 gene was 27.6% (3694/14,827) (95% CI 22.9%, 32.3%). Sub-group analysis showed that aggregate prevalence of non-synonymous SNPs in pfkelch13 gene was higher, 45.4% (95% CI 35.4%, 55.3%) in Southeast Asia as opposed to 7.6% (95% CI 5.6%, 9.5%) in the African region. A total of 165 independent k13 mutations were identified across malaria-affected regions globally. A total of 16 non-validated k13 mutations were associated with increased ART parasite clearance half-life (t1/2 > 5 h). The majority, 45.5% (75/165), of the mutations were reported in single P. falciparum parasite infections. Of the 165 k13-mutations, over half were reported as new alleles. Twenty (20) non-propeller mutations in the pfkelch13 gene were identified.

CONCLUSION:

This review identified emergence of potential ART-resistance mediating k13 mutations in the African region. Diversity of mutations in pfkelch13 gene is highest in African region compared to SEA. Mutations outside the pfkelch13 propeller region associated with increased ART parasite clearance half-life occur in malaria-affected regions.

KEYWORDS:

Africa; Artemisinin; K13-propeller gene polymorphism; Malaria; Plasmodium falciparum

PMID:
30846002
PMCID:
PMC6407282
DOI:
10.1186/s12936-019-2701-6
[Indexed for MEDLINE]
Free PMC Article

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