A novel intron variant is associated with emerging pfdhps mutant haplotypes in West and Central African Plasmodium falciparum

Sulfadoxine-pyrimethamine plays a key role in Plasmodium falciparum chemoprevention across Africa, yet the protective efficacy of SP is undermined by mutations conferring resistance in the genes encoding dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps). The emergence and spread of the pfdhps 431V mutation suggests that this may confer resistance and be selected by drug use. Here, we report a non-coding mutation a548383t, which expands a di-nucleotide repeat in the first intron of pfpppk-dhps. The first intron and second exon of the pfdhps gene were analysed by target amplicon sequencing of 929 P. falciparum-positive blood samples from Nigeria, Cameroon, Tanzania, The Democratic Republic of Congo, and Côte d'Ivoire. The intron mutation was found in Nigeria, Côte d'Ivoire, and Cameroon in association with the 431V mutation. In particular, the intron mutation was most highly associated with the VAGKGS haplotype (OR = 211.7, P < 0.001), followed by the VAGKAS (OR = 39.2, P < 0.001), and VAGKAA (OR = 33.6, P < 0.001) haplotypes. Additionally, a reduced di-nucleotide repeat diversity was observed in 431V-positive variants. The intron variant is significantly associated with the 431V mutation which is consistent with previous reports of selective sweeps around VAGKGS. The association of the 548383t mutation with both VAGKGS, VAGKAS and VAGKAA might indicate these lineages either have a common ancestor or that the intron variant 548383t has a functional association with 431V. More research is needed to determine if the association is simply genetic hitchhiking, or if the intron variant confers a phenotypic advantage.

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Publication Details

Journal
International Journal for Parasitology Drugs and Drug Resistance
Published
2025-08-26
DOI
https://doi.org/10.1016/j.ijpddr.2025.100611
Primary Topic
Malaria Research and Control
Type
article
Field-Weighted Citation Impact
0.00

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article

A novel intron variant is associated with emerging pfdhps mutant haplotypes in West and Central African Plasmodium falciparum

William Yavo, Ana Chopo-Pizarro, Vito Baraka, Valerie Akoua Bedia et al.
International Journal for Parasitology Drugs and Drug Resistance
Malaria Research and Control
article

A novel intron variant is associated with emerging pfdhps mutant haplotypes in West and Central African Plasmodium falciparum

William Yavo, Ana Chopo-Pizarro, Vito Baraka, Valerie Akoua Bedia, Peter Thelma Ngwa Niba, Andria Mousa, Destin Mbongi, Neema B. Kulaya, Emma Filtenborg Hocke, Colin J. Sutherland, Éric Mukomena Sompwe, Wilfred Fon Mbacham, Gauthier Mesia Kahunu, Helle Hansson, Khalid B. Beshir, Paterne Akpa Gnagne, Akindeh M. Nji, Patrick Mitashi Mulopo, Cally Roper, Michael Alifrangis, Oluseye O. Bolaji, Hypolite Muhindo Mavoko, Adebanjo J. Adegbola, Papy Mandoko Nkoli, Innocent Mbulli Ali, Abibatou Konaté, Hervé Menan
article en

Abstract

Sulfadoxine-pyrimethamine plays a key role in Plasmodium falciparum chemoprevention across Africa, yet the protective efficacy of SP is undermined by mutations conferring resistance in the genes encoding dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps). The emergence and spread of the pfdhps 431V mutation suggests that this may confer resistance and be selected by drug use. Here, we report a non-coding mutation a548383t, which expands a di-nucleotide repeat in the first intron of pfpppk-dhps. The first intron and second exon of the pfdhps gene were analysed by target amplicon sequencing of 929 P. falciparum-positive blood samples from Nigeria, Cameroon, Tanzania, The Democratic Republic of Congo, and Côte d'Ivoire. The intron mutation was found in Nigeria, Côte d'Ivoire, and Cameroon in association with the 431V mutation. In particular, the intron mutation was most highly associated with the VAGKGS haplotype (OR = 211.7, P < 0.001), followed by the VAGKAS (OR = 39.2, P < 0.001), and VAGKAA (OR = 33.6, P < 0.001) haplotypes. Additionally, a reduced di-nucleotide repeat diversity was observed in 431V-positive variants. The intron variant is significantly associated with the 431V mutation which is consistent with previous reports of selective sweeps around VAGKGS. The association of the 548383t mutation with both VAGKGS, VAGKAS and VAGKAA might indicate these lineages either have a common ancestor or that the intron variant 548383t has a functional association with 431V. More research is needed to determine if the association is simply genetic hitchhiking, or if the intron variant confers a phenotypic advantage.

International Journal for Parasitology Drugs and Drug ResistanceVol. 29
University of Copenhagen (DK), Université de Yaoundé I (CM), University of Lubumbashi (CD), Université de Dschang (CM), Kinshasa General Hospital (CD), Copenhagen University Hospital (DK), University of Kinshasa (CD), London School of Hygiene & Tropical Medicine (GB), National Institute of Biomedical Research (CD), Kilimanjaro Christian Medical Centre (TZ), Institut Pasteur de Côte d'Ivoire (CI), Ministry of Health (BB), Centre Hospitalier Universitaire de Cocody (CI), London Centre for Neglected Tropical Disease Research (GB), National Institute for Medical Research (TZ), Obafemi Awolowo University (NG)
Wellcome Trust, Danida Fellowship Centre, Udenrigsministeriet, European and Developing Countries Clinical Trials Partnership
Openalex Percentile: Top 70%
Malaria Research and Control
DOIOpen Access PDFOpenAlex
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