Genetic variations in human ATP2B4 gene alter Plasmodium falciparum in vitro growth in RBCs from Gambian adults.
Journal
Malaria journal
ISSN: 1475-2875
Titre abrégé: Malar J
Pays: England
ID NLM: 101139802
Informations de publication
Date de publication:
05 Jan 2023
05 Jan 2023
Historique:
received:
10
02
2022
accepted:
03
11
2022
entrez:
5
1
2023
pubmed:
6
1
2023
medline:
10
1
2023
Statut:
epublish
Résumé
Polymorphisms in ATP2B4 coding for PMCA4b, the primary regulator of erythrocyte calcium concentration, have been shown by GWAS and cross-sectional studies to protect against severe malaria but the mechanism remains unknown. Using a recall-by-genotype design, we investigated the impact of a common haplotype variant in ATP2B4 using in vitro assays that model erythrocyte stage malaria pathogenesis. Ninety-six donors representing homozygote (carriers of the minor allele, C/C), heterozygote (T/C) and wildtype (T/T) carriers of the tagging SNP rs1541252 were selected from a cohort of over 12,000 participants in the Keneba Biobank. Red blood cells (RBCs) from homozygotes showed reduced PMCA4b protein expression (mean fluorescence intensities (MFI = 2428 ± 124, 3544 ± 159 and 4261 ± 283], for homozygotes, heterozygotes and wildtypes respectively, p < 0.0001) and slower rates of calcium expulsion (calcium t The data support the hypothesis that this ATP2B4 genotype, common in The Gambia and other malaria-endemic areas, protects against severe malaria through the suppression of parasitaemia during an infection. Reduction in parasite density plays a pivotal role in disease outcome by minimizing all aspects of malaria pathogenesis. Follow up studies are needed to further elucidate the mechanism of protection and to determine if this ATP2B4 genotype carries a fitness cost or increases susceptibility to other human disease.
Sections du résumé
BACKGROUND
BACKGROUND
Polymorphisms in ATP2B4 coding for PMCA4b, the primary regulator of erythrocyte calcium concentration, have been shown by GWAS and cross-sectional studies to protect against severe malaria but the mechanism remains unknown.
METHODS
METHODS
Using a recall-by-genotype design, we investigated the impact of a common haplotype variant in ATP2B4 using in vitro assays that model erythrocyte stage malaria pathogenesis. Ninety-six donors representing homozygote (carriers of the minor allele, C/C), heterozygote (T/C) and wildtype (T/T) carriers of the tagging SNP rs1541252 were selected from a cohort of over 12,000 participants in the Keneba Biobank.
RESULTS
RESULTS
Red blood cells (RBCs) from homozygotes showed reduced PMCA4b protein expression (mean fluorescence intensities (MFI = 2428 ± 124, 3544 ± 159 and 4261 ± 283], for homozygotes, heterozygotes and wildtypes respectively, p < 0.0001) and slower rates of calcium expulsion (calcium t
CONCLUSION
CONCLUSIONS
The data support the hypothesis that this ATP2B4 genotype, common in The Gambia and other malaria-endemic areas, protects against severe malaria through the suppression of parasitaemia during an infection. Reduction in parasite density plays a pivotal role in disease outcome by minimizing all aspects of malaria pathogenesis. Follow up studies are needed to further elucidate the mechanism of protection and to determine if this ATP2B4 genotype carries a fitness cost or increases susceptibility to other human disease.
Identifiants
pubmed: 36604655
doi: 10.1186/s12936-022-04359-4
pii: 10.1186/s12936-022-04359-4
pmc: PMC9817369
doi:
Substances chimiques
ATP2B4 protein, human
EC 3.6.1.8
Calcium
SY7Q814VUP
Plasma Membrane Calcium-Transporting ATPases
EC 3.6.3.8
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5Subventions
Organisme : Medical Research Council
ID : MC_PC_MR/R020183/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U123292699
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00026/3
Pays : United Kingdom
Organisme : Medical Research Council
ID : MCA760-5QX00
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2023. The Author(s).
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