Identification of ATP2B4 Regulatory Element Containing Functional Genetic Variants Associated with Severe Malaria

Genome-wide association studies for severe malaria (SM) have identified 30 genetic variants mostly located in non-coding regions. Here, we aimed to identify potential causal genetic variants located in these loci and demonstrate their functional activity. We systematically investigated the regulator...

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Bibliographic Details
Published in:International journal of molecular sciences 2022-05, Vol.23 (9), p.4849
Main Authors: Nisar, Samia, Torres, Magali, Thiam, Alassane, Pouvelle, Bruno, Rosier, Florian, Gallardo, Frederic, Ka, Oumar, Mbengue, Babacar, Diallo, Rokhaya Ndiaye, Brosseau, Laura, Spicuglia, Salvatore, Dieye, Alioune, Marquet, Sandrine, Rihet, Pascal
Format: Article
Language:English
Subjects:
Annotations
Biochemistry, Molecular Biology
Calcium (intracellular)
Calcium ions
Chromosomes
CRISPR
enhancer
Equilibrium
Erythrocytes
functional genomics
gene reporter
Genetic diversity
Genetic Predisposition to Disease
Genome-wide association studies
Genome-Wide Association Study
Genomes
Genotype & phenotype
Human health and pathology
Humans
Life Sciences
Linkage disequilibrium
Malaria
Malaria - genetics
Plasma Membrane Calcium-Transporting ATPases - genetics
Polymorphism, Single Nucleotide
Population
promoter
regulatory element
Regulatory Sequences, Nucleic Acid
Single-nucleotide polymorphism
SNP
Transcription factors
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Summary:Genome-wide association studies for severe malaria (SM) have identified 30 genetic variants mostly located in non-coding regions. Here, we aimed to identify potential causal genetic variants located in these loci and demonstrate their functional activity. We systematically investigated the regulatory effect of the SNPs in linkage disequilibrium (LD) with the malaria-associated genetic variants. Annotating and prioritizing genetic variants led to the identification of a regulatory region containing five SNPs in LD with rs10900585. We found significant associations between SM and rs10900585 and our candidate SNPs (rs11240734, rs1541252, rs1541253, rs1541254, and rs1541255) in a Senegalese population. Then, we demonstrated that both individual SNPs and the combination of SNPs had regulatory effects. Moreover, CRISPR/Cas9-mediated deletion of this region decreased transcript and protein levels and increased Ca intracellular concentration in the K562 cell line. Our data demonstrate that severe malaria-associated genetic variants alter the expression of encoding a plasma membrane calcium-transporting ATPase 4 (PMCA4) expressed on red blood cells. Altering the activity of this regulatory element affects the risk of SM, likely through calcium concentration effect on parasitaemia.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms23094849