Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 9, Pages -Publisher
MDPI
DOI: 10.3390/ijms23094849
Keywords
regulatory element; enhancer; promoter; SNP; functional genomics; gene reporter; CRISPR-cas9; calcium; malaria
Funding
- African Higher Education Centers of Excellence project (CEA-SAMEF) at UCAD
- French ministry of research
- Higher Education Commission (HEC) from Pakistan
- Pasteur Institute in Dakar
- Pasteur Institute in Paris
- French embassy in Senega
- INSERM
- Aix-Marseille University
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This study systematically investigated the regulatory effect of genetic variants associated with severe malaria and identified a regulatory region that affects the risk of severe malaria. The study also demonstrated the functional activity of the identified genetic variants.
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 ATP2B4 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 ATP2B4 transcript and protein levels and increased Ca2+ intracellular concentration in the K562 cell line. Our data demonstrate that severe malaria-associated genetic variants alter the expression of ATP2B4 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.
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