An erythroid-specific ATP2B4 enhancer mediates red blood cell hydration and malaria susceptibility.
AffiliationMontreal Heart Institute and Universite de Montreal, Montreal, Quebec, Canada
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AbstractThe lack of mechanistic explanations for many genotype-phenotype associations identified by GWAS precludes thorough assessment of their impact on human health. Here, we conducted an expression quantitative trait locus (eQTL) mapping analysis in erythroblasts and found erythroid-specific eQTLs for ATP2B4, the main calcium ATPase of red blood cells (rbc). The same SNPs were previously associated with mean corpuscular hemoglobin concentration (MCHC) and susceptibility to severe malaria infection. We showed that Atp2b4-/- mice demonstrate increased MCHC, confirming ATP2B4 as the causal gene at this GWAS locus. Using CRISPR-Cas9, we fine mapped the genetic signal to an erythroid-specific enhancer of ATP2B4. Erythroid cells with a deletion of the ATP2B4 enhancer had abnormally high intracellular calcium levels. These results illustrate the power of combined transcriptomic, epigenomic, and genome-editing approaches in characterizing noncoding regulatory elements in phenotype-relevant cells. Our study supports ATP2B4 as a potential target for modulating rbc hydration in erythroid disorders and malaria infection.
CitationAn erythroid-specific ATP2B4 enhancer mediates red blood cell hydration and malaria susceptibility. 2017, 127 (8):3065-3074 J. Clin. Invest.
JournalThe Journal of Clinical Investigation
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- Issue date: 2017 Jun
- Decreased calcium pump expression in human erythrocytes is connected to a minor haplotype in the ATP2B4 gene.
- Authors: Zámbó B, Várady G, Padányi R, Szabó E, Németh A, Langó T, Enyedi Á, Sarkadi B
- Issue date: 2017 Jul
- An ATP2B4 polymorphism protects against malaria in pregnancy.
- Authors: Bedu-Addo G, Meese S, Mockenhaupt FP
- Issue date: 2013 May 15
- Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study.
- Authors: Ndila CM, Uyoga S, Macharia AW, Nyutu G, Peshu N, Ojal J, Shebe M, Awuondo KO, Mturi N, Tsofa B, Sepúlveda N, Clark TG, Band G, Clarke G, Rowlands K, Hubbart C, Jeffreys A, Kariuki S, Marsh K, Mackinnon M, Maitland K, Kwiatkowski DP, Rockett KA, Williams TN, MalariaGEN Consortium.
- Issue date: 2018 Aug
- Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci.
- Authors: Castaldi PJ, Cho MH, Zhou X, Qiu W, Mcgeachie M, Celli B, Bakke P, Gulsvik A, Lomas DA, Crapo JD, Beaty TH, Rennard S, Harshfield B, Lange C, Singh D, Tal-Singer R, Riley JH, Quackenbush J, Raby BA, Carey VJ, Silverman EK, Hersh CP
- Issue date: 2015 Feb 15