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An erythroid-specific ATP2B4 enhancer mediates red blood cell hydration and malaria susceptibility
Samuel Lessard, … , Daniel E. Bauer, Guillaume Lettre
Samuel Lessard, … , Daniel E. Bauer, Guillaume Lettre
Published July 17, 2017
Citation Information: J Clin Invest. 2017;127(8):3065-3074. https://doi.org/10.1172/JCI94378.
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Research Article Genetics Hematology Article has an altmetric score of 9

An erythroid-specific ATP2B4 enhancer mediates red blood cell hydration and malaria susceptibility

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Abstract

The 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.

Authors

Samuel Lessard, Emily Stern Gatof, Mélissa Beaudoin, Patrick G. Schupp, Falak Sher, Adnan Ali, Sukhpal Prehar, Ryo Kurita, Yukio Nakamura, Esther Baena, Jonathan Ledoux, Delvac Oceandy, Daniel E. Bauer, Guillaume Lettre

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Figure 2

ATP2B4 eQTLs overlap an erythroid-specific regulatory region and are associated with rbc traits.

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ATP2B4 eQTLs overlap an erythroid-specific regulatory region and are as...
(A) Association of the rs10751452 C allele with decreased ATP2B4 expression in human erythroblasts (n = 24, P = 5.3 × 106). LD between rs10751452 and the ATP2B4 sentinel GWAS SNP, rs7551442, is r2 = 1.0. Normalized expression corresponds to residuals of log10(FPKM) after correcting for cell developmental stage in a linear regression model. Box plots represent the median (central line), the first and third quartiles (hinges), and the lowest and highest values inside 1.5 times the interquartile range from the hinges (whiskers). (B) Knockout of Atp2b4 in mice induces a dose-dependent increase in MCHC (n = 26, P = 0.0027). (C) ATP2B4 eQTLs overlap erythroid enhancers and cluster around an erythroid-specific DHS bound by GATA1 and TAL1. This site is not present in undifferentiated CD34+ HSPCs. Several GATA1-binding motifs are clustered inside this regulatory region. eQTLs for ATP2B4 are associated with MCHC and RDW in the UKBB. (D) Zoom-in of the erythroid-specific regulatory region (left DHS peak) in intron 1 of ATP2B4. We note the near-perfect concordance between the UKBB association results and the eQTL results in erythroblasts as well as the overlap of these SNPs with an erythroid-specific enhancer and GATA1/TAL1 sites. All statistical tests were performed using linear regression.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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