Genetic polymorphisms and expression of Rhesus blood group RHCE are associated with 2,3-bisphosphoglycerate in humans at high altitude

Abstract

Red blood cell (RBC) metabolic reprogramming upon exposure to high altitude contributes to physiological human adaptations to hypoxia, a multifaceted process critical to health and disease. To delve into the molecular underpinnings of this phenomenon, first, we performed a multi-omics analysis of RBCs from six lowlanders after exposure to high-altitude hypoxia, with longitudinal sampling at baseline, upon ascent to 5,100 m and descent to sea level. Results highlighted an association between erythrocyte levels of 2,3-bisphosphoglycerate (BPG), an allosteric regulator of hemoglobin that favors oxygen off-loading in the face of hypoxia, and expression levels of the Rhesus blood group RHCE protein. We then expanded on these findings by measuring BPG in RBCs from 13,091 blood donors from the Recipient Epidemiology and Donor Evaluation Study. These data informed a genome-wide association study using BPG levels as a quantitative trait, which identified genetic polymorphisms in the region coding for the Rhesus blood group RHCE as critical determinants of BPG levels in erythrocytes from healthy human volunteers. Mechanistically, we suggest that the Rh group complex, which participates in the exchange of ammonium with the extracellular compartment, may contribute to intracellular alkalinization, thus favoring BPG mutase activity.

Keywords: hypoxia; metabolomics; red blood cell.

Fig. 1.

Multi-omics characterization of RBCs from the Expedition 5300 study (A). Time series-ANOVA and linear discriminant analyses identified top metabolites (B and C; line plot for BPG in D), and proteins (E and F) affected by ascent, acclimatization, and descent. In (G), BPG promotes oxygen off-loading by stabilizing the deoxygenated state of hemoglobin during acclimatization to high altitude. In packed RBCs from 13,091 volunteers from the REDS RBC Omics study, BPG levels are affected by donor age (H), sex (I), and ethnicity (J). mQTL analyses identified an association between BPG levels and SNPs on chromosome 1 (K), in the region coding for RHCE (locus zoom in L). In L, colors represent estimated linkage disequilibrium with the lead SNP (diamond–rs636889) based on the full (“ALL”) 1K genomes reference. Other shapes indicate: Framestop and splice (triangle), NonSynonymous (inverted triangle), and None-of-the-above (filled circle). Proposed mechanism (M).