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

• 成果类型: Article
• 署名作者: D'Alessandro, Angelo; Earley, Eric J.; Nemkov, Travis; Stephenson, Daniel; Dzieciatkowska, Monika; Hansen, Kirk C.; Minetti, Giampaolo; Champigneulle, Benoit; Stauffer, Emeric; Pichon, Aurelien; Furian, Michael; Verges, Samuel; Kleinman, Steven; Norris, Philip J.; Busch, Michael P.; Page, Grier P.; Kaestner, Lars
• 署名单位: University of Colorado System; University of Colorado Anschutz Medical Campus; Research Triangle Institute; University of Pavia; Communaute Universite Grenoble Alpes; Universite Grenoble Alpes (UGA); Institut National de la Sante et de la Recherche Medicale (Inserm); Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Claude Bernard Lyon 1; Universite de Poitiers; University of Zurich; University of British Columbia; Vitalant; Vitalant Research Institute; Saarland University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14002
• DOI: 10.1073/pnas.2315930120
• 发表日期: 2024-01-02

摘要

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.