Into Thin Air: Genetic Factors Drive Metabolic Adaptations Linked to Acclimatization

What is it about?

The genetic factors are associated with changes in metabolism that allow red blood cells to deliver oxygen more efficiently throughout the body

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Why is it important?

At higher altitudes, oxygen is limited, making it more difficult for people to breathe. Red blood cells deliver oxygen to tissues using hemoglobin, one of the most abundant proteins in the human body. “Each blood cell has 250-270 million copies of hemoglobin,” said Angelo D’Alessandro, PhD, a professor in the Department of Biochemistry and Molecular Genetics at the University of Colorado School of Medicine (SOM). In a study recently published in the Proceedings of the National Academy of Sciences (PNAS), D’Alessandro and colleagues sought to understand the molecular changes that occur in hemoglobin and red blood cells when oxygen is limited, particularly at high altitudes. Hemoglobin breathes and “changes in structure depending on whether or not it has oxygen bound to it,” said D’Alessandro, the director of the Metabolomics Core Facility at the SOM and the University of Colorado Cancer Center. “Within the first seven days at high altitude, you have the same number of red blood cells, but they become more efficient at releasing oxygen into the tissues.” When exposed to low-oxygen environments, the human body starts producing more 2,3-bisphosphoglycerate (BPG), a molecule that promotes the release of oxygen from hemoglobin; however, it was previously unclear how the body accomplishes this. ‘Connect the dots’ In this study, the researchers performed a multi-omics analysis of blood samples from six individuals that traveled to La Rincondada, Peru, the highest permanent settlement in the world at 5,100 meters (16,404 feet). D’Alessandro and colleagues found that the subjects’ BPG levels increased after being exposed to the high-altitude, hypoxic environment. Interestingly, the BPG levels were correlated with the protein expression levels of a component of the Rhesus (Rh) blood type, specifically RHCE. To validate these results, the researchers then tested an additional 13,091 samples from blood donors enrolled in the Recipient Epidemiology and Donor Evaluation Study (REDS), a program launched in 1989 to improve the safety of blood transfusions. They analyzed red blood cell levels of BPG and linked the results to genomics data on each one of these donors. The results independently identified a (genome-wide) association between red blood cell BPG levels and blood type, specifically Rh status. The researchers hypothesized that the Rh proteins help facilitate the transfer of ammonium into the red blood cells, creating a more alkaline environment, which favors the metabolic activity of the enzyme responsible for producing BPG. According to D’Alessandro, the results were rather “intuitive,” but up until now, no other research group has been able to perform such a large, comprehensive analysis. “We, for the first time, have collected the largest dataset from a metabolic standpoint and a genomic standpoint on BPG,” he said. “We were able to connect the dots because we not only had plenty of samples to perform the analyses, but also developed innovative, ultra-high-throughput techniques that allowed us to perform these analyses that were unthinkable just five years ago.” The study was entirely data-driven, and the analysis was performed using advanced techniques, such as machine learning and artificial intelligence. Studying hypoxia is important for health and disease The new findings can be used to help better understand how blood type influences BPG synthesis and oxygen delivery under other hypoxic conditions, like playing sports or during emergency blood transfusions.

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