Image of the lungs to illustrate individuals with chronic obstructive pulmonary disease (COPD), which can be influenced by genetic variation in EPAS1 gene, which impacts oxygen saturation in the blood
Credit: artacet/Getty Images

Genetic variation in the EPAS1 gene that influences our ability to store oxygen in the blood may be behind differences in symptoms and outcomes in people with diseases such as chronic obstructive pulmonary disease (COPD).

Tatum Simonson, founder and co-director of the Center for Physiological Genomics of Low Oxygen at University of California San Diego School of Medicine, and colleagues have discovered variants in the EPAS1 gene in some people with Tibetan and Andean highland ancestry that influence how well a person is able to store oxygen in the blood.

The genetic variants are thought to have evolved to allow people living at high altitudes to adapt to low oxygen conditions.

“There are people with COPD who breathe a lot and maintain a higher oxygen saturation. Others with the same disease don’t breathe as much, and their oxygen saturation is low,” said Simonson in a press statement.

“Researchers suspect there may be genetic differences underlying this variation, similar to the variation we find in pathways important for oxygen sensing and responses underlying natural selection at high altitude.”

Past research has isolated physiological characteristics that are unique to Tibetan and Andean highlanders compared with lowland populations such as lower hemoglobin concentration and altered metabolic function in Tibetans and increased uterine artery diameter, birth weight, and exercise capacity in some Andean populations.

It can be tricky to prove a genetic link to these characteristics, but variation in the Endothelial PAS Domain Protein 1 (EPAS1) gene, which encodes the alpha subunit of HIF-2, is strong in high altitude communities and is thought to be due to natural selection. In Tibetan communities a variant of EPAS1 allows less oxygen to be carried in the blood without ill effects.

Previous work did not find conclusive evidence of such a variant in Andean communities, but the current study, published in Science Advances, shows that a group of highlanders living in the Andes in Peru also carry an EPAS1 variant with a similar function to that seen in Tibetan groups, albeit one that works in a different way to achieve the same objective.

“Tibetans have, in general, an average lower hemoglobin concentration, and their physiology deals with low oxygen in a way that doesn’t increase their red blood cells to excessively high levels. Now we have the first signs of evidence that Andeans are also going down that path, involving the same gene, but with a protein-coding change. Evolution has worked in these two populations, on the same gene, but in different ways,” said Simonson.

As well as shining a light on different pathways in human evolution, this research also shows the importance of sampling diverse population groups when developing precision medicine databases and carrying out clinical trials. With genomic medicine becoming significantly more mainstream, as well as increased global population movements, basing new treatments and diagnostic or prognostic tools on data from diverse databases is increasingly important.

“In precision medicine, it’s important to recognize variation in genetic backgrounds, specifically in historically understudied populations,” Simonson said.

“If we can find some shared genetic factors in populations in an extreme environment, that may help us understand aspects of health and disease in that group and groups more locally. In that way, this study aims to push research forward, and towards comprehensive personalized medicine approaches in clinics here in San Diego.”

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