High-Altitude Pulmonary Hypertension in Cattle May Unlock New Insights into Human PH

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In a study titled “Increased prevalence of EPAS1 variant in cattle with high-altitude pulmonary hypertension,” researchers discovered two genetic variants responsible for brisket disease in cattle that may provide clues to human conditions associated with pulmonary hypertension.

The study was published in the journal Nature Communications.

High-altitude pulmonary hypertension (HAPH) is the underlying cause of death of cattle in the Rocky Mountains because it leads to right heart failure, a condition brisket disease. Because the cattle live in high altitudes where low oxygen level is normal, blood vessels in their lungs are often constricted. Over time in hypoxia (oxygen deficient) conditions, lungs develop pulmonary hypertension as a consequence of increased blood pressure due to prolonged vasoconstriction. As pressure builds, the heart’s right chamber has to work harder to pump blood to the lungs, which can result in muscle failure and death.

While Brisket disease represents an enormous cost, the genetic variants responsible for bovine HAPH are currently unknown. In this new research, researchers at the Vanderbilt University Medical Center set out to identify the underlying gene(s) of brisket disease. In collaboration with experts in brisket disease at Colorado State University, researchers performed whole-exome sequencing in blood samples from cattle herds with pulmonary hypertension. The authors discovered animals with HAPH carried a double mutation in the hypoxia inducible factor gene, HIF2α, which resulted in increased expression of HIF2α target genes.

The team also discovered that the genetic variant they identified was actually prevalent in lowland cattle, but HIF2α had no effect because it is constantly degraded. However, when inserted in a low oxygen environment the HIF2α mutated protein is functional.

The team highlighted that additional studies are required to understand how the newly identified variants lead to HAPH disease and to provide clues to human diseases, such as non-familial pulmonary hypertension in patients with pulmonary fibrosis.

“A genetic variant in cattle might tell us why some humans get into trouble at sea level and at altitude,” said Dr. John H. Newman, a professor of Pulmonary Medicine at Vanderbilt University Medical Center, in a press release.

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