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

04.20.2015

Source: Pulmonary Hypertension News

In a new study entitled “Increased prevalence of EPAS1 variant in cattle with high-altitude pulmonary hypertension,” researchers discovered two genetic variants responsible forBrisket disease in cattle which may provide clues to human conditions associated with pulmonary hypertension. The study was published in the journal Nature Communications.

organic-dairy-cows.jpgHigh-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 known as Brisket disease. As this type of cattle lives in high altitudes, their lungs often experience low oxygen, leading to constriction in lungs’ blood vessels. Over time in hypoxia conditions, lungs develop pulmonary hypertension as a consequence of increased blood pressure due to prolonged vasoconstriction. As the pressure builds, the heart right chamber has to make an extra effort to pump blood to the lungs, resulting in heart 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 an expert team in Brisket disease at Colorado State University, researchers performed whole-exome sequencing (a technique employed to determine the variations of all within coding regions, the exome, within the genome) in blood samples from cattle herds with pulmonary hypertension. The authors discovered animals with HAPH carried a double mutation in the hypoxia inducible factor geneHIF2α, which resulted in increased expression of HIF2α target genes.

Notably, the team discovered that the genetic variant they identified was actually prevalent in lowland cattle. At low altitude, HIF2α has no effect since it is constantly degraded. However, when inserted in an hypoxic environment, such as those in high altitudes, the HIF2α mutated protein is functional. The variable is a gain of function mutation that only induces pulmonary hypertension in the hypoxic state of high altitudes.

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

John H. Newman, M.D., the Elsa S. Hanigan Professor of Pulmonary Medicine at Vanderbilt University Medical Centercommented in a press release, “A genetic variant in cattle might tell us why some humans get into trouble at sea level and at altitude.”

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