John H. Newman, Timothy N. Holt, Joy D. Cogan, Bethany Womack, John A. Phillips III, Chun Li, Zachary Kendall, Kurt R. Stenmark, Milton G. Thomas, R. Dale Brown, Suzette R. Riddle, James D. West, Rizwan Hamid
Vanderbilt University School of Medicine. Colorado State University. Case Western Reserve University. University of Colorado.
United States
Nature Communications
Nat Commun 2015;
DOI: 10.1038/ncomms7863
Abstract
High-altitude pulmonary hypertension (HAPH) has heritable features and is a major cause of death in cattle in the Rocky Mountains, USA. Although multiple genes are likely involved in the genesis of HAPH, to date no major gene variant has been identified. Using whole-exome sequencing, we report the high association of an EPAS1 (HIF2α) double variant in the oxygen degradation domain of EPAS1 in Angus cattle with HAPH, mean pulmonary artery pressure >50 mm Hg in two independent herds. Expression analysis shows upregulation of 26 of 27 HIF2α target genes in EPAS1 carriers with HAPH. Of interest, this variant appears to be prevalent in lowland cattle, in which 41% of a herd of 32 are carriers, but the variant may only have a phenotype when the animal is hypoxemic at altitude. The EPAS1 variant will be a tool to determine the cells and signalling pathways leading to HAPH.
Category
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Genetic Factors Associated with Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes