title: Increased prevalence of EPAS1 variant in cattle with high-altitude pulmonary hypertension.
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.
authors: Department of Medicine, Division of Allergy, Pulmonary and Critical Care, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors: John H
authors: JH
authors: Newman
authors: Department of Veterinary Sciences, College of Agricultural Science, Colorado State University, Ft Collins, Colorado 80523, USA.
authors: Timothy N
authors: TN
authors: Holt
authors: Department of Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors: Joy D
authors: JD
authors: Cogan
authors: Department of Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors: Bethany
authors: B
authors: Womack
authors: Department of Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors: John A
authors: JA
authors: Phillips
authors: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors: Chun
authors: C
authors: Li
authors: Department of Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors: Zachary
authors: Z
authors: Kendall
authors: Cardiovascular Pulmonary Research Laboratory, Department of Medicine and Pediatrics, University of Colorado, Denver Colorado 80045, USA.
authors: Kurt R
authors: KR
authors: Stenmark
authors: Department of Animal Science, Colorado State University, Ft Collins, Colorado 80523, USA.
authors: Milton G
authors: MG
authors: Thomas
authors: Cardiovascular Pulmonary Research Laboratory, Department of Medicine and Pediatrics, University of Colorado, Denver Colorado 80045, USA.
authors: R Dale
authors: RD
authors: Brown
authors: Cardiovascular Pulmonary Research Laboratory, Department of Medicine and Pediatrics, University of Colorado, Denver Colorado 80045, USA.
authors: Suzette R
authors: SR
authors: Riddle
authors: Department of Medicine, Division of Allergy, Pulmonary and Critical Care, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors: James D
authors: JD
authors: West
authors: Department of Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors: Rizwan
authors: R
authors: Hamid
mesh_terms: D000483:Alleles; D000532:Altitude Sickness / Q000235:genetics / Q000662:veterinary*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002417:Cattle; D002418:Cattle Diseases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000662:veterinary*; D008297:Male; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1