Increased prevalence of EPAS1 variant in cattle with high-altitude pulmonary hypertension - PubMed (original) (raw)

Timothy N Holt 2, Joy D Cogan 3, Bethany Womack 3, John A Phillips 3rd 3, Chun Li 4, Zachary Kendall 3, Kurt R Stenmark 5, Milton G Thomas 6, R Dale Brown 5, Suzette R Riddle 5, James D West 1, Rizwan Hamid 3

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Increased prevalence of EPAS1 variant in cattle with high-altitude pulmonary hypertension

John H Newman et al. Nat Commun. 2015.

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.

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Figures

Figure 1

Figure 1. Mean pulmonary arterial pressure in 41 Angus cattle dwelling at high altitude.

Of the 20 HAPH (high-altitude pulmonary hypertension PAP>50 mm Hg), 15 carried the EPAS1 variant and all of the cattle with the highest PAP carried the variant. Four of the 21 unaffected cattle carried the variant, and these 4 had the highest pressure, albeit normal PAP <38 mm Hg of the group.

Figure 2

Figure 2. Sequence of filtering and analysis of WES data using an autosomal dominant model.

First filter was variant found in all five HAPH and in none unaffected. Second filter was the presence in 4/5 HAPH and 1/5 affected, yielding 103 genes. Filter 3 was 4/5 HAPH and 0/5 unaffected, yielding 9 genes. Sanger sequencing reduced the number to two candidates, EPAS1 and PDPR. Taqman assay revealed no association with PDPR, but highly significant association of HAPH with EPAS1 variant.

Figure 3

Figure 3. Graphic depiction of the known EPAS1 domains.

bHLH, basic Helix–Loop–Helix; PAS, Per-Arnt-Sim domain; ODDD, oxygen-dependent degradation domain; N-TAD, N-terminal transactivation domain; C-TAD, C-terminal transactivation domain. The two variants are in the ODDD domain of the protein.

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