Evaluation of EPAS1 variants for association with bovine congestive heart failure

Authors: Heaton, Michael - Mike; BASSETT, ADAM - University Of Nebraska; WHITMAN, KATHY - University Of Nebraska; KRAFSUR, GRETA - University Of Colorado; LEE, SANG IN - University Of Nebraska; CARLSON, JADEN - University Of Nebraska; CLARK, HALDEN - University Of Nebraska; Sadd, Helen; PELSTER, MADELINE - University Of Nebraska; BASNAYAKE, VERONICA - Geneseek Inc, A Neogen Company; GROTELUESCHEN, DALE - University Of Nebraska; VANDER LEY, BRIAN - University Of Nebraska

Submitted to: F1000Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/25/2019
Publication Date: 7/25/2019
Citation: Heaton, M.P., Bassett, A.S., Whitman, K.J., Krafsur, G.M., Lee, S., Carlson, J.M., Clark, H.J., Smith, H.R., Pelster, M.C., Basnayake, V., Grotelueschen, D.M., Vander Ley, B.L. 2019. Evaluation of EPAS1 variants for association with bovine congestive heart failure. F1000Research. 8:1189. https://doi.org/10.12688/f1000research.19951.1.
DOI: https://doi.org/10.12688/f1000research.19951.1

Interpretive Summary: Congestive heart failure in feedlot cattle has become increasingly common in the Western Great Plains of North America. This disease is a complex untreatable condition involving high blood pressure in the lungs, which leads to subsequent heart failure and death. Reports of cattle losses to this illness (sometimes referred to as “brisket disease”) have exceeded $250,000 annually in individual operations, surpassing losses from bovine respiratory disease. These are well-managed beef cattle with high genetic merit. Consequently, reducing the impact of bovine congestive heart failure is a high priority for the cattle industry. A major gene (EPAS1) had been previously reported to be associated with heart failure in beef cattle pastured in the Rocky Mountains of North America (up to 8590 ft). In the present report, we tested feedlot cattle raised and finished in the Western Great Plains (approximately 4000 ft) to determine whether the EPAS1 gene was playing a major role in causing the disease at moderate altitudes. More than 100 animals with end-stage heart failure were evaulated, together with their healthy pen mates originating from more than 30 different ranch operations. No significant genetic association of EPAS1 with heart failure was observed. This suggests that identifying genetic risk factors underlying bovine congestive heart failure may require a genome-wide search.

Technical Abstract: Background: Bovine congestive heart failure (BCHF) has become increasingly prevalent in feedlot cattle in the Western Great Plains of North America. BCHF is an untreatable complex condition involving pulmonary hypertension that culminates in right ventricular failure and death. A protein variant of hypoxia-inducible factor 2 alpha (HIF2a, encoded by the endothelial PAS domain-containing protein 1 gene, EPAS1) was previously reported to be associated with pulmonary hypertension at altitudes exceeding 2,000 m. Our aim was to evaluate EPAS1 haplotypes for association with BCHF in feedlot cattle raised at moderate altitudes (1,200 m). Methods: Paired samples of clinical cases and unaffected controls were collected at four feedlots in Nebraska and Wyoming. Each pair (n =102) was matched for source, pen, breed type, sex, arrival date, and management conditions. Cases were identified by animal caretakers, euthanized, and diagnosis was confirmed at necropsy. Cases were derived from 30 different ranch operations, with the largest source contributing 32. Animals were tested for eight EPAS1 haplotypes encoding 36 possible different diploid combinations. Results: The common, ancestral EPAS1 haplotype encoding HIF2a with alanine (A) at position 606 and glycine (G) at position 610 was equally frequent in cases and controls (0.67). The EPAS1 variant haplotype reported to be associated with disease (encoding threonine (T) at position 606 and serine (S) at position 610) was not enriched in cases compared with controls (0.21 and 0.25, respectively). Frequencies of other EPAS1 haplotypes (e.g., encoding Q270, L362, or G671) were each less than 0.05 overall. McNemar’s test with 45 discordant pairs showed the linked T606/S610 variant was not associated with BCHF (OR = 0.73, CI95 0.38 -1.4, p-value = 0.37). Conclusions: HIF2a polypeptide variants were not significantly associated with BCHF in feedlot cattle at moderate altitudes. Thus, a wider search is needed to identify genetic risk factors underlying this disease.