Intrinsic Response to Hypoxic Stress Associated with Cellular Metabolism and Inflammation in Beef Cattle

Congestive heart failure secondary to pulmonary hypertension (PH) is a leading cause of calf mortality at altitudes > 2100 m and is becoming increasingly problematic in cattle. Cattle with mean pulmonary arterial pressure (PAP) > 50 mmHg are considered to be at risk of heart failure. Because PAP is expensive to measure and moderately heritable, it is an ideal trait for genomic and (or) marker-assisted selection. The objective of this study was to identify functional gene categories underlying QTL associated with yearling PAP. Angus cattle (n = 1,690) phenotyped for yearling PAP score were genotyped using the Illumina BovineSNP50 Beadchip. Associated SNP were identified using a multi-locus mixed model genome-wide association approach. Genes within 2.5 kb of associated SNP were identified using the UCSC Bos taurus UMD 3.1 assembly. Functional cluster analyses were conducted using DAVID. Associated SNP with PH for heifers (41 loci), males (bulls and steers; 30 loci), and combined data (males and females; 47 loci) reached nominal significance (P < 0.001). No concordant SNP were detected between sexes suggesting a sex-linked relationship with PH. The majority of associated SNP resided on chromosomes 1, 4, 7 and 16 among the various sex categories. Prominent candidate genes ARRDC3, TBC1D14, ITPR1 and GSTA1 were identified among females, and males and compiled sex groups. Genes underlying associated SNP-QTL for all analyses clustered into functional categories that included ion binding, glycosylation and cytokine activity, which support hypotheses that hypoxia-induced PH in cattle is a consequence of altered cellular metabolism and inflammation pathways.