Genetic Regulation of Biomarkers as Stress Proxies in Dairy Cows

Abstract

Stress in livestock reduces productivity and is a welfare concern. At a physiological level, stress is associated with the activation of inflammatory responses and increased levels of harmful reactive oxygen species. Biomarkers that are indicative of stress could facilitate the identification of more stress-resilient animals. We examined twenty-one metabolic, immune response, and liver function biomarkers that have been associated with stress in 416 Italian Simmental and 436 Italian Holstein cows which were genotyped for 150K SNPs. Single-SNP and haplotype-based genome-wide association studies were carried out to assess whether the variation in the levels in these biomarkers is under genetic control and to identify the genomic loci involved. Significant associations were found for the plasma levels of ceruloplasmin (Bos taurus chromosome 1-BTA1), paraoxonase (BTA4) and γ-glutamyl transferase (BTA17) in the individual breed analysis that coincided with the position of the genes coding for these proteins, suggesting that their expression is under cis-regulation. A meta-analysis of both breeds identified additional significant associations with paraoxonase on BTA 16 and 26. Finding genetic associations with variations in the levels of these biomarkers suggests that the selection for high or low levels of expression could be achieved rapidly. Whether the level of expression of the biomarkers correlates with the response to stressful situations has yet to be determined.

Keywords: biomarkers; candidate loci; cattle; genetics; stress.

Figure 1

Association signals on BTA1 for ceruloplasmin. Single SNPs with SNP names are indicated, HaploBlocks are indicated as rectangles containing the number of overlapping HaploAlleles in the significant region. SNP markers and haploblocks are indicated: Black = Italian Holstein; red = Italian Simmental. The location of the ceruloplasmin gene (CP) is indicated by the blue box.

Figure 2

Association signals on BTA4 for paraoxonase. Single SNPs with SNP names are indicated and HaploBlocks are indicated as rectangles containing the number of overlapping HaploAlleles in the significant region. SNP markers and haploblocks are indicated: Black = Italian Holstein; red = Italian Simmental. The location of the paroxonase-1 gene (PON1) is indicated in the blue box.

Figure 3

Associations on BT17 with γ-glutamyl-transferase level. Single SNPs, with SNP names, significantly associated with the GGT phenotype are indicated, and HaploBlocks are indicated as rectangles containing the number of overlapping HaploAlleles in the significant region. SNP markers and haploblocks are indicated: Black = Italian Holstein; red = Italian Simmental. The locations of the γ-glutamyl-transferase-1 and γ-glutamyl-transferase-5 genes (GGT1 and GGT5, respectively) are indicated in the blue boxes.

Figure 4

Manhattan plot of PON Genome-Wide Association Studies (GWAS) single-SNP meta-analysis. The upper horizontal dotted line is set at the nominal significant threshold values of p = 0.05 following Bonferroni correction for the number of SNP markers. The lower dotted line indicates the suggestive threshold value. The BTA4 peak corresponds to the PON1 gene. A significant peak is seen in BTA26 and a suggestive peak is seen in BTA16. An isolated significant SNP marker is seen in BTA17.