Abstract
Glucocorticoids produced in the adrenal cortex under the control of the hypothalamic-pituitary axis play a vital role in the maintenance of basal and stress-related homeostasis and influence health and well-being. To identify loci affecting regulation of the hypothalamic-pituitary-adrenal (HPA) axis in the pig we performed a genome-wide association study for two parameters of acute and long-term adrenal activity: plasma cortisol level and adrenal weight. We detected a major quantitative trait locus at the position of the glucocorticoid receptor gene (NR3C1) – a key regulator of HPA axis activity. To determine the causal variant(s), we resequenced the coding region of NR3C1 and found three missense single nucleotide polymorphisms (SNPs). SNP c.1829C>T, leading to a p.Ala610Val substitution in the ligand binding domain, showed large (about 0.6× and 1.2× phenotypic standard deviations for cortisol level and adrenal weight, respectively), and highly significant (2.1E-39≤log10(1/p)≤1.7E+0) negative effects on both traits. We were able to replicate the association in three commercial pig populations with different breed origins. We analyzed effects of the p.Ala610Val substitution on glucocorticoid-induced transcriptional activity of porcine glucocorticoid receptor (GR) in vitro and determined that the substitution introduced by SNP c.1829C>T increased sensitivity of GR by about two-fold. Finally, we found that non-coding polymorphisms in linkage disequilibrium with SNP c.1829C>T have only a minor effect on the expression of NR3C1 in tissues related to the HPA axis. Our findings provide compelling evidence that SNP c.1829C>T in porcine NR3C1 is a gain-of-function mutation with a major effect on the activity of the adrenal gland. Pigs carrying this SNP could provide a new animal model to study neurobiological and physiological consequences of genetically based GR hypersensitivity and adrenal hypofunction.
Highlights
Hormones produced by the adrenal gland play a vital role in maintaining homeostasis, during stress
Among all analyzed single nucleotide polymorphisms (SNPs), ALGA0106239 and DRGA0017574 showed the highest linkage disequilibrium (LD) (r2 = 0.781) with SNP c.1829C.T. These results provide strong genetic evidence that SNP c.1829C.T is responsible for the association of NR3C1 with plasma cortisol level and adrenal weight indicated in the present study by the genome-wide association study (GWAS) and previously by the analysis of SNP c.*2122G.A [8]
We contribute to the understanding of the genetics of this axis in the pig by identifying a polymorphism in NR3C1 with a major effect on adrenal activity and by detecting several other genomic regions/ QTL affecting plasma cortisol level and adrenal weight, most of which are novel
Summary
Hormones produced by the adrenal gland (corticosteroids and catecholamines) play a vital role in maintaining homeostasis, during stress. Glucocorticoids (in the pig, cortisol) produced by adrenocortical cells of the zona fasciculata under the control of the hypothalamic-pituitary axis facilitate coping with stress and adaptation by influencing various neurobiological, metabolic, and immune processes [1]. Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis has adverse effects on health status and well-being. In different species, including the pig, glucocorticoid secretion shows large inter-individual variation that has a considerable genetic component [4,5]. Little is known about the underlying genetic variants; their identification and utilization as simple DNA markers in molecular breeding is a promising approach to improving adaptation potential, health, and welfare in pigs and in farm animals in general [6]. Implementation of traditional breeding programs for these traits, based on phenotypic data, is hampered by their difficult and expensive ascertainment [7]
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