Impact of Single Nucleotide Polymorphisms on HPA-Axis Functionality in Depression

The hypothalamic-pituitary-adrenal (HPA) axis is responsible for regulating the secretion of the glucocorticoid hormone cortisol in response to stress. Diseases of cortisol dysregulation, such as Cushing’s syndrome (hypercortisolism) and Addison’s disease (hypocortisolism), share a common symptom of depression. Based on this we, and others, have hypothesized that single nucleotide polymorphisms (SNPs) in the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and other genes associated with cortisol regulation may contribute to depression. Our study investigated the genotypic frequency of several SNPs that affect GR and MR sensitivity to cortisol in a clinical population. DNA samples were acquired via buccal swab from patients suspected of suffering from depression. Extracted DNA was analyzed using a novel multiplex allele-specific polymerase chain reaction assay to determine the allelic frequency of SNPs associated with hypersensitivity or resistance to cortisol. Saliva samples were also collected from these patients via buccal wash and analyzed using an ELISA assay to measure cortisol levels. In addition, patients completed multiple measures of depression and anxiety. Preliminary results showed that mutant haplotypes of three specific alleles in the GR, BclI (rs41423247), N363S (rs56149945), and TthlllI (rs10052957), as well as rs120 (rs12086634) in 11𝛽-HSD, were seen more frequently in the patient population compared to the general population. Although depression (as measured by the Beck Depression Inventory) and salivary cortisol did not change significantly between clinic visits, there was a significant decrease in state anxiety (as measured by the State-Trait Anxiety Inventory) between visits for patients with the wild type or heterozygous BclI haplotype while patients with the homozygous mutant haplotype did not show a change in state anxiety.  This is the first demonstration that genotypic variation in cortisol sensitivity is associated with changes in stress anxiety. This could lead to more specific and successful treatments for depression with the goal of improving patient outcomes.