Single nucleotide polymorphisms and subcellular localization of glucocorticoid receptor‐associated signaling proteins associated with cortisol‐mediated stress response

Abstract

The goal of our study was to identify correlations between interpersonal genetic variability in healthy volunteers and alterations in the glucocorticoid receptor‐associated signaling pathway. Salivary cortisol (CORT) concentrations were measured in healthy volunteers (n=66) before and after CORT stimulation in order to determine variability in circulating CORT levels and CORT response. Statistical analysis revealed inter‐participant CORT variability in concentration or percent change were not exclusively correlated to participant demographics, health history, or glucocorticoid receptor (GR) single nucleotide polymorphisms (SNPs). Interestingly, nuclear localization of the GR‐associated molecular chaperone protein hsp90 correlated with an elevated pre‐stimulus CORT concentration. To investigate the observed CORT response‐hsp90 localization association further, coding and proximal coding regions of the constitutively expressed hsp90 gene (HSP90AA) were sequenced to identify a possible genetic linkage. Eight hsp90 SNPs were identified, four of which were not reported in the NCBI database. All participants expressed at least two of the hsp90 SNPs, with some participants exhibiting as many as five. These data demonstrate inter‐person differences in CORT response, nuclear hsp90 concentrations, and GR‐associated SNPs are readily detected and potentially interrelated.