Variability in HSP90AB1 and HSP90AA1 Are Not Correlated with Phenotypic Differences in Glucocorticoid Receptor‐Mediated Response or Subcellular Hsp90 Localization

Abstract

Hsp90 is a highly conserved eukaryotic chaperone protein responsible for mediating a multitude of intracellular signaling molecules, including those associated with the glucocorticoid receptor (GR) and stress response. The goal of this study was to identify the extent to which single nucleotide polymorphisms (SNPs) in genes encoding hsp90 correlated with previously observed phenotypic variations in circulating cortisol and hsp90 subcellular localization. Salivary cortisol was measured in healthy volunteers before and after HPA stimulation via mild cardiovascular stress. Whole exome sequencing of a matched participant pair identified HSP90AB1, encoding the stress‐inducible isoform of hsp90, as a potential causal candidate gene warranting further examination. Exons of HSP90AB1 and HSP90AA1 were amplified and sequenced in 20 participants with known differences in cortisol response and hsp90 localization using PCR and the Sanger method. Out of the twenty participants, three HSP90AB1 and eight HSP90AA1 SNPs were found, all of which were registered in the NCBI SNP database. Interestingly, a discrepancy in results was observed between SNPs called by whole exome analysis and those detected by Sanger sequencing. Although no correlation was found between analyzed SNPs, cortisol response, and hsp90 localization, further work utilizing this methodology and consideration of phenotypic polygenicity will likely provide a more comprehensive understanding of hsp90‐mediated GR signaling.