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New research presented at the 59th Annual European Society for Paediatric Endocrinology Meeting looked at the link between an increased risk of heart disease and stress hormone sensitivity. The study has been published in the Journal of Hormone Research in Paediatrics.

“In clinical practice, healthy subjects are characterized by differences in glucocorticoid sensitivity that may influence the therapeutic outcome and any adverse effects of synthetic glucocorticoids,” study author Nicolas C. Nicolaides told us. “Thus, it would be very helpful for clinicians to have a fast and accurate methodology that would enable the classification of individuals based on their tissue sensitivity to glucocorticoids. In this study, we used proteomics to identify a panel of proteins that could distinguish glucocorticoid-resistant from glucocorticoid-sensitive healthy subjects, who do not harbor any genetic defects in the human glucocorticoid receptor (NR3C1) gene.” 

The aim of the study was to identify a group of proteins that could distinguish glucocorticoid-resistant from glucocorticoid-sensitive healthy subjects, who do not carry any genetic defects, such as polymorphisms or mutations, in the human glucocorticoid receptor (NR3C1) gene.

This study is the third part of a large project. Researchers have recently published their findings on transcriptomics and metabolomics analyses in healthy subjects with differences in tissue sensitivity to glucocorticoids, which have also been presented in previous ESPE Annual Meetings.

“Applying a published methodology designed for the study of glucocorticoid sensitivity in healthy adults, 101 healthy subjects were given a very low dose (0.25mg) of dexamethasone at midnight, and were polarized into the 10% most sensitive (S) and 10% most resistant (R) according to the 08:00h serum cortisol concentrations determined the following morning,” Nicolaides told us. “One month later, ten percent of the cohort, i.e., 11 participants on each side of the ranking, with no NR3C1 mutations or polymorphisms, were selected as the most glucocorticoid-sensitive and most glucocorticoid-resistant, respectively. Selected subjects were analyzed and compared with proteomics using Liquid Chromatography - Mass Spectrometry (LC-MS/MS).” 

Researchers detected 110 up-regulated and 66 down-regulated proteins in the S compared to the R group. Interestingly, the majority of the up-regulated proteins were found to play an important role in how erythrocytes exchange oxygen and carbon dioxide, as well as in the normal function and activity of platelets, which contribute substantially to the coagulation. To predict the response to cortisol prior to administration, further analysis demonstrated a panel of proteins that could be used to distinguish S from R subjects. Among the proteins identified, apolipoprotein A4 (APOA4) and gelsolin (GSN) were the most important ones in the classification, a finding that needs further investigation to determine their prognostic capacity. These results prove for the first time that the most glucocorticoid sensitive (S) subjects have a proteomic profile indicative of erythrocyte gas exchange and platelet activation. 

“It was really surprising to find proteins involved in erythrocyte gas exchange and platelet activation in the most glucocorticoid sensitive subjects, because they were healthy participants without any known stress-related health problems,” Nicolaides told us. “It seems that this group of participants is more capable to cope with any stressors. On the other hand, if these subjects face chronic stress, they have higher risk of infarctions due to increased platelet activation.”

Nicolaides told us that he speculates that if the most glucocorticoid sensitive subjects are exposed to excessive or prolonged stress, the extreme platelet activation could predispose to clot formation in the heart and brain, leading to infarctions. 

“Stress management methods might be useful even in healthy individuals to prevent the development of stress-related diseases,” Nicolaides told us. “Our next step is to undertake larger studies in order to elucidate further the role of omics’ analysis in determining tissue sensitivity to glucocorticoids in healthy subjects.”