Glucocorticoid pharmacogenetics in Addison's disease - The role of the immunophilin FK506-binding protein (FKBP51) for glucocorticoid sensitivity

Abstract

There is great variation in the inter-individual sensitivity to glucocorticoids. The immunophilin FK506 binding protein (FKBP51) confers short-loop negative feedback inhibition of the glucocorticoid signalling pathway. FKBP51 keeps the human glucocorticoid receptor (hGR)-protein complex in a state of low hormone binding affinity, and will thus inhibit the effect of glucocorticoids. We investigated the role of FKBP51 for the variation in sensitivity to glucocorticoids in patients with primary adrenal insufficiency (Addison's disease). The specific aim of this study was to evaluate the association between the single nucleotide polymorphism (SNP) rs1360780 in the FKBP5 gene encoding FKBP51 and the individual glucocorticoid sensitivity in patients with Addison's disease. Seventeen patients with Addison's disease and 19 controls were genotyped using allelic discrimination assay. In morning blood samples, taken after 18 hours medication fast in the patients, glucocorticoid sensitivity in leukocytes was assessed in an in vitro cell proliferation assay; that is, stimulation with mitogenic lectin phytohemagglutinin (PHA), and incubation with various concentrations of dexamethasone. The FKBP5 expression and the FKBP51 protein levels in leukocytes was determined before and after intravenous infusion of 100 mg hydrocortisone to the patients; using real-time PCR and Western blot analysis respectively. The cell proliferation assay points to increased glucocorticoid sensitivity in Addison's patients associated with the rs1360780 variant T-allele (P=0.001). No such association was found for the controls. The FKBP5 expression, FKBP51 protein levels and ACTH and cortisol levels showed no genotype specific pattern in our study. Increased understanding of the inter-individual glucocorticoid sensitivity and the mechanisms behind may improve treatment with glucocorticoids and increase the knowledge about the pathogenesis of diseases related to glucocorticoid sensitivity, such as depression and metabolic syndrome. Further research is needed to establish the definitive role of FKBP51 and its isoforms, and the the association rs1360780 with glucocorticoid sensitivity.