The Role of Glucocorticoid Receptor SNPs in Receptor Function and Metabolic Disease
Condition: Glucose Homeostasis; Protein Metabolism; Lipid Metabolism; Respiratory Function; Connective Tissue Metabolism
MeSH terms: Metabolic Diseases
Study type: Observational

Summary: 
      Background:

      - Glucocorticoids are primary stress response hormones released from the adrenal gland when
      an individual is under stress. Chronic or ongoing elevation of these hormones due to
      prolonged stress or medical treatments can have numerous harmful effects. Researchers are
      interested in learning more about how these hormones affect cell growth, development, and
      death. To study glucocorticoid hormones, researchers plan to use the medication
      dexamethasone, which affects the parts of cells that respond to glucocorticoid hormones.

      Objectives:

      - To study glucocorticoid stress hormones in healthy individuals before and after receiving
      dexamethasone.

      Eligibility:

        -  Healthy individuals at least 18 years of age.

        -  Participants must not be using certain medications that may affect the dexamethasone
           test, including hormonal contraception, steroid-based drugs, and some antidepressants.

      Design:

        -  This study will require an initial screening visit and a second study visit. The visits
           are estimated to require about 1 to 2 hours of participation over a period of up to 14
           days.

        -  Participants will be screened at visit 1 with a full physical examination and medical
           history, and an initial blood sample for testing.

        -  For visit 2, participants will be asked to abstain from all food and drinks except for
           water for 12 hours before the appointment, and will take one tablet of dexamethasone 9
           hours before the appointment.

        -  Participants will have a second blood sample taken during visit 2, and will receive a
           snack after the blood is drawn.
    

Detailed description: 
      STUDY DESIGN:

      This in vivo and in vitro observational gene association study will investigate the
      functional relevance of SNPs in the NR3C1 gene in selected populations. A subgroup of the EPR
      will be genotyped to identify novel SNPs in the NR3C1 gene. The most promising SNPs for
      functional relevance in in vitro assays will be examined. Individuals with and without
      functionally relevant, novel SNPs will be recruited for further study. In part 1, lymphocytes
      from these participants will be isolated, exposed ex vivo to corticosteroids, and gene
      expression profiles in response to this stimulus will be compared. In part 2, in vivo effect
      of these SNPs in steroid responsiveness will be evaluated by performing a modified low dose
      dexamethasone suppression test comparing by genotype. The study design is innovative as a
      gene association study in the sense that participants are recruited on the basis of genotype
      and then the phenotype of each participant is observed.

      STUDY DURATION:

      It is anticipated that the study will require 48 months to complete participants study
      visits.

      PRIMARY OBJECTIVE:

      Investigate in vivo the role of hGR SNPs (hGR9beta A3669B, hGR N363S) in steroid
      responsiveness by performing a modified dexamethasone suppression test and comparing
      responses by genotype.

      SECONDARY OBJECTIVE:

      Investigate the role of hGR SNPs (hGR9beta A3669B, hGR N363S) in human steroid responsiveness
      by comparing (across genotypes) gene expression profiles of isolated macrophages and
      lymphocytes exposed ex vivo to corticosteroids.

      PRIMARY ENDPOINT:

      Measure the change in serum cortisol levels after modified dexamethasone suppression test.

      SECONDARY ENDPOINT:

      Measure gene expression fold changes by microarray analysis after ex vivo glucocorticoid
      exposure of macrophages and lymphocytes; validation of affected RNA (elevated or decreased
      expression) through PCR analysis.
    

Observational model: Cohort
Time perspective: Prospective
Keywords: Genetic Polymorphism; Glucocorticoid; Health Volunteer; HV