The Role of Glucocorticoid Receptor SNPs in Receptor Function and Metabolic Disease
| Status: | Recruiting |
|---|---|
| Conditions: | Orthopedic, Endocrine, Gastrointestinal, Pulmonary |
| Therapuetic Areas: | Endocrinology, Gastroenterology, Pulmonary / Respiratory Diseases, Orthopedics / Podiatry |
| Healthy: | No |
| Age Range: | 18 - 100 |
| Updated: | 1/12/2019 |
| Start Date: | September 30, 2010 |
| Contact: | Lisa B Barber, MEd |
| Email: | lisa.barber@nih.gov |
| Phone: | (984) 287-4410 |
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.
- 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.
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.
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.
- INCLUSION CRITERIA FOR PART 1 AND 2:
- Male or female 18 years of age or older at the time of enrollment
- Must be a participant in the EPR study
- Are genotyped and determined to be heterozygote or homozygote carriers of one of the
two hGR SNPs (hGR9B A3669G and hGR N363S) or are wild type at the SNP location
- Able to understand and provide written informed consent to participate in the study
- Able to travel to the CRU
- Willing and able to fast for periods of up to 12 hours during the study
- Healthy participants as defined by the International Red Cross guidelines (Healthy
means that an individual feels well and can perform normal activities. If the
individual has a chronic condition such as diabetes or high blood pressure, healthy
also means that they are being treated and the condition is under control).
EXCLUSION CRITERIA:
Exclusion Criteria for Part 1
Participants with the following history will be excluded from part 1 of the study:
- Any glucocorticoid use within approximately 14 days of scheduled visit 1 including
oral, inhaled, nasal sprays, and cream (dermal/mucosal)
- Pregnant or currently breastfeeding
- Planning to use certain medications because they can affect test results.
- Any condition that, in the investigator's opinion, places the participant at undue
risk for complications.
Exclusion Criteria for Part 2
Participants with the following history will be excluded from part 2 of the study to avoid
confounding the dexamethasone suppression test:
- Any glucocorticoid use within approximately 14 days of scheduled visit 2 including
oral, inhaled, nasal sprays, and cream (dermal/mucosal)
- Pregnant or currently breastfeeding
- Currently enrolled in another clinical research study and/or is receiving an
investigational agent for any reason
- Does not agree to take dexamethasone at scheduled time
- Planning to use certain medications such as corticosteroids, estrogens, or
tetracyclines prior to the visit 2, because they can affect test results. If the
participant is willing to withhold these medications for 14 days, then the participant
will be allowed to participate in visit 2.
Participants with the following history will be excluded from part 2 of the study because
the dexamethasone may cause potential harm to the participant:
- High blood pressure of 160/10 mm Hg or above.
- Active coronary artery disease (angina) or moderate to severe heart failure stage New
York Heart Association III-IV
- Renal failure
- Glaucoma
- Uncontrolled psychiatric disorders such as bipolar disorder or schizoaffective
disorder
- Active systemic fungal infection
- Prior hypersensitivity reaction to Dexamethasone
- Currently receiving treatment for cancer (certain cancers, like lung cancer make
adrenocorticotropic hormone (ACTH), and all induce stress)
- Any condition that, in the investigator's opinion, places the participant at undue
risk for complications
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