Characterization of an adrenocorticotropin (ACTH) receptor promoter polymorphism leading to decreased adrenal responsiveness to ACTH.
The ACTH receptor has a pivotal role in the regulation of adrenal cortisol secretion. Here, we describe a polymorphism within the transcription initiation site of the ACTH receptor promoter altering the consensus sequence from CTC to CCC. The prevalence of the polymorphism in 1266 unrelated healthy men was 80.2% for CTC/CTC, 19.0% for CTC/CCC, and 0.8% for CCC/CCC, respectively. In vitro studies using luciferase assays demonstrated a lower basal (CCC, 73 +/- 4%; CTC, 100 +/- 5%; P = 0.02) and forskolin-stimulated (CCC, 143 +/- 13%; CTC, 194 +/- 15%; P = 0.0008) promoter activity in the CCC construct compared with CTC. The clinical significance of the in vitro findings was investigated by a 6-h ACTH stimulation test with increasing ACTH(1-24) doses in normal subjects, demonstrating a blunted cortisol response in CCC/CCC subjects compared with CTC/CTC individuals (area under the curve, 12176 +/- 966; 16334 +/- 1051 nmol/liter.min; P < 0.03). Accordingly, after CRH stimulation, subjects with CCC/CCC showed a higher ACTH/cortisol ratio (P < 0.05) suggesting a decreased adrenal responsiveness to endogenous ACTH. In conclusion, we describe an ACTH receptor promoter polymorphism that results in a lower promoter activity in vitro and is associated with a lower cortisol secretion to prolonged ACTH stimulation in vivo. This polymorphism might influence cortisol homeostasis under stress conditions.
Slawik
Marc
M
Medizinische Klinik Innenstedt, Ludwig-Maximilians-Universitaet Muenchen, Ziemsenstrasse 1, D-80336 Munich, Germany.
Reisch
Nicole
N
Zwermann
Oliver
O
Maser-Gluth
Christiane
C
Stahl
Maik
M
Klink
Albrecht
A
Reincke
Martin
M
Beuschlein
Felix
F
D000311:Adrenal Glands / Q000502:physiology*; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D003366:Cosyntropin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005787:Gene Frequency; D005858:Germany; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism; D008297:Male; D051379:Mice; D011110:Polymorphism, Genetic / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics*; D018043:Receptors, Corticotropin / Q000235:genetics*
D005938:Glucocorticoids; D018043:Receptors, Corticotropin; D003366:Cosyntropin; D005576:Colforsin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone