Association of the exon 3 deleted/full-length GHR polymorphism with recombinant growth hormone dose in growth hormone-deficient adults.
OBJECTIVE
Contradictory reports exist regarding the influence of the exon 3 deleted (d3)/full-length (fl) growth hormone receptor (GHR) polymorphism on responsiveness to recombinant human growth-hormone therapy in idiopathic short stature, small for gestational age and GH-deficient children, Turner syndrome patients and GH-deficient adults. In some of these studies, the d3 allele was associated with increased responsiveness to GH. The aim of this study was to test this association in a group of GH-deficient adult patients receiving recombinant GH treatment.


METHODS
Patients were derived from the prospective German Pfizer International Metabolic Study (KIMS) Pharmacogenetics Study. The GHRd3/fl polymorphism was determined in 133 German adult patients (66 men and 67 women; mean age: 45.4 years +/- 13.1 standard deviation; majority Caucasian) with a GH-deficiency of different origin. Patients received GH treatment for 12 months with a finished dose-titration of GH and standardized insulin-like growth factor (IGF)-1 measurements in one central laboratory. GH dose after 1 year of treatment, IGF-1 serum concentrations, IGF-1 standard deviation score (SDS) values and anthropometric data were analyzed by GHRd3/fl genotypes.


RESULTS
After 1 year of GH treatment, the individually required GH dose was significantly lower in GH-deficient patients carrying one or two d3 alleles, compared with patients with the full-length receptor (p = 0.04). Genotype groups (d3-allele carriers vs noncarriers) showed no significant differences in IGF-1 serum concentrations (p = 0.51), IGF-1 SDS (p = 0.36) nor in gender (p = 0.53), age (p = 0.28), weight (p = 0.13), height (p = 0.53) or BMI (p = 0.15).


CONCLUSIONS
The d3-allele carriers required approximately 25% less exogenous GH compared with the homozygous fl-allele carriers, which may express an increased responsiveness to exogenous GH. Variability of the individually required GH dose in adult GH-deficient patients may therefore be partly due to the GHRd3/fl polymorphism. Further studies are required to confirm these results.
Division of Endocrinology & Diabetology, University Hospital Giessen and Marburg GmbH, Philipps-University Marburg, Baldingerstrasse, 35033 Marburg, Germany. meyersi@med.uni-marburg.de
Silke
S
Meyer
Stephan
S
Schaefer
Lisette
L
Stolk
Pascal
P
Arp
André G
AG
Uitterlinden
Ursula
U
Plöckinger
Günter K
GK
Stalla
Ulrich
U
Tuschy
Matthias M
MM
Weber
Alexander
A
Weise
Andreas
A
Pfützner
Peter H
PH
Kann
D000328:Adult; D000483:Alleles; D005091:Exons / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D019382:Human Growth Hormone / Q000172:deficiency / Q000235:genetics* / Q000627:therapeutic use*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D010597:Pharmacogenetics / Q000379:methods; D011110:Polymorphism, Genetic / Q000235:genetics*; D011446:Prospective Studies; D011986:Receptors, Somatotropin / Q000235:genetics*; D011994:Recombinant Proteins / Q000627:therapeutic use; D017384:Sequence Deletion; D013997:Time Factors
D011986:Receptors, Somatotropin; D011994:Recombinant Proteins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I