Exp Clin Endocrinol Diabetes 2007; 115 - P01_079
DOI: 10.1055/s-2007-972335

The exon 3-deleted/full-length (d3/fl) growth hormone (GH) receptor polymorphism determines GH dose in GH-deficient adults

S Meyer 1, C Brück 1, D Ivan 1, U Köhler 1, P Arp 2, AJ van der Lely 2, AG Uitterlinden 2 PH Kann 1, on behalf of the German KIMS Board and the German KIMS Pharmacogenetics Study Group
  • 1University Hospital Gießen and Marburg GmbH, Philipps-University Marburg, Division of Endocrinology & Diabetology, Marburg, Germany
  • 2Erasmus University Medical School, Department of Internal Medicine, Rotterdam, Netherlands

Objectives: The exon 3-deleted/full-length growth hormone receptor (d3/fl GHR; 5p13–12) polymorphism has recently been associated with responsiveness to growth hormone (GH) therapy in idiopathic-short-stature-, small-for-gestational-age-, Turner- and GH-deficient children. The GHRd3-allele was accompanied by an increased responsiveness to GH.

Aim of this study was to test this association in a group of GH-deficient adult patients receiving recombinant GH-treatment.

Methods: The d3/fl GHR polymorphism was determined in 133 German adult patients (66 men, 67 women; mean age 45.4 years±13.1 SD; majority Caucasian) with GH-deficiency of different origin, derived from the prospective KIMS Pharmacogenetics Study. Patients received GH-treatment for 12 months with finished dose-titration of GH and standardized IGF-1 measurements. GH dose after one year of treatment, IGF- and IGF-SDS values and anthropometric data were analyzed by d3/fl GHR genotypes.

Results: The d3/fl GHR genotype distribution (59.4% fl/fl; 36.8% fl/d3; 3.8% d3/3) followed Hardy-Weinberg-equilibrium (p=0.44) and d3-allele frequency was 22%.

After one year of GH-treatment, the required GH dose was significantly lower in GH-deficient patients carrying one (d3/fl) or two d3-alleles (d3/d3), compared to patients with the full-length receptor (fl/fl) (p=0.04). Genotype groups showed no significant differences in IGF-1 serum concentrations (p=0.78), IGF-1 SDS values (p=0.39) nor in gender (p=0.53), age (p=0.28), weight (p=0.08), height (p=0.68) or BMI (p=0.13).

Conclusion: As the GHRd3-allele-carrying patients required less exogenous GH compared to the fl/fl-carrying patients to reach reference-based IGF-1 serum concentrations, our data support the theory, that there is an increased responsiveness to exogenous GH in association with the GHRd3-allele. Variability of the required amounts of exogenous GH in adult GH-deficient patients may therefore partly be explained by the d3/fl GHR polymorphism.