Genetic Polymorphisms in the Growth Hormone Receptor: Impact on Growth Response and Disease Susceptibility

Growth hormone (GH) promotes height growth by stimulating bone and cartilage cell proliferation, and influences carbohydrate and lipid metabolism through a direct stimulatory effect by GH, and an indirect effect mediated by insulin- like growth factor 1 (IGF-1). The effects of GH are mediated by the interaction between GH and the GH receptor (GHR). In response to GH, two GHR polypeptides form dimers and turn on a cascade of signal transduction leading to activation of gene transcription. The mechanisms of marked patient-to-patient variability in response to GH have remained elusive thus far. Recent pharmacogenetics studies suggest that the growth promotion by GH treatment is influenced by a variation in the human GHR gene (d3/fl-GHR) in patients who have been diagnosed to be small for gestational age, with GH-deficiency (GHD), idiopathic short stature, or Turner syndrome, although this genetic effect still remains controversial. Another report demonstrated the Leu544Ile SNP of the GHR gene to be associated with cholesterol levels during GH treatment in patients with GHD. This paper provides a critical overview and synthesis of the emerging findings on the GHR polymorphisms in relation to GH responsiveness or disease susceptibilities, and the attendant molecular aspects of the characteristic polymorphisms. The potential clinical application of GHR genetic variation is discussed for the optimization of the GH dosage in children or adults in order to enable them to reach their ideal final height as well as to prevent cardiovascular complications.