Growth hormone (GH) pharmacogenetics: influence of GH receptor exon 3 retention or deletion on first-year growth response and final height in patients with severe GH deficiency

Abstract

Context: A polymorphism in GHR gene, the presence or absence of exon 3, has been shown to influence the 1- and 2-yr growth responses to human recombinant GH (hGH) therapy in children without GH deficiency (GHD).

Objective: The objective of this study was to assess the influence of GHR-exon-3 genotype on the short and long-term response to hGH therapy in children with GHD.

Setting: The study was conducted in the university hospital.

Design and patients: Genotype and retrospective analysis was performed on data of 75 children with GHD.

Intervention: INTERVENTION consisted of hGH treatment at a mean dose of 33 mug/kg.d and GHR-exon-3 genotype by multiplex PCR.

Main outcome measures: The main outcome measures were GHR genotype: full-length (fl) and exon 3-deleted (d3) alleles, growth velocity in 58 children who remained prepubertal during the first year, and adult height in 44 patients with GHD after 7.5 +/- 3.0 yr of treatment.

Results: Clinical and laboratory data at the start of treatment and hGH doses were indistinguishable among patients with different GHR-exon-3 genotypes (fl/fl vs. fl/d3 or d3/d3). Patients carrying at least one GHRd3 allele had a significantly better growth velocity in the first year of hGH replacement (12.3 +/- 2.6 vs. 10.6 +/- 2.3 cm/yr; P < 0.05) and achieved a taller adult height (final height sd score, -0.8 +/- 1.1 vs. -1.7 +/- 1.2; P < 0.05) when compared with patients homozygous for GHRfl alleles.

Conclusions: Patients with GHD who are homozygous for GHR exon 3 fl were less responsive to short- and long-term hGH therapy. Approximately half of the population is homozygous for GHRfl, and future studies adjusting hGH therapy to genotype may improve outcome.