title: 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: BACKGROUND
  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.
  
  
  METHODS
  The study was conducted in the university hospital.
  
  
  METHODS
  Genotype and retrospective analysis was performed on data of 75 children with GHD.
  
  
  METHODS
  INTERVENTION consisted of hGH treatment at a mean dose of 33 mug/kg.d and GHR-exon-3 genotype by multiplex PCR.
  
  
  METHODS
  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.
authors.affiliation: Hospital das Clinicas, Laboratorio de Hormonios, Avenida Dr Eneas de Carvalho Aguiar 155 PAMB, 2 andar Bloco 6, 05403-900, São Paulo, Brazil. alexj@usp.br
authors.forename: Alexander A L
authors.initials: AA
authors.lastname: Jorge
authors.forename: Frederico G
authors.initials: FG
authors.lastname: Marchisotti
authors.forename: Luciana R
authors.initials: LR
authors.lastname: Montenegro
authors.forename: Luciani R
authors.initials: LR
authors.lastname: Carvalho
authors.forename: Berenice B
authors.initials: BB
authors.lastname: Mendonca
authors.forename: Ivo J P
authors.initials: IJ
authors.lastname: Arnhold
mesh_terms: D000293:Adolescent; D001827:Body Height / Q000235:genetics*; D002648:Child; D005091:Exons; D005260:Female; D005838:Genotype; D006130:Growth Disorders / Q000188:drug therapy / Q000235:genetics*; D006720:Homozygote; D019382:Human Growth Hormone / Q000172:deficiency* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D011627:Puberty; D011986:Receptors, Somatotropin / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D011986:Receptors, Somatotropin; D019382:Human Growth Hormone