title: Growth hormone pharmacogenetics: the interactive effect of a microsatellite in the IGF1 promoter region with the GHR-exon 3 and -202 A/C IGFBP3 variants on treatment outcomes of children with severe GH deficiency.
abstract: Insulin-like growth factor type 1 (IGF1) is a mediator of growth hormone (GH) action, and therefore, IGF1 is a candidate gene for recombinant human GH (rhGH) pharmacogenetics. Lower serum IGF1 levels were found in adults homozygous for 19 cytosine-adenosine (CA) repeats in the IGF1 promoter. The aim of this study was to evaluate the influence of (CA)n IGF1 polymorphism, alone or in combination with GH receptor (GHR)-exon 3 and -202 A/C insulin-like growth factor binding protein-3 (IGFBP3) polymorphisms, on the growth response to rhGH therapy in GH-deficient (GHD) patients. Eighty-four severe GHD patients were genotyped for (CA)n IGF1, -202 A/C IGFBP3 and GHR-exon 3 polymorphisms. Multiple linear regressions were performed to estimate the effect of each genotype, after adjustment for other influential factors. We assessed the influence of genotypes on the first year growth velocity (1st y GV) (n=84) and adult height standard deviation score (SDS) adjusted for target-height SDS (AH-TH SDS) after rhGH therapy (n=37). Homozygosity for the IGF1 19CA repeat allele was negatively correlated with 1st y GV (P=0.03) and AH-TH SDS (P=0.002) in multiple linear regression analysis. In conjunction with clinical factors, IGF1 and IGFBP3 genotypes explain 29% of the 1st y GV variability, whereas IGF1 and GHR polymorphisms explain 59% of final height-target-height SDS variability. We conclude that homozygosity for IGF1 (CA)19 allele is associated with less favorable short- and long-term growth outcomes after rhGH treatment in patients with severe GHD. Furthermore, this polymorphism exhibits a non-additive interaction with -202 A/C IGFBP3 genotype on the 1st y GV and with GHR-exon 3 genotype on adult height.
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42 do Hospital das Clínicas, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil. laynyfiorot@hotmail.com
authors.forename: E F
authors.initials: EF
authors.lastname: Costalonga
authors.forename: S R R
authors.initials: SR
authors.lastname: Antonini
authors.forename: G
authors.initials: G
authors.lastname: Guerra
authors.forename: R R D
authors.initials: RR
authors.lastname: Coletta
authors.forename: M M
authors.initials: MM
authors.lastname: Franca
authors.forename: A F
authors.initials: AF
authors.lastname: Braz
authors.forename: B B
authors.initials: BB
authors.lastname: Mendonca
authors.forename: I J P
authors.initials: IJ
authors.lastname: Arnhold
authors.forename: A A L
authors.initials: AA
authors.lastname: Jorge
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D013006:Growth Hormone / Q000008:administration & dosage / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D002352:Carrier Proteins; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C051815:somatotropin-binding protein