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

Autor(es)

Costalonga, E. F. ^[1] ; Antonini, S. R. R. ^[2] ; Guerra-Junior, G. ^[3] ; Coletta, R. R. D. ^[1] ; Franca, M. M. ^[1] ; Braz, A. F. ^[1] ; Mendonca, B. B. ^[1] ; Arnhold, I. J. P. ^[1] ; Jorge, A. A. L. ^{[1, 4]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Med, Disciplina Endocrinol, Hosp Clin, Unidade Endocrinol Desenvolvimento, Lab Hormonios, BR-01246903 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Pediat, BR-01246903 Sao Paulo - Brazil

^[3] Univ Estadual Campinas, Fac Med, Dept Pediat, Sao Paulo - Brazil

^[4] Univ Sao Paulo FMUSP, Fac Med, Disciplina Endocrinol, Unidade Endocrinol Genet LIM Hosp Clin 25, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PHARMACOGENOMICS JOURNAL; v. 12, n. 5, p. 439-445, OCT 2012.
• Citações Web of Science: 12

Resumo

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. The Pharmacogenomics Journal (2012) 12, 439-445; doi:10.1038/tpj.2011.13; published online 5 April 2011 (AU)

• Processo FAPESP: 05/04726-0 - Caracterização molecular das doenças endócrinas congênitas que afetam o crescimento e o desenvolvimento
• Beneficiário: Ana Claudia Latronico Xavier
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 06/55763-5 - Farmacogenômica do tratamento com hormônio de crescimento (GH) recombinante humano em crianças com deficiência GH
• Beneficiário: Everlayny Fiorot Costalonga
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto