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The –202 A Allele of Insulin-Like Growth Factor Binding Protein-3 (IGFBP3) Promoter Polymorphism Is Associated with Higher IGFBP-3 Serum Levels and Better Growth Response to Growth Hormone Treatment in Patients with Severe Growth Hormone Deficiency

Unidade de Endocrinologia do Desenvolvimento (E.F.C., B.B.M., I.J.P.A., A.A.L.J.), Laboratorio de Hormonios e Genetica Molecular LIM/42, Faculdade de Medicina da Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Departamento de Pediatria (S.R.A.), Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, 14049-900 Sao Paulo, Brazil; and Departamento de Pediatria (G.G.J.), Faculdade de Medicina de Campinas, 13083-100 Sao Paulo, Brazil

Address all correspondence and requests for reprints to: Alexander A. L. Jorge, Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42, Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr. Enéas de Carvalho Aguiar, no. 155, PAMB, 2 degree andar, bloco 6, São Paulo, Brazil. E-mail: alexj{at}usp.br.

Context: Genetic factors that influence the response to recombinant human GH (rhGH) therapy remain mostly unknown. To date, only the GH receptor gene has been investigated.

Objective: The aim of the study was to assess the influence of a polymorphism in the IGF-binding protein-3 (IGFBP-3) promoter region (–202 A/C) on circulating IGFBP-3 levels and growth response to rhGH therapy in children with GH deficiency (GHD).

Design and Patients: –202 A/C IGFBP3 genotyping (rs2854744) was correlated with data of 71 children with severe GHD who remained prepubertal during the first year of rhGH treatment.

Main Outcome Measures: We measured IGFBP-3 levels and first year growth velocity (GV) during rhGH treatment.

Results: Clinical and laboratory data at the start of treatment were indistinguishable among patients with different –202 A/C IGFBP3 genotypes. Despite similar rhGH doses, patients homozygous for the A allele presented higher IGFBP-3 SD score levels and higher mean GV in the first year of rhGH treatment than patients with AC or CC genotypes (first year GV, AA = 13.0 ± 2.1 cm/yr, AC = 11.4 ± 2.5 cm/yr, and CC = 10.8 ± 1.9 cm/yr; P = 0.016). Multiple linear regression analyses demonstrated that the influence of –202 A/C IGFBP3 genotype on IGFBP-3 levels and GV during the first year of rhGH treatment was independent of other variables.

Conclusion: The –202 A allele of IGFBP3 promoter region is associated with increased IGFBP-3 levels and GV during rhGH treatment in prepubertal GHD children.