title: Genetic predictors of long-term response to growth hormone (GH) therapy in children with GH deficiency and Turner syndrome: the influence of a SOCS2 polymorphism.
abstract: BACKGROUND
  There is great interindividual variability in the response to GH therapy. Ascertaining genetic factors can improve the accuracy of growth response predictions. Suppressor of cytokine signaling (SOCS)-2 is an intracellular negative regulator of GH receptor (GHR) signaling.
  
  
  OBJECTIVE
  The objective of the study was to assess the influence of a SOCS2 polymorphism (rs3782415) and its interactive effect with GHR exon 3 and -202 A/C IGFBP3 (rs2854744) polymorphisms on adult height of patients treated with recombinant human GH (rhGH).
  
  
  METHODS
  Genotypes were correlated with adult height data of 65 Turner syndrome (TS) and 47 GH deficiency (GHD) patients treated with rhGH, by multiple linear regressions. Generalized multifactor dimensionality reduction was used to evaluate gene-gene interactions.
  
  
  RESULTS
  Baseline clinical data were indistinguishable among patients with different genotypes. Adult height SD scores of patients with at least one SOCS2 single-nucleotide polymorphism rs3782415-C were 0.7 higher than those homozygous for the T allele (P < .001). SOCS2 (P = .003), GHR-exon 3 (P= .016) and -202 A/C IGFBP3 (P = .013) polymorphisms, together with clinical factors accounted for 58% of the variability in adult height and 82% of the total height SD score gain. Patients harboring any two negative genotypes in these three different loci (homozygosity for SOCS2 T allele; the GHR exon 3 full-length allele and/or the -202C-IGFBP3 allele) were more likely to achieve an adult height at the lower quartile (odds ratio of 13.3; 95% confidence interval of 3.2-54.2, P = .0001).
  
  
  CONCLUSIONS
  The SOCS2 polymorphism (rs3782415) has an influence on the adult height of children with TS and GHD after long-term rhGH therapy. Polymorphisms located in GHR, IGFBP3, and SOCS2 loci have an influence on the growth outcomes of TS and GHD patients treated with rhGH. The use of these genetic markers could identify among rhGH-treated patients those who are genetically predisposed to have less favorable outcomes.
authors.affiliation: Unidade de Endocrinologia Genetica (A.F.B., E.B.T., R.C.S., A.C.M., A.A.L.J.), Laboratorio de Endocrinologia Celular e Molecular LIM/25, Disciplina de Endocrinologia da Faculdade de Medicina, Universidade de Sao Paulo, 01246-903 Sao Paulo, Brazil; Unidade de Endocrinologia do Desenvolvimento (A.F.B., E.F.C., R.C.S., A.C.M., B.C.M., I.J.P.A., A.A.L.J.), Laboratorio de Hormonios e Genetica Molecular LIM/42, Disciplina de Endocrinologia, Faculdade de Medicina, Universidade de Sao Paulo, 05403-900 Sao Paulo, Brazil; Departamento de Pediatria (G.G.-J.), Universidade Estadual de Campinas, 13083-100 Campinas, Brazil; and Departamento de Puericultura e Pediatria (S.R.R.A.), Faculdade de Medicina de Ribeirao Preto, Universidade de São Paulo, 14040-900 Ribeirao Preto, Brazil.
authors.forename: Adriana F
authors.initials: AF
authors.lastname: Braz
authors.forename: Everlayny F
authors.initials: EF
authors.lastname: Costalonga
authors.forename: Ericka B
authors.initials: EB
authors.lastname: Trarbach
authors.forename: Renata C
authors.initials: RC
authors.lastname: Scalco
authors.forename: Alexsandra C
authors.initials: AC
authors.lastname: Malaquias
authors.forename: Gil
authors.initials: G
authors.lastname: Guerra-Junior
authors.forename: Sonir R R
authors.initials: SR
authors.lastname: Antonini
authors.forename: Berenice B
authors.initials: BB
authors.lastname: Mendonca
authors.forename: Ivo J P
authors.initials: IJ
authors.lastname: Arnhold
authors.forename: Alexander A L
authors.initials: AA
authors.lastname: Jorge
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006130:Growth Disorders / Q000188:drug therapy* / Q000235:genetics*; D013006:Growth Hormone / Q000627:therapeutic use; D019382:Human Growth Hormone / Q000172:deficiency / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics*; D016896:Treatment Outcome; D014424:Turner Syndrome / Q000188:drug therapy* / Q000235:genetics*
chemical_list: C106643:SOCS2 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D019382:Human Growth Hormone; D013006:Growth Hormone