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

Author(s)

Braz, Adriana F. ^{[1, 2]} ; Costalonga, Everlayny F. ^[2] ; Trarbach, Ericka B. ^[1] ; Scalco, Renata C. ^{[1, 2]} ; Malaquias, Alexsandra C. ^{[1, 2]} ; Guerra-Junior, Gil ^[3] ; Antonini, Sonir R. R. ^[4] ; Mendonca, Berenice B. ^[2] ; Arnhold, Ivo J. P. ^[2] ; Jorge, Alexander A. L. ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Fac Med, Lab Endocrinol Celular & Mol LIM 25, Unidade Endocrinol Genet, Disciplina Endocrinol, BR-01246903 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med, Lab Hormonios & Genet Mol LIM 42, Unidade Endocrinol Desenvolvimento, Disciplina End, BR-05403900 Sao Paulo - Brazil

^[3] Univ Estadual Campinas, Dept Pediat, BR-13083100 Campinas - Brazil

^[4] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Puericultura & Pediat, BR-14040900 Ribeirao Preto - Brazil

• Document type: Journal article
• Source: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM; v. 99, n. 9, p. E1808-E1813, SEP 2014.
• Web of Science Citations: 9

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). Design and Patients: 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). Conclusion: 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. (AU)

• FAPESP's process: 13/03236-5 - New approaches and methodologies in molecular-genetic studies of growth and pubertal development disorders
• Grantee: Alexander Augusto de Lima Jorge
• Support Opportunities: Research Projects - Thematic Grants