Genetic Polymorphisms as Predictive Markers of Response to Growth Hormone Therapy in Children with Growth Hormone Deficiency

Abstract

Objective Growth hormone (GH) deficiency (GHD) is commonly treated with recombinant human GH (rhGH). Individual response to rhGH therapy varies widely and there is evidence that variations in growth-related genes, e. g. the GH receptor (GHR) gene, may impact treatment response. We aimed to identify genetic polymorphisms which could serve as predictive markers of response to rhGH therapy.

Methods We conducted a genetic analysis of single nucleotide polymorphisms (SNPs) and the GHR exon 3 deletion in 101 paediatric GHD patients receiving rhGH. Patients were analysed for 13 known SNPs in 11 genes of the GH axis (SOS1, IGFR1, GAB1, LHX4, IGFBP3, GRB10, GHRHR, GHSR), growth plate (VDR, ESR1) and cell cycle (CDK4). Individual index of responsiveness (IoR) values were compared by genotype. We also analysed the potential association between the IoR and the GHR exon 3 deletion. IoRs were analysed by genotype by one-way analysis of variance and unpaired t-test.

Results Variations in two SNPs, rs2888586 (SOS1) and rs2069502 (CDK4), and the GHR exon 3 deletion were significantly associated with response to rhGH treatment.

Conclusions Genetic variations are potentially suitable as predictive markers of rhGH treatment response in GHD. Genetic analysis provides a starting point for individualised treatment of GHD.

Zusammenfassung

Zielsetzung Wachstumshormonmangel (growth hormone (GH) deficiency (GHD)) wird allgemein mit rekombinantem Wachstumshormon (recombinant human GH, rhGH) behandelt. Das individuelle Ansprechen auf die rhGH-Therapie variiert stark. Es gibt Hinweise darauf, dass Variationen in wachstumsrelevanten Genen, z. B. im Gen des GH-Rezeptors (GHR), das Therapieansprechen beeinflussen. Ziel dieser Studie war es, genetische Polymorphismen zu identifizieren, die als prädiktive Marker des Ansprechens auf eine rhGH-Therapie dienen könnten.

Methoden Es wurden 101 Kinder mit rhGH-behandeltem GH-Mangel genetisch auf das Vorliegen von Einzelnukleotid-Polymorphismen (single nucleotide polymorphisms (SNPs)) und einer Deletion im Exon 3 des GHR-Gens untersucht. Gesucht wurde nach 13 bekannten SNPs in 11 Genen der GH-Achse (SOS1, IGFR1, GAB1, LHX4, IGFBP3, GRB10, GHRHR, GHSR), der Epiphysenfuge (VDR, ESR1) und des Zellzyklus (CDK4). Die Werte für den Index der individuellen Ansprechbarkeit (individual index of responsiveness (IoR)) wurden nach Genotyp miteinander verglichen. Untersucht wurde auch eine potenzielle Assoziation zwischen IoR und GHR-Exon-3-Deletion. Die statistische IoR-Auswertung nach Genotyp erfolgte mithilfe einfaktorieller Varianzanalysen und t-Tests.

Ergebnisse Variationen in 2 SNPs, rs2888586 (SOS1) und rs2069502 (CDK4), sowie die GHR-exon-3 Deletion waren signifikant mit dem Ansprechen auf eine rhGH-Therapie assoziiert.

Schlussfolgerungen Genetische Variationen eignen sich bei GH-Mangel potenziell als prädiktive Marker des Ansprechens auf eine rhGH-Therapie. Eine genetische Analyse eignet sich als Ausgangspunkt für die individualisierte Behandlung eines GH-Mangels.

Key words

single nucleotide polymorphism - growth hormone deficiency - treatment response - genetic marker - response prediction

Schlüsselwörter

Einzelnukleotid-Polymorphismus - Wachstumshormonmangel - Therapieansprechen - genetischer Marker - Vorhersage des Therapieansprechens

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