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Pharmacogenomics J. 2014 Feb;14(1):54-62. doi: 10.1038/tpj.2013.14. Epub 2013 Apr 9.

Pharmacogenomics of insulin-like growth factor-I generation during GH treatment in children with GH deficiency or Turner syndrome.

Author information

1
Manchester Academic Health Sciences Centre, Royal Manchester Children's Hospital, Manchester, UK.
2
Clinica Pediatrica, Università degli Studi di Verona, Verona, Italy.
3
Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
4
Paediatric Endocrine Unit, Hospital General Universitario Gregorio Marañón and Universidad Complutense, Madrid, Spain.
5
St Petersburg State Pediatric Medical Academy, Department of Endocrinology, St Petersburg, Russia.
6
Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
7
Merck Serono S.A.-Geneva, Geneva, Switzerland.
8
Merck KGaA, Darmstadt, Germany.
9
Genizon Biosciences, St Laurent, Quebec, Canada.
10
Department Pediatrie, Service d'Endocrinologie & Diabétologie Pédiatriques, Hôpital Mère-Enfant-Université Claude Bernard, Lyon, France.

Abstract

Individual responses to growth hormone (GH) treatment are variable. Short-term generation of insulin-like growth factor-I (IGF-I) is recognized as a potential marker of sensitivity to GH treatment. This prospective, phase IV study used an integrated genomic analysis to identify markers associated with 1-month change in IGF-I (ΔIGF-I) following initiation of recombinant human (r-h)GH therapy in treatment-naïve children with GH deficiency (GHD) (n=166) or Turner syndrome (TS) (n=147). In both GHD and TS, polymorphisms in the cell-cycle regulator CDK4 were associated with 1-month ΔIGF-I (P<0.05). Baseline gene expression was also correlated with 1-month ΔIGF-I in both GHD and TS (r=0.3; P<0.01). In patients with low IGF-I responses, carriage of specific CDK4 alleles was associated with MAPK and glucocorticoid receptor signaling in GHD, and with p53 and Wnt signaling pathways in TS. Understanding the relationship between genomic markers and early changes in IGF-I may allow development of strategies to rapidly individualize r-hGH dose.

PMID:
23567489
PMCID:
PMC3959225
DOI:
10.1038/tpj.2013.14
[Indexed for MEDLINE]
Free PMC Article

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