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

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.

Transcriptomics and machine learning predict diagnosis and severity of growth hormone deficiency

“…The PREDICT study was a phase IV, open-label, prospective pharmacogenomic study examining response to GH therapy; it enrolled 125 prepubertal children (78 male, 47 female), aged 2-15 years, with a diagnosis of GH deficiency, reached after two pharmacological stimulation tests according to local protocols, with a peak GH concentration of <10 μg/l. Details of the inclusion and exclusion criteria have previously been reported (14,35). In brief, prior to enrollment in the study, none of the children had received GH therapy; children with GHD due to central nervous system tumors or radiotherapy were excluded, but children born small for gestational age were not.…”

Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: Revision of human observations and mechanistic insight from rodents

“…Increased adiposity could also lead to increased aromatase activity and conversion of androgens to estrogens (de Ridder et al, 1992). Catch-up growth in children with low birth weight is associated with a rise in serum leptin (Jaquet et al, 1999) and IGF-1 (Stevens et al, 2014). Rodent models indicate that neonatal leptin could play a crucial role in the development of some neural connections controlling GnRH secretion (Bouret, 2004) and leptin is known to facilitate GnRH secretion peripubertally (Sanchez-Garrido and Tena-Sempere, 2013).…”

Network analysis: a new approach to study endocrine disorders

“…The possibility of stratifying patients based on genetic variation of response to GH therapy led to the development of the PREDICT study, the aim of which was to assess the genomic profiles of GHD and TS children in response to GH therapy by the analysis of both genetic and transcriptomic data , Stevens et al 2013a. Integrating gene expression and genetic data has provided mechanistic insight into growth response and helped to support the identification of genes with predictive value of growth response.…”

“…Integrating gene expression and genetic data has provided mechanistic insight into growth response and helped to support the identification of genes with predictive value of growth response. Insulin-like growth factor 1 (IGF1) production over the first month of treatment (Stevens et al 2013a) and first-year growth responses to recombinant human GH (r-hGH) therapy ) have both been studied using this approach and several growthrelated pathways involved in response to GH therapy have been identified beyond the traditional GH and IGF1 signalling pathways. These included the MAPK pathway, a pathway well known to be involved in growth (Yamauchi et al 1997, Hanson et al 2012) but considered to have a less prominent role than the GH pathway.…”

“…In the MAPK pathway, multiple single nucleotide polymorphisms (SNPs) in genes associated with response to GH therapy were located in both GHD and TS and these genes were shown to be located in network clusters that also contained gene expression changes associated with response to GH therapy. A network analysis using prioritisation by the connectivity of gene expression associated with the carriage of CDK4 alleles linked to IGF1 change over the first month of GH treatment also highlighted the role of the MAPK pathway's response in GHD children (Stevens et al 2013a). From these models, proof of principal has been established, that it is possible to identify genetic biomarkers of growth response which could have important predictive potential.…”