FP20-6 Gene Expression Networks Associated with Changes in Serum Insulin (Ins), Ins-like Growth Factor-I (IGF-I), and Growth in Growth Hormone (GH)-Treated Children with GH Deficiency (GHD)

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP20-Growth: Clinical Trials & Observational Studies
Clinical
Sunday, June 16, 2013: 10:45 AM-11:15 AM
Presentation Start Time: 11:10 AM
Room 122 (Moscone Center)

Poster Board SUN-629
Adam Stevens*1, Chiara De Leonibus2, Benoit Destenaves3, Maria Dolores Rodriguez-Arnao4, Geoffrey Ambler5, John Raelson6, Pierre Chatelain7 and Peter Ellis Clayton8
1University of Manchester, Manchester, United Kingdom, 2Manchester Academic Health Sciences Centre, Royal Manchester Children's Hospital, Manchester, United Kingdom, 3Merck Serono S.A., Geneva, Switzerland, 4Paediatric Endocrine Unit, Hospital General Universitario Gregorio Maranon, Madrid, Spain, 5The Children's Hospital at Westmead, Sydney, Australia, 6Genizon BioSciences, Quebec, Canada, 7Universite Claude Bernard, Lyon, France, 8Royal Manchester Children's Hospital, Manchester, United Kingdom
BACKGROUND: In children with GHD, recombinant-human (r-h)GH therapy promotes growth while also inducing lipolysis, increasing glucose levels and altering Ins sensitivity. Mechanisms common to these responses are not well defined.

OBJECTIVES: To investigate the association between markers of Ins sensitivity (change in fasting glucose and Ins over 1mth) and markers of growth (change in IGF-I over 1mth and height velocity [HV] over 1yr) in relation to baseline gene expression.

METHODS: Prepubertal children with GHD (n=125) were enrolled from the PREDICT (NCT00256126) and PREDICT long-term follow-up (NCT00699855) studies. Whole blood gene expression was determined at baseline (Affymetrix Human Genome U133 Plus 2.0 Array), changes in biomarkers (Glucose, Ins, IGF-I) were assessed after 1mth on r-hGH (median dose 33µg/kg/d), and HV measured after 1yr. First, correlations between changes in these clinical markers were assessed adjusted for age, gender, and body mass index. Second, associations between basal gene expression and changes in clinical markers were assessed using rank regression. Third, genes common to pairs of related markers (glucose+Ins; Ins+IGF-I; IGF-I+HV) were subjected to a network analysis based on all known interacting partners for these genes (generating an ‘interactome’ model [Biogrid]). Fourth, overlap of these interactomes between the marker pairs was examined and highly connected networks identified (ClusterOne algorithm). Finally, pathway associations within these networks were determined (hypergeometric test).

RESULTS: (1) Changes in glucose + Ins were correlated (p<0.05). Changes in IGF-I correlated with Ins (p<0.001) but not glucose (p=0.34). HV at 1yr correlated with 1mth changes in IGF-I (p<0.002) but not with glucose or Ins. (2) Changes in clinical markers were associated with 891 (Ins), 1844 (Gluc), 3583 (IGF-I), and 2140 (HV) genes. (3) 72 (glucose+Ins), 101 (Ins+IGF-I), and 317 (IGF-I+HV) genes were common to each correlated pair. (4) The top pathways associated with the networks derived from these comparisons included adipocyte differentiation (p<1.5x10-34) and cell-cycle regulation (p<3.6x10-11).

CONCLUSIONS: We have used a network biology approach based on baseline gene expression in children with GHD to determine common pathways that underlie glucose, insulin, IGF-I, and growth responses to r-hGH. These data could be used to generate individual gene expression profiles associated with both the efficacy and safety of r-hGH.

Disclosure: AS: Speaker, Merck Serono. CD: Research Funding, NovoNordisk ESPE Research Fellowship. BD: Employee, Merck Serono. MDR: Investigator, Merck Serono. JR: Consultant, Merck Serono. PC: Speaker, Merck Serono, Investigator, Merck Serono, Consultant, Merck Serono. PEC: Speaker, Merck Serono, Investigator, Merck Serono. Nothing to Disclose: GA

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This study was supported by Merck Serono S.A. Geneva, Switzerland, a branch of Merck Serono S.A. Coinsins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany.
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