hrp0084p1-83 | Growth Hormone | ESPE2015

Genetic Markers Contribute to the PREDICTION of Response to GH in Severe but not Mild GH Deficiency

Stevens Adam , Murray Philip , Wojcik Jerome , Raelson John , Koledova Ekaterina , Chatelain Pierre , Clayton Peter

Background: Single nucleotide polymorphisms (SNPs) associated with the response to GH therapy have previously been identified in growth hormone deficient (GHD) children in the PREDICT long-term follow-up (LTFU) study (NCT00699855).Objective and hypotheses: To assess the effect of GHD severity on the predictive value of genetic markers of growth response.Method: We used pre-pubertal GHD children (peak GH <10 μg/l) from the ...

hrp0084p2-418 | GH &amp; IGF | ESPE2015

Random Forest Classification Predicts Response to Recombinant GH in GH Deficient Children Using Baseline Clinical Parameters and Genetic Markers

Stevens Adam , Murray Philip , Wojcik Jerome , Raelson John , Koledova Ekaterina , Chatelain Pierre , Clayton Peter

Background: Prediction of response to recombinant GH (r-GH) is currently based on regression modelling. This approach generates a prediction equation which can be applied to data from an individual child. However this method can underestimate the effect of inter-dependent variables. Random forest classification (RFC) is an alternative prediction method based on decision trees that is not sensitive to the relationships between variables.Objective and hypo...

hrp0086fc8.1 | Growth: Clinical | ESPE2016

Transcriptomics and Machine Learning Methods Accurately Predict Diagnosis and Severity of Childhood Growth Hormone Deficiency

Murray Philip , Stevens Adam , Koledova Ekaterina , Chatelain Pierre , Clayton Peter

Background: The diagnosis of Growth Hormone Deficiency (GHD) involves the use of GH stimulation tests that require day case admission, multiple blood sampling and are associated with significant adverse effects.Aim: To assess the utility of gene expression (GE) profiling and candidate SNP analysis for the diagnosis of and classification of GHD.Method: Pre-pubertal treatment-naïve children with GHD (n=98) were enrolled from the...

hrp0086fc14.6 | Growth : Mechanisms | ESPE2016

In vitro and in vivo Evidence for a Growth Inhibitory Role of the Transcription Factor ZBTB38 Throughout Pre- and Post-Natal Life

Parsons Sam , Stevens Adam , Whatmore Andrew , Murray Philip , Clayton Peter

Background: Single nucleotide polymorphisms (SNPs) within the promotor and 5’UTR of the transcriptional factor, ZBTB38, are associated with adult height and idiopathic short stature although their precise auxological effects have not previously been described. In addition, the molecular mechanisms through which ZBTB38 affects growth have not been fully elucidated but potential downstream mediators are suggested to include MCM10 or IGF2.Objectives: <...

hrp0086rfc14.5 | Growth : Mechanisms | ESPE2016

Gene Expression Profiling of Children with GH Deficiency (GHD) Prior to Treatment with Recombinant Human Growth Hormone (r-hGH) is Associated with Growth Response Over Five Years of Therapy

Stevens Adam , Murray Philip , Koledova Ekaterina , Chatelain Pierre , Clayton Peter

Background: The relationship of pre-treatment gene expression (GE) to long-term growth response in GHD is unknown. Prediction of long-term response to r-hGH therapy would allow better decision making about start and maintenance doses and hence cost:benefit.Objective and hypotheses: To assess the relationship of baseline GE to response to r-hGH over 5 years of therapy in GHD children.Method: Pre-pubertal children with GHD (n</em...

hrp0082fc7.3 | Growth promoting therapies | ESPE2014

Gene Expression Networks Associated with Changes in Serum Markers of Metabolism and Growth in GH-Treated Children with GH Deficiency

Stevens Adam , De Leonibus Chiara , Chatelain Pierre , Clayton Peter

Introduction: Growth promoting effects of GH occur in parallel with its impact on insulin sensitivity and lipid metabolism; underlying biological networks that link these actions are not defined. Our objective was to identify gene expression (GE) networks linking growth with metabolic responses in GH-treated children with GHD.Methods/design: Pre-pubertal children with GH Deficiency GHD (n=125) were enrolled from the PREDICT short-term (NCT002561...

hrp0082fc4.2 | Growth | ESPE2014

The Effect of grB10-Deficiency in Zebrafish: A Translational Animal Model to Study Human Growth

De Leonibus Chiara , Barinaga-Rementeria Ramirez Irene , Hurlstone Adam , Clayton Peter , Stevens Adam

Background: GRB10 negatively regulates IGF1 signalling, influences growth and promoter polymorphisms are associated with GH response1. GRB10 knockout-mouse models display foetal overgrowth2, however, the mouse model has only partial similarity to human growth3. There is evidence that the zebrafish is an appropriate model to study growth4 and has the advantage of being easily genetically manipulated.<p class="abs...

hrp0092fc12.4 | Growth and Syndromes (to include Turner Syndrome) | ESPE2019

Integration of Transcriptomic and Epigenomic Data in Childhood Identifies a Subset of Individuals Born Small for Gestational Age (SGA) with "catch-up" Growth Who Become Pre-Hypertensive in Early Adulthood

Garner Terence , Murray Philip , Sellers Robert , Whatmore Andrew , Clayton Peter , Stevens Adam

Background: Children born SGA are known to develop cardiometabolic conditions in adulthood1. Nothing is known about the relationship of the transcriptome (gene expression) and epigenome (DNA methylation) to birth size and the future development of cardiometabolic disease.Aim: To identify, I) differences and functional links between epigenome age-7years, transcriptome age-9years associated and ...

hrp0092fc12.6 | Growth and Syndromes (to include Turner Syndrome) | ESPE2019

An Integrated Systems Biology Analysis of the Genome, Epigenome and Transcriptome Identifies a Distinct Pattern of Hypermethylation Associated with Low Childhood Growth

Garner Terence , Sellers Robert , Guo Hui , Whatmore Andrew , Clayton Peter , Stevens Adam , Murray Philip

Background: Current data from genome wide association studies (GWAS) explains 24.6% of the variation in adult height from 3290 single nucleotide polymorphisms (SNPs)1. Data on the genetic control of growth velocity during childhood is more limited and no previous studies have linked childhood growth to changes in the transcriptome (gene expression) or epigenome (DNA methylation). Here we present a systems biology approach to understand mid-child...

hrp0082fc4.3 | Growth | ESPE2014

Oscillations in Gene Expression Profiles Across Childhood Highlight the Relation of Growth and Specific Metabolic Functions in Both Sexes

Stevens Adam , Knight Christopher , De Leonibus Chiara , Dowsey Andrew , Swainston Neil , Murray Philip , Clayton Peter

Background: The phases of human growth are associated with gene expression (GE) changes1, raising the possibility that rhythmic patterns of GE occur throughout childhood.Objective: In this study, we have assessed time-series patterns of GE profiles associated with age to characterise oscillations.Methods: GE analysis was conducted on cells of lymphoid origin from normal individuals through childhood (n=87, 43 ma...