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...

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...

hrp0082fc7.2 | Growth promoting therapies | ESPE2014

The rs1024531 GRB10 Promoter Polymorphism is Associated with Response to GH Therapy in Patients with GH Deficiency: Validation by in vitro Functional Analysis

De Leonibus Chiara , Hanson Daniel , Murray Philip , Stevens Adam , Clayton Peter

Background: GH response is influenced by genetic polymorphisms, including the rs1024531 polymorphism (A/G) in the promoter region of GRB10, a negative regulator of signaling through the IGF1 receptor. Allele A is associated with borderline lower baseline IGF1 SDS and 1.5-fold higher response to GH compared to allele G in children with GHD (P=0.0006).Objective: To test functional impact of the rs1024531 polymorphism in an in vitro</e...

hrp0082p1-d3-165 | Growth (2) | ESPE2014

Validating Genetic Markers of Response to Recombinant Human GH in Children with GH Deficiency or Turner Syndrome: Results From the PREDICT Validation Study

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

Introduction: Genetic markers associated with the response to recombinant human GH (r-hGH) have been identified in Growth Hormone Deficiency (GHD) and Turner Syndrome (TS) children in the PREDICT long-term follow-up (LTFU) prospective study (NCT00699855).1 A validation (VAL) study (NCT01419249) was conducted to confirm association.Methods/design: Inclusion criteria for GHD and TS children were identical in the LTFU and VAL studies (GHD defined...

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 ...

hrp0084p2-394 | GH &amp; IGF | ESPE2015

Gene Expression Profiles in GH Deficient Children Relate Peak GH Levels to Circadian Clock, Chromatin Remodelling, and WNT Signalling Pathways

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

Background: GH deficiency (GHD) is classically defined on the basis of a cut-off applied to the peak GH level during stimulation tests; a process with recognised limitations. Identifying the functional role of genes whose expression is associated with pGH may help with our understanding and classification of GHD.Objective and hypotheses: Identify patterns of gene expression (GE) related to pGH and to describe the function, and regulation of these genes.<...

hrp0084p2-398 | GH &amp; IGF | ESPE2015

The In vitro Functional Analysis of Gene Promoter Region Single Nucleotide Polymorphisms Associated with GH Response in Children with GH Deficiency

De Leonibus Chiara , Murray Philip , Hanson Dan , Stevens Adam , Clayton Peter

Background: Response to GH treatment has been associated with single nucleotide polymorphisms (SNPs) within the promoter region of growth-related genes including GRB10 (rs1024531 (A/G, allele A increased response)), IGFBP3 (rs3110697 (G/A, G increased response)), CYP19A1 (rs10459592 (T/C, T increased response)) and SOS1 (rs2888586 (G/C, C increased response)). SOS1 is a positive regulator of GH signalling (MAPK pathway); the aromatase CYP19A1 promotes oestrogen synthesis to im...

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...

hrp0094p2-239 | Fetal, neonatal endocrinology and metabolism (to include hypoglycaemia) | ESPE2021

Antenatal Markers Related to Fetal Growth Restriction Can Predict Childhood Systolic Blood Pressure

Perchard Reena , Higgins Lucy , Garner Terence , Stevens Adam , Johnstone Edward , Clayton Peter ,

Background: Being born small for gestational age (SGA) is linked with higher systolic blood pressure (SBP). Fetuses with growth restriction (FGR) may be either SGA or appropriate size for gestational age at birth. However, it is not known which factors contributing to size at birth influence the relationship with SBP.Aim: To determine whether antenatal markers of FGR can predict the upper quartile of childhood SBP.<p...

hrp0097rfc4.1 | Growth and syndromes (to include Turner syndrome) | ESPE2023

Functional networks reveal pathways linking early growth to childhood blood pressure in the Manchester BabyGRO Study

Perchard Reena , Garner Terence , Stevens Adam , Higgins Lucy , Johnstone Edward , Clayton Peter

Background: Many studies have associated being born small for gestational age (SGA) [and by implication having suboptimal fetal growth (SFG)] to childhood cardiometabolic risk markers. However, not all growth-restricted pregnancies result in SGA. In the Manchester BabyGRO study, we focussed on pregnancies at risk of SFG with most babies born AGA, and using transcriptomic and metabolomic data we have identified pathways related to higher child systolic blood pr...