RT Journal Article
SR Electronic
T1 Gene expression signatures predict response to therapy with growth hormone
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 637892
DO 10.1101/637892
A1 Adam Stevens
A1 Philip Murray
A1 Chiara De Leonibus
A1 Terence Garner
A1 Ekaterina Koledova
A1 Geoffrey Ambler
A1 Jia-Woei Hou
A1 Klaus Kapelari
A1 Jean Pierre Salles
A1 Gerhard Binder
A1 Mohamad Maghnie
A1 Stefano Zucchini
A1 Elena Bashnina
A1 Julia Skorodok
A1 Diego Yeste
A1 Alicia Belgorosky
A1 Juan-Pedro Lopez Siguero
A1 Regis Coutant
A1 Eirik Vangsøy-Hansen
A1 Lars Hagenäs
A1 Jovanna Dahlgren
A1 Cheri Deal
A1 Pierre Chatelain
A1 Peter Clayton
YR 2019
UL http://biorxiv.org/content/early/2019/05/17/637892.abstract
AB Recombinant human growth hormone (r-hGH) is used as a therapeutic agent for disorders of growth including growth hormone deficiency (GHD) and Turner syndrome (TS). Treatment is costly and current methods to model response can only account for up to 60% of the variance. The aim of this work was to take a novel genomic approach to growth prediction. GHD (n=71) and TS patients (n=43) were recruited in a study on the long term response to r-hGH over five years of therapy. Pharmacogenomic analysis was performed using 1219 genetic markers and baseline blood transcriptome. Random forest was used to determine predictive value of transcriptomic data associated with growth response. No genetic marker passed the stringency criteria required for predictive value. However, we demonstrated that transcriptomic data can be used to predict growth with a high accuracy (AUC > 0.9) for short and long term therapeutic response in GHD and TS. Network models identified an identical core set of genes in both GHD and TS at each year of therapy whose expression can be used to classify therapeutic response to r-hGH. Combining transcriptomic markers with clinical phenotype was shown to significantly reduce predictive error. We have characterised the utility of baseline transcriptome for the prediction of growth response including the identification of a set of common genes in GHD and TS. This work could be translated into a single genomic test linked to a prediction algorithm to improve clinical management.One Sentence Summary A blood transcriptome signature predicts response to recombinant human growth hormone in both growth hormone deficient and Turner syndrome childrenTrial registration numbers: NCT00256126 & NCT00699855