Pharmacogenomics applied to growth disorders: impact ofgenes on clinical and cellular responses to recombinant humangrowth hormone (r-hGH) and on Zebrafish growth

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Abstract

There is significant inter-individual variation in growth response to recombinantgrowth hormone (r-hGH) in children with growth hormone deficiency (GHD).Clinical and biochemical factors influencing the r-hGH response have beenidentified, but current prediction models explain only 40 to 60% of its variability.Some of this unexplained variation may be attributable to genetic variants and theirpotential interactions with clinical and environmental factors.The aims of this thesis were: 1) to study the gene-environment interaction related tor-hGH response in children with GHD, and 2) to assess the functional activity of thegenetic variants in cell and animal models. For 1), phenotypic data were collected onpatients from the PREDICT Long Term Follow-Up Study (NCT00699855), whichhas identified predictive genetic markers related to r-hGH response. As latitudeaffects stature, a gene-environment interaction was assessed in relation tolatitude/summer daylight exposure (SDE) and carriage of seven SNPs previouslyassociated with high growth response. In addition, the relationship between basalgene expression (GE) in these children and the SDE/gene interaction was studied.For 2), the transcriptional activity of two genetic markers (GRB10 and SOS1) withthe greatest influence on response was tested. A morpholino oligonucleotidemediated knock-down of Grb10 in Zebrafish (ZF) was developed, as a preliminarystep to establish ZF as an animal model for testing genetic markers on growth.GHD patients from latitudes with higher SDE had a better 1st year height velocity(HV) compared to lower SDE (p=0.019), with HV over all groups correlating withSDE (r=0.256, p=0.006). There was a significant interaction between the SNP andSDE (p<0.05) in relation to growth response, with the magnitude and direction of theinteraction being gene dependent. The effect of carriage of SNPs in IGFBP3, TGF-αand TP53 on HV was greater in patients from locations with higher SDE; theconverse was found for GRB10 and CYP19A1. The “circadian clock” (p=8.1x10-11)was identified as a primary associated biological function underlying thismechanism. The in vitro analysis identified differential transcription activity atbaseline and after growth hormone (GH) stimulation for alleles within GRB10 andSOS1 SNPs. The animal model confirmed in vivo the effect of Grb10 on growth anddevelopment. Grb10 GE changes were identified during the growth phases, with amajor peak in early embryogenesis. Knock-down of Grb10 led to proportionateovergrowth, implying important effects of Grb10 on growth suppression and wholebodysize.These findings have confirmed that: 1) the genetic markers of response to r-hGH aresignificantly influenced by environmental factor, namely SDE, and have functionalconsequences when tested in vitro; 2) a homologue of a human growth gene can besuccessfully manipulated in ZF. This work expands our knowledge and introducesthe possibility of modelling of pharmacogenomics in relation to growth disorders.

Keyword(s)

Growth; Growth Hormone; Growth Hormone Deficiency; Polymorphism

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