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

Chiara De Leonibus

    Research output: ThesisDoctoral Thesis

    Abstract

    There is significant inter-individual variation in growth response to recombinant growth hormone (r-hGH) in children with growth hormone deficiency (GHD). Clinical and biochemical factors influencing the r-hGH response have been identified, but current prediction models explain only 40 to 60% of its variability. Some of this unexplained variation may be attributable to genetic variants and their potential interactions with clinical and environmental factors. The aims of this thesis were: 1) to study the gene-environment interaction related to r-hGH response in children with GHD, and 2) to assess the functional activity of the genetic variants in cell and animal models. For 1), phenotypic data were collected on patients from the PREDICT Long Term Follow-Up Study (NCT00699855), which has identified predictive genetic markers related to r-hGH response. As latitude affects stature, a gene-environment interaction was assessed in relation to latitude/summer daylight exposure (SDE) and carriage of seven SNPs previously associated with high growth response. In addition, the relationship between basal gene expression (GE) in these children and the SDE/gene interaction was studied. For 2), the transcriptional activity of two genetic markers (GRB10 and SOS1) with the greatest influence on response was tested. A morpholino oligonucleotide mediated knock-down of Grb10 in Zebrafish (ZF) was developed, as a preliminary step 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 with SDE (r=0.256, p=0.006). There was a significant interaction between the SNP and SDE (p
    Original languageEnglish
    Awarding Institution
    Publisher
    Publication statusPublished - Feb 2015

    Keywords

    • Growth
    • Polymorphism
    • Gene-environment interaction

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