Effect of summer daylight exposure and genetic background on growth in growth hormone deficient children

The response to growth hormone in humans is dependent on phenotypic, genetic and environmental factors. The present study in children with growth hormone deficiency (GHD) collected worldwide characterised gene-environment interactions on growth response to recombinant human growth hormone (r-hGH). Growth responses in children are linked to latitude, and we found that a correlation of latitude, summer daylight exposure (SDE) was a key environmental factor related to growth response to r-hGH. In turn growth response was determined by an interaction between both SDE and genes known to affect growth response to r-hGH. In addition analysis of associated networks of gene expression implicated a role for circadian clock pathways and specifically the developmental transcription factor NANOG. This work provides the first observation of gene-environment interactions in children treated with r-hGH. Whole blood from patients with growth hormone deficiency (GHD) was used for RNA extraction and hybridization on Affymetrix microarrays. Reduction of globin messenger RNA was undertaken using the Ambion GLOBIN Clear Human Kit (Life Technologies, Paisley, UK). Complementary RNA was generated using the Two-Cycle Eukaryotic Target Labelling Kit (Affymetrix, Santa Clara, CA, USA) and a final quality check performed before hybridization to Affymetrix GeneChip® Human Genome U133 Plus 2.0 Arrays. Arrays were then scanned on an Affymetrix GeneChip 7G scanner and assessed for quality against internal and hybridization controls. Confounding effects due to variations in cell populations and outliers were examined by cross validation using principal component analysis and iso-map multidimensional scaling (Qlucore Omics Explorer 2.2, Qlucore, Lund, Sweden).