Carriage of the exon 3 deletion in the GH receptor (GHR) gene has been reported to enhance growth response to GH therapy. JAK2 and PI3K are involved in signal transduction from the GH (JAK2/PI3K) and IGF1 (PI3K) receptors. We have investigated whether a single nucleotide polymorphism within these genes influences growth response to GH therapy. DNA was taken, with ethical approval, from 104 children treated with GH therapy. Diagnoses were: GHD (n=44), TS (n=23), SGA (n=15), PWS (n=9), ISS (n=4), SD (n=4) and CRI (n=5). Clinical and auxological data were obtained from case records. We examined the 97348G/A polymorphism in exon 19 of JAK2 and the 73167G/A polymorphism in exon 15 of PI3Kinase catalytic subunit α (PI3KCA), by PCR and subsequent restriction enzyme digestion. Factors influencing change in height SDS over 2 years were assessed by backwards linear regression (independent variables: genotype, mean parental height SDS, birth weight SDS, age at start of GH treatment, starting height SDS, starting BMI SDS, starting GH dose, and mean GH dose over 2 years). Genotype frequencies for JAK2 were AA=23, AG=76 and GG=5. Genotype frequencies for PI3KCA were AA=0, AG=54 and GG=50. JAK2 and PI3K genotype did not feature in prediction models during analysis of all patient data, irrespective of diagnosis. However, PI3K genotype did feature in the prediction model for the GHD cohort. In the absence of genotype this prediction model accounted for 36% of the variability in growth response. By including genotype an improved model, accounting for 51% of the variability, was derived. The PI3KCA 73167G/A polymorphism appears to influence growth response to GH, in GHD patients. A systematic approach to assess the effect of multiple genes related to GH/IGF1 signalling pathways should be undertaken to evaluate their genetic contribution to growth response for patients receiving GH therapy.
10 - 12 Nov 2009
British Society for Paediatric Endocrinology and Diabetes