Endocrine Abstracts

Carriage of the exon 3 deletion in the GH receptor (GHR) gene has been reported to enhance growth response to GH therapy in a range of conditions. JAK2 and PI3Kinase are involved in signal transduction from the GH (JAK2/PI3Kinase) and IGF-1 (PI3Kinase) receptors. We have investigated whether single nucleotide polymorphisms within these genes influence growth response to GH therapy. DNA was taken, with ethical approval, from 97 children treated with GH therapy in a single growth centre. Diagnoses were: GHD (n=44), TS (n=22), SGA (n=13), PWS (n=9), ISS (n=5) and skeletal dysplasias (n=4). 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 alpha (PI3KCA) by PCR and subsequent restriction enzyme digestion. The main outcome measure of this study was change in height SDS over 2 years (ΔHTSDS 0–2 years). Factors influencing ΔHTSDS 0–2 years were assessed by backwards linear regression (independent variables: genotype, birth weight SDS (BWSDS), diagnostic group (DG), age at start of GH treatment (AGEST), starting BMI SDS, starting height SDS (STHTSDS), mean parental height SDS, starting GH dose (STGH), and mean GH dose over two years (GH2YRS)). The genotype frequencies for JAK2 were AA=22, AG=70 and GG=5. 32% of the variability in ΔHTSDS 0–2 years was accounted for by genotype (P=0.01), BWSDS (P=0.09), DG (P=0.05), AGEST (P=0.03) and STHTSDS (P<0.01). The genotype frequencies for PI3KCA were AA=0, AG=50 and GG=47. Variability in ΔHTSDS 0–2 years was influenced by AGEST, STHTSDS and GH dose, but not genotype. The JAK2 97348G/A SNP genotype appears to influence growth response to GH. A systematic approach to assess the effect of multiple genes related to GH/IGF-1 signalling pathways, using pharmacogenetic techniques, should be undertaken to evaluate the overall genetic contribution to growth response on GH.