ESPE Abstracts

Background: The growth and IGF1 responses to GH treatment show a large variation across children with idiopathic short stature (ISS). Compliance and GH regimens are important determinants. The d3 variant of the GH receptor (GHR) is a significant genetic predictor. The role of individual epigenetics had not been studied. The IGF1 locus is an attractive candidate where CG methylation could influence GH action.

Objectives: To study GH effects on a) IGF1 gene expression in mononuclear blood cells (PBMC) in children with ISS b) IGF1 increase during a generation test (ght) c) IGF1 response to GH treatment (GHT) d) growth response to GT.

Patients: 75 ISS children underwent an IGF1 ght; 145 ISS children were studied during GHT. All children were pre-pubertal.

Methods: CG methylation of the two IGF1 promoters (P1 and P2) quantified by bisulfite-PCR-pyrosequencing.

Results: CG methylation of the P2 promoter (not P1) had a strong consistent effect on the whole spectrum of GH responses: a) inverse correlation with IGF1 transcripts in PBMC b) inverse correlation with IGF1 increase during ght c) inverse correlation with IGF1 increase and d) growth increase during GHT. P2 methylation contributed a large fraction to the variance in response to ght and GHT: the greater the methylation, the lower the response.

Conclusion: Individual variation of CG methylation at the IGF1 locus is an important predictor of acute and chronic responses to GH administration. Our observation provides a first example of pharmaco-epigenetics in endocrinology. It also reveals a source of physiological variation in individual GH sensitivity.