The P2 promoter of the IGF1 gene is a major epigenetic locus for GH responsiveness

Abstract

Short children using growth hormone (GH) to accelerate their growth respond to this treatment with a variable efficacy. The causes of this individual variability are multifactorial and could involve epigenetics. Quantifying the impact of epigenetic variation on response to treatments is an emerging challenge. Here we show that methylation of a cluster of CGs located within the P2 promoter of the insulin-like growth factor 1 (IGF1) gene, notably CG-137, is inversely closely correlated with the response of growth and circulating IGF1 to GH administration. For example, variability in CG-137 methylation contributes 25% to variance of growth response to GH. Methylation of CGs in the P2 promoter is negatively associated with the increased transcriptional activity of P2 promoter in patients' mononuclear blood cells following GH administration. Our observation indicates that epigenetics is a major determinant of GH signaling (physiology) and of individual responsiveness to GH treatment (pharmacoepigenetics).

Growth Hormone Deficiency in Prepubertal Children: Predictive Markers of Cardiovascular Disease

“…A link between epigenetics, decreased IGF-I/postnatal growth and increased risk of CV events has already been described in newborns with intrauterine growth restriction, where specific epigenetic signatures including methylation within the IGF2 gene and genes involved in carbohydrate metabolism have been identified [46]. Other reports indicate the role of IGF2 gene promoter region methylation in characterizing GH response in children with idiopathic short stature [47,48]. …”

The role of epigenomics in personalized medicine

“…For example, methylation of the P2 promoter of the IGF1 gene affects transcriptional response to growth hormone (GH) [93]. GH is mainly used to treat children with short stature due to growth hormone deficiency.…”

“…Ouni et al . [93] measured P2-driven and total IGF1 transcripts before and 12 h after the GH injection and found an increase in P2-driven transcripts with a very strong inverse correlation with CG-137 methylation. This correlation accounted for ~ 25% of the variability in the response to GH.…”

Genomic insights into growth and its disorders

“…A series of recent studies by Pierre Bougneres’ group found that the methylation status of a cluster of CGs dinucleotides located within the proximal part of the P2 promoter of the IGF-1 ( IGF1 ) gene was correlated to individual GH sensitivity on the IGF-1 generation test as well as first year response to recombinant GH treatment in ISS patients(28, 29). Methylation status as a single CG dinucleotide (CG-137) explained 25% of the variance of growth response to growth hormone in the study of 136 children 28 .…”