Higher methylation of the IGF1 P2 promoter is associated with idiopathic short stature.

Abstract

Idiopathic short stature (ISS) has a strong familial component, but genetics explains only part of it. Indeed, environmental factors act on human growth either directly or through epigenetic factors that remain to be determined. Given the importance of the GH/IGF1 axis for child growth, we suspected that such epigenetic factors could involve the CG methylation at the IGF1 gene P2 promoter, which was recently shown to be a transcriptional regulator for IGF1 gene and a major contributor to GH sensitivity. Explore whether the methylation of the two IGF1 low-CG-rich promoters (P1 and P2) is associated with ISS. A total of 94 children with ISS were compared with 119 age-matched children of normal height for the methylation of CGs located within the IGF1 promoters measured with bisulphite PCR pyrosequencing. The methylation of 5 CGs of the P2 promoter was higher in ISS children, notably CG-137 (49±4% in ISS vs 46±4 % in control children, P=9×10-5 ). This was also true for CG-611 of the P1 promoter (93±3% vs 91±3% P=10-4 ). The CG methylation of the IGF1 promoters thus takes place among the multifactorial factors that are associated with ISS.