ESPE Abstracts (2016) 86 FC14.2

CG Methylation at the IGF1 P2 Promoter is a Major Epigenetic Determinant of Postnatal, Not Foetal Growth

Myriam Ounib, Catherine Le Stunffb, Anne Laure Castella & Pierre Bougnèresa,b

aPediatric Endocrinology, Bicêtre, France; bU1169INSERM, Bicêtre, France

Background: The height of children has a Gaussian distribution. Genetics explain an important part of individual variability, but no single genomic variant accounts for more than 0.3% of height variance. At the interface of genetics and environment, epigenetics is expected to contribute to phenotypic variability. IGF1 is an attractive locus to test this hypothesis.

Objectives: To quantify the effect of CG methylation of IGF1 promoters on height.

Patients: a) 216 children of various heights b) 94 children with idiopathic short stature (ISS) c) 46 children with intra-uterine growth retardation (IUGR) d) 12 children undergoing surgical procedures for independent reasons. All were studied before puberty.

Methods: CG methylation of IGF1 promoters P1 and P2 was measured using bisulfite-PCR-pyrosequencing. IGF1 gene expression was measured in various tissues with qPCR.

Results: Methylation was 50% lower in liver and growth plates, indicating that P2 is a tissue-differentially methylated region (t-DMR). Methylation showed an inverse correlation with P2 transcriptional activity in mononuclear blood cells and in transfection experiments. P2 methylation showed a strong inverse association with IGF1 and growth: methylation contributed 13% to height variance and 10% to circulating IGF1 variance. P2 methylation was higher in ISS than in children of normal stature, notably at CG-137 (P 9.10−5), but showed no difference between IUGR and children of normal birth size.

Conclusion: The observed association of IGF1 P2 methylation with gene expression supports true biological causality. Epigenetics at the IGF1 locus is a major determinant of postnatal, not fœtal, growth.

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