The IGF1 P2 promoter is an epigenetic QTL for circulating IGF1 and human growth

Clinical Epigenetics

Pierre Bougnères¹  Delphine Fradin²  Anne-Laure Castell¹  Marie-Pierre Belot²  Yasemin Gunes²  Meriem Ouni² 

[1] Department of Pediatric Endocrinology and Diabetes, I3E Pole, Bicêtre Hospital, Paris Sud University, rue du Général Leclerc Le Kremlin-Bicêtre, Paris 94276, France;Institut National de la Santé et de la Recherche Médicale U986, Bicêtre Hospital, Paris Sud University, 80 rue du Général Leclerc Le Kremlin-Bicêtre, Paris 94276, France

关键词: t-DMR;    DNA methylation;    Epigenetics;    IGF1;    Height;    Short stature;    Growth;    QTLepi;   

Others  :  1147827
DOI  :  10.1186/s13148-015-0062-8

 received in 2014-12-01, accepted in 2015-02-19,  发布年份 2015

【 摘 要 】

Background

Even if genetics play an important role, individual variation in stature remains unexplained at the molecular level. Indeed, genome-wide association study (GWAS) have revealed hundreds of variants that contribute to the variability of height but could explain only a limited part of it, and no single variant accounts for more than 0.3% of height variance. At the interface of genetics and environment, epigenetics contributes to phenotypic diversity. Quantifying the impact of epigenetic variation on quantitative traits, an emerging challenge in humans, has not been attempted for height. Since insulin-like growth factor 1 (IGF1) controls postnatal growth, we tested whether the CG methylation of the two promoters (P1 and P2) of the IGF1 gene is a potential epigenetic contributor to the individual variation in circulating IGF1 and stature in growing children.

Results

Child height was closely correlated with serum IGF1. The methylation of a cluster of six CGs located within the proximal part of the IGF1 P2 promoter showed a strong negative association with serum IGF1 and growth. The highest association was for CG-137 methylation, which contributed 13% to the variance of height and 10% to serum IGF1. CG methylation (studied in children undergoing surgery) was approximately 50% lower in liver and growth plates, indicating that the IGF1 promoters are tissue-differentially methylated regions (t-DMR). CG methylation was inversely correlated with the transcriptional activity of the P2 promoter in mononuclear blood cells and in transfection experiments, suggesting that the observed association of methylation with the studied traits reflects true biological causality.

Conclusions

Our observations introduce epigenetics among the individual determinants of child growth and serum IGF1. The P2 promoter of the IGF1 gene is the first epigenetic quantitative trait locus (QTL^epi) reported in humans. The CG methylation of the P2 promoter takes place among the multifactorial factors explaining the variation in human stature.

【 授权许可】

   
2015 Ouni et al.; licensee BioMed Central.

【 图 表 】

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