Ouni Meriem, Gunes Yasemin, Belot Marie-Pierre, Castell Anne-Laure, Fradin Delphine, Bougnères Pierre
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.
Department of Pediatric Endocrinology and Diabetes, I3E Pole, Bicêtre Hospital, Paris Sud University, rue du Général Leclerc Le Kremlin-Bicêtre, Paris, 94276 France.
Clin Epigenetics. 2015 Mar 13;7(1):22. doi: 10.1186/s13148-015-0062-8. eCollection 2015.
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.
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.
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.
即使遗传学发挥着重要作用，但个体身高差异在分子水平上仍无法得到充分解释。事实上，全基因组关联研究（GWAS）已发现数百个影响身高变异的变体，但仅能解释其中有限的一部分，且没有单个变体对身高变异的贡献率超过0.3%。在遗传学与环境的交叉领域，表观遗传学促成了表型多样性。量化表观遗传变异对数量性状的影响，这在人类中是一个新出现的挑战，尚未针对身高进行尝试。由于胰岛素样生长因子1（IGF1）控制出生后的生长，我们测试了IGF1基因两个启动子（P1和P2）的CG甲基化是否是导致生长中儿童循环IGF1和身高个体差异的潜在表观遗传因素。
儿童身高与血清IGF1密切相关。位于IGF1 P2启动子近端的一组六个CG的甲基化与血清IGF1和生长呈强烈负相关。关联度最高的是CG - 137甲基化，其对身高变异的贡献率为13%，对血清IGF1的贡献率为10%。（在接受手术的儿童中研究的）CG甲基化在肝脏和生长板中降低了约50%，表明IGF1启动子是组织差异甲基化区域（t - DMR）。在单核血细胞和转染实验中，CG甲基化与P2启动子的转录活性呈负相关，这表明观察到的甲基化与所研究性状之间的关联反映了真正的生物学因果关系。
我们的观察结果表明表观遗传学是儿童生长和血清IGF1个体决定因素之一。IGF1基因的P2启动子是人类中报道的首个表观遗传数量性状位点（QTL(epi)）。P2启动子的CG甲基化是解释人类身高变异的多因素之一。
Zotero 插件
