Moore Gudrun E, Ishida Miho, Demetriou Charalambos, Al-Olabi Lara, Leon Lydia J, Thomas Anna C, Abu-Amero Sayeda, Frost Jennifer M, Stafford Jaime L, Chaoqun Yao, Duncan Andrew J, Baigel Rachel, Brimioulle Marina, Iglesias-Platas Isabel, Apostolidou Sophia, Aggarwal Reena, Whittaker John C, Syngelaki Argyro, Nicolaides Kypros H, Regan Lesley, Monk David, Stanier Philip
Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK
Genetics and Epigenetics in Health and Diseases Section, Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London WC1N 1EH, UK.
Philos Trans R Soc Lond B Biol Sci. 2015 Mar 5;370(1663):20140074. doi: 10.1098/rstb.2014.0074.
Identifying the genetic input for fetal growth will help to understand common, serious complications of pregnancy such as fetal growth restriction. Genomic imprinting is an epigenetic process that silences one parental allele, resulting in monoallelic expression. Imprinted genes are important in mammalian fetal growth and development. Evidence has emerged showing that genes that are paternally expressed promote fetal growth, whereas maternally expressed genes suppress growth. We have assessed whether the expression levels of key imprinted genes correlate with fetal growth parameters during pregnancy, either early in gestation, using chorionic villus samples (CVS), or in term placenta. We have found that the expression of paternally expressing insulin-like growth factor 2 (IGF2), its receptor IGF2R, and the IGF2/IGF1R ratio in CVS tissues significantly correlate with crown-rump length and birthweight, whereas term placenta expression shows no correlation. For the maternally expressing pleckstrin homology-like domain family A, member 2 (PHLDA2), there is no correlation early in pregnancy in CVS but a highly significant negative relationship in term placenta. Analysis of the control of imprinted expression of PHLDA2 gave rise to a maternally and compounded grand-maternally controlled genetic effect with a birthweight increase of 93/155 g, respectively, when one copy of the PHLDA2 promoter variant is inherited. Expression of the growth factor receptor-bound protein 10 (GRB10) in term placenta is significantly negatively correlated with head circumference. Analysis of the paternally expressing delta-like 1 homologue (DLK1) shows that the paternal transmission of type 1 diabetes protective G allele of rs941576 single nucleotide polymorphism (SNP) results in significantly reduced birth weight (-132 g). In conclusion, we have found that the expression of key imprinted genes show a strong correlation with fetal growth and that for both genetic and genomics data analyses, it is important not to overlook parent-of-origin effects.
确定胎儿生长的基因输入将有助于理解常见且严重的妊娠并发症，如胎儿生长受限。基因组印记是一种表观遗传过程，它使一个亲本等位基因沉默，导致单等位基因表达。印记基因在哺乳动物胎儿生长发育中很重要。有证据表明，父源表达的基因促进胎儿生长，而母源表达的基因抑制生长。我们评估了关键印记基因的表达水平是否与孕期胎儿生长参数相关，无论是在妊娠早期使用绒毛膜绒毛样本（CVS），还是在足月胎盘期。我们发现，CVS组织中父源表达的胰岛素样生长因子2（IGF2）及其受体IGF2R的表达以及IGF2/IGF1R比值与头臀长和出生体重显著相关，而足月胎盘期的表达则无相关性。对于母源表达的 plekstrin 同源样结构域家族 A 成员 2（PHLDA2），在妊娠早期的 CVS 中无相关性，但在足月胎盘中存在高度显著的负相关。对PHLDA2印记表达调控的分析产生了一种母源和复合的祖母源控制的遗传效应，当遗传一份PHLDA2启动子变体时，出生体重分别增加93/155克。生长因子受体结合蛋白10（GRB10）在足月胎盘中的表达与头围显著负相关。对父源表达的δ样1同源物（DLK1）的分析表明，rs941576单核苷酸多态性（SNP）的1型糖尿病保护性G等位基因的父源传递导致出生体重显著降低（-132克）。总之，我们发现关键印记基因的表达与胎儿生长密切相关，并且对于遗传和基因组数据分析而言，重要的是不要忽视亲本来源效应。
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