Research Article: Abundances of placental imprinted genes CDKN1C, PHLDA2 and IGF-2 are related to low birth weight and early catch-up growth in full-term infants born small for gestational age

Date Published: June 13, 2019

Publisher: Public Library of Science

Author(s): Yan Xing, Huiqiang Liu, Yunpu Cui, Xinli Wang, Xiaomei Tong, Umberto Simeoni.


Children born small for gestational age (SGA) generally have a catch-up growth and rapid weight gain in the first years of life, which is a high risk of insulin resistance and cardiovascular diseases later in life. It was reported that the level of imprinted genes IGF-2, CDKN1C and PHLDA2 regulates placental growth. We assessed these imprinted genes expression levels in placental tissue and their influences on catch-up growth of full-term SGA infants. The protein and mRNA levels of placental CDKN1C, PHLDA2 and IGF-2 were analyzed in 29 full-term SGA and 29 full-term infants born appropriate for gestational age (AGA) using quantitative RT-PCR and Western blot assay, respectively. Catch-up growth was indicated by increased standard deviation score (ΔSDS) of weight at 1, 3 and 6 months relative to birth weight (BW). Correlations between indicated variables were evaluated using Pearson correlation coefficient analysis. Compared to AGA infants, CDKN1C and PHLDA2 levels were significantly increased, whereas IGF-2 was significantly reduced in SGA infants. The value of ΔSDS was significantly higher in SGA than that in AGA infants. For SGA status, Pearson analysis shows i) a negative correlation of CDKN1C and PHLDA2 abundances with BW, and a positive correlation of IGF-2 with BW, ii) no correlation between the three imprinted gene abundances and placental weight (PW), and between PW and BW, iii) a positive correlation of PHLDA2 abundance with CDKN1C, and iv) a positive correlation of CDKN1C and PHLDA2 abundances with ΔSDS, and a negative correlation of IGF-2 with ΔSDS at 1, 3 and 6 months. Taken together, increased CDKN1C and PHLDA2 and reduced IGF-2 abundances in placental tissue were related to BW and early period catch-up growth in full-term SGA infants. Placental CDKN1C, PHLDA2 and IGF-2 level monitoring may be useful for predicting and preventing the development of SGA.

Partial Text

Small for gestational age (SGA) is generally defined as low birth weight (BW) at 10th percentile or at less than -2 standard deviations from the mean [1,2]. Little is known about the exact underlying mechanism by which SGA births occur. It has been reported that several factors are related to the development of SGA [1,2]. The lack of nutritional supply to the fetus is regarded as one of the major causes of reduced fetal growth [3]. Alterations of the expressions of specific imprinted genes are related to appropriate fetal and placental growth [4].

In the present study, we measured and compared the levels of three imprinted genes CDKN1C, PHLDA2 and IGF-2 in placental tissues between the SGA and AGA infants of full-term gestation. Upregulation of CDKN1C and PHLDA2 as well as downregulation of IGF-2 were detected at mRNA and protein levels in the SGA infants as compared with the AGA infants. Consistently, it has been reported that the mRNA levels of PHLDA2 and CDKN1C were increased whereas the IGF-2 mRNA levels were decreased in human intrauterine growth restriction (IUGR) placentas [12]. Nevertheless, the data from 36 full-term SGA and 41 full-term AGA infants did not show any associations of placental PHLDA2 transcript abundances with maternal placental or neonatal parameters [18]. Moreover, upregulation of the PHLDA2 mRNA levels were not detected in the SGA placentas [18]. This contradictory might be caused by the differences of the SGA samples. A combination of constitutionally small births and cases of fetal growth retardation were used. In addition, the SGA mothers were significantly shorter than the AGA ones; short, small mothers are genetically programmed to have smaller babies compared to their taller counterparts [18]. In chorionic villus samples that were collected at 12 weeks of gestation that subsequently resulted in normal live births at term, the SGA neonates had significantly lower IGF-2 mRNA levels than the AGA ones [10]. Low IGF-2 mRNA levels were also reported in the placentas in growth-restricted pregnancies [19,20]. Some studies assessed plasma IGF-2 protein levels after birth in the SGA infants [21], showing downregulation in the full-term SGA infants than in the full-term AGA ones. Recently, a large birth cohort was performed to map the profile of imprinted genes in placental samples in large for gestational age (LGA), SGA and AGA infants [22]. Notably, early, term and late of gestational age were combined in this study [22]. 10 differentially expressed genes were identified across BW categories; 6 genes including ABCA1, BLCAP, MEG3, MEST, NDN, and PLAGL1 were upregulated in the LGA infants compared to the SGA infants, and 4 genes including DLK1, H19, IGF-2 and NNAT were upregulated in the LGA infants compared to the SGA and AGA infants [22].