Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Early Life Health Institute, Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, 200092, China.
Lunenfeld-Tanenbaum Research Institute, Prosserman Centre for Population Health Research, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Faculty of Medicine, University of Toronto, L5-240, Murray Street 60, Toronto, ON, M5G 1X5, Canada.
Clin Epigenetics. 2022 Dec 30;14(1):192. doi: 10.1186/s13148-022-01412-6.
Fetal overgrowth "programs" an elevated risk of type 2 diabetes in adulthood. Epigenetic alterations may be a mechanism in programming the vulnerability. We sought to characterize genome-wide alterations in placental gene methylations in fetal overgrowth and the associations with metabolic health biomarkers including leptin, adiponectin and fetal growth factors.
Comparing genome-wide placental gene DNA methylations in large-for-gestational-age (LGA, an indicator of fetal overgrowth, n = 30) versus optimal-for-gestational-age (OGA, control, n = 30) infants using the Illumina Infinium Human Methylation-EPIC BeadChip, we identified 543 differential methylation positions (DMPs; 397 hypermethylated, 146 hypomethylated) at false discovery rate < 5% and absolute methylation difference > 0.05 after adjusting for placental cell-type heterogeneity, maternal age, pre-pregnancy BMI and HbA1c levels during pregnancy. Twenty-five DMPs annotated to 20 genes (QSOX1, FCHSD2, LOC101928162, ADGRB3, GCNT1, TAP1, MYO16, NAV1, ATP8A2, LBXCOR1, EN2, INCA1, CAMTA2, SORCS2, SLC4A4, RPA3, UMAD1,USP53, OR2L13 and NR3C2) could explain 80% of the birth weight variations. Pathway analyses did not detect any statistically significant pathways after correcting for multiple tests. We validated a newly discovered differentially (hyper-)methylated gene-visual system homeobox 1 (VSX1) in an independent pyrosequencing study sample (LGA 47, OGA 47). Our data confirmed a hypermethylated gene-cadherin 13 (CDH13) reported in a previous epigenome-wide association study. Adiponectin in cord blood was correlated with its gene methylation in the placenta, while leptin and fetal growth factors (insulin, IGF-1, IGF-2) were not.
Fetal overgrowth may be associated with a large number of altered placental gene methylations. Placental VSX1 and CDH13 genes are hypermethylated in fetal overgrowth. Placental ADIPOQ gene methylations and fetal circulating adiponectin levels were correlated, suggesting the contribution of placenta-originated adiponectin to cord blood adiponectin.
胎儿生长过度“编程”成年后患 2 型糖尿病的风险增加。表观遗传改变可能是编程易感性的一种机制。我们试图描述胎儿生长过度时胎盘基因甲基化的全基因组改变，并研究其与代谢健康生物标志物（包括瘦素、脂联素和胎儿生长因子）的关联。
通过使用 Illumina Infinium Human Methylation-EPIC BeadChip 比较大型胎儿（LGA，胎儿生长过度的指标，n=30）与适合胎龄（OGA，对照，n=30）婴儿的全基因组胎盘基因 DNA 甲基化，我们在调整胎盘细胞类型异质性、母亲年龄、妊娠前 BMI 和妊娠期间 HbA1c 水平后，确定了 543 个差异甲基化位置（DMPs；397 个高甲基化，146 个低甲基化），假发现率<5%，绝对甲基化差异>0.05。25 个 DMP 注释到 20 个基因（QSOX1、FCHSD2、LOC101928162、ADGRB3、GCNT1、TAP1、MYO16、NAV1、ATP8A2、LBXCOR1、EN2、INCA1、CAMTA2、SORCS2、SLC4A4、RPA3、UMAD1、USP53、OR2L13 和 NR3C2）可以解释 80%的出生体重变化。在进行多次检验校正后，通路分析未检测到任何具有统计学意义的通路。我们在一个独立的焦磷酸测序研究样本（LGA 47，OGA 47）中验证了一个新发现的差异（高）甲基化基因-视蛋白同源盒 1（VSX1）。我们的数据证实了先前全基因组关联研究报告的基因-钙粘蛋白 13（CDH13）的高甲基化。脐带血中的脂联素与胎盘内的基因甲基化相关，而瘦素和胎儿生长因子（胰岛素、IGF-1、IGF-2）则不相关。
胎儿生长过度可能与大量改变的胎盘基因甲基化有关。胎儿生长过度时胎盘 VSX1 和 CDH13 基因呈高甲基化。胎盘 ADIPOQ 基因甲基化与胎儿循环脂联素水平相关，提示胎盘来源的脂联素对脐带血脂联素的贡献。
