Chatterjee Suvo, Zeng Xuehuo, Ouidir Marion, Tesfaye Markos, Zhang Cuilin, Tekola-Ayele Fasil
Epidemiology Branch, Division of Population Health Research, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, 20892, MD, USA.
Section of Sensory Science and Metabolism (SenSMet), National Institute on Alcohol Abuse and Alcoholism & National Institute of Nursing Research, National Institutes of Health, Bethesda, MD, 20814, USA.
Placenta. 2022 Apr;121:82-90. doi: 10.1016/j.placenta.2022.03.004. Epub 2022 Mar 12.
Small for gestational age at birth (SGA), often a consequence of placental dysfunction, is a risk factor for neonatal morbidity and later life cardiometabolic diseases. There are sex differences in placental gene expression and fetal growth. Here, we investigated sex-specific associations between gene expression in human placenta measured using RNA sequencing and SGA status using data from ethnic diverse pregnant women in the NICHD Fetal Growth Studies cohort (n = 74).
Gene expression measures were obtained using RNA-Sequencing and differential gene expression between SGA (birthweight <10th percentile) and appropriate for gestational age (AGA: ≥10th and <90th percentile) was tested separately in males (12 SGA and 27 AGA) and females (9 SGA and 26 AGA) using a weighted mean of log ratios method with adjustment for mode of delivery and ethnicity.
At 5% false discovery rate (FDR), we identified 40 differentially expressed genes (DEGs) related to SGA status among males (95% up- and 5% down-regulated) and 314 DEGs among females (32.5% up- and 67.5% down-regulated). Seven female-specific DEGs overlapped with known imprinted genes (AXL, CYP24A1, GPR1, PLAGL1, CMTM1, DLX5, LY6D). The DEGs in males were significantly enriched for immune response and inflammation signaling pathways whereas the DEGs in females were enriched for organ development signaling pathways (FDR<0.05). Sex-combined analysis identified no additional DEGs, rather 98% of the sex-specific DEGs were no longer significant and the remaining 2% were attenuated.
This study revealed sex-specific human placental gene expression changes and molecular pathways associated with SGA and underscored that unravelling the pathogenesis of SGA warrants consideration of fetal sex as a biological variable.
gov, Unique identifier: NCT00912132.
出生时小于胎龄（SGA）通常是胎盘功能障碍的结果，是新生儿发病和日后发生心脏代谢疾病的危险因素。胎盘基因表达和胎儿生长存在性别差异。在此，我们利用美国国立儿童健康与人类发展研究所（NICHD）胎儿生长研究队列中不同种族孕妇的数据（n = 74），研究了通过RNA测序测量的人类胎盘基因表达与SGA状态之间的性别特异性关联。
使用RNA测序获得基因表达测量值，并分别在男性（12例SGA和27例适于胎龄[AGA]：≥第10百分位数且<第90百分位数）和女性（9例SGA和26例AGA）中，采用对数比率加权均值法并调整分娩方式和种族，测试SGA（出生体重<第10百分位数）与适于胎龄之间的差异基因表达。
在5%的错误发现率（FDR）下，我们在男性中鉴定出40个与SGA状态相关的差异表达基因（DEG）（95%上调和5%下调），在女性中鉴定出314个DEG（32.5%上调和67.5%下调）。7个女性特异性DEG与已知的印记基因（AXL、CYP24A1、GPR1、PLAGL1、CMTM1、DLX5、LY6D）重叠。男性中的DEG在免疫反应和炎症信号通路中显著富集，而女性中的DEG在器官发育信号通路中富集（FDR<0.05）。性别联合分析未发现其他DEG，相反，98%的性别特异性DEG不再显著，其余2%的DEG减弱。
本研究揭示了与SGA相关的性别特异性人类胎盘基因表达变化和分子途径，并强调阐明SGA的发病机制需要将胎儿性别作为一个生物学变量来考虑。
gov，唯一标识符：NCT00912132。
