Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48105, USA.
Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, School of Medicine, San Francisco, CA 94158, USA.
Gigascience. 2022 Feb 15;11. doi: 10.1093/gigascience/giac004.
Preterm birth is defined by the onset of labor at a gestational age shorter than 37 weeks, and it can lead to premature birth and impose a threat to newborns' health. The Puerto Rico PROTECT cohort is a well-characterized prospective birth cohort that was designed to investigate environmental and social contributors to preterm birth in Puerto Rico, where preterm birth rates have been elevated in recent decades. To elucidate possible relationships between metabolites and preterm birth in this cohort, we conducted a nested case-control study to conduct untargeted metabolomic characterization of maternal plasma of 31 women who experienced preterm birth and 69 controls who underwent full-term labor at 24-28 gestational weeks.
A total of 333 metabolites were identified and annotated with liquid chromatography/mass spectrometry. Subsequent weighted gene correlation network analysis shows that the fatty acid and carene-enriched module has a significant positive association (P = 8e-04, FDR = 0.006) with preterm birth. After controlling for potential clinical confounders, a total of 38 metabolites demonstrated significant changes uniquely associated with preterm birth, where 17 of them were preterm biomarkers. Among 7 machine-learning classifiers, the application of random forest achieved a highly accurate and specific prediction (AUC = 0.92) for preterm birth in testing data, demonstrating their strong potential as biomarkers for preterm births. The 17 preterm biomarkers are involved in cell signaling, lipid metabolism, and lipid peroxidation functions. Additional modeling using only the 19 spontaneous preterm births (sPTB) and controls identifies 16 sPTB markers, with an AUC of 0.89 in testing data. Half of the sPTB overlap with those markers for preterm births. Further causality analysis infers that suberic acid upregulates several fatty acids to promote preterm birth.
Altogether, this study demonstrates the involvement of lipids, particularly fatty acids, in the pathogenesis of preterm birth.
早产是指在妊娠 37 周前分娩，可能导致早产，并威胁新生儿的健康。波多黎各 PROTECT 队列是一个特征良好的前瞻性出生队列，旨在研究波多黎各早产的环境和社会因素，近年来那里的早产率有所上升。为了阐明该队列中代谢物与早产之间的可能关系，我们进行了一项嵌套病例对照研究，对 31 名经历早产的妇女和 69 名在 24-28 孕周足月分娩的对照妇女的母体血浆进行非靶向代谢组学特征分析。
共鉴定并注释了 333 种代谢物。随后的加权基因相关网络分析表明，富含脂肪酸和萜烯的模块与早产有显著正相关（P=8e-04， FDR=0.006）。在控制潜在的临床混杂因素后，共有 38 种代谢物与早产有显著的独特关联，其中 17 种是早产的生物标志物。在 7 种机器学习分类器中，随机森林的应用对测试数据中的早产具有高度准确和特异的预测（AUC=0.92），表明它们作为早产生物标志物具有很强的潜力。这 17 种早产生物标志物参与细胞信号转导、脂质代谢和脂质过氧化功能。仅使用 19 例自发性早产（sPTB）和对照进行的额外建模确定了 16 个 sPTB 标志物，在测试数据中的 AUC 为 0.89。一半的 sPTB 与早产标志物重叠。进一步的因果分析推断，壬二酸上调几种脂肪酸以促进早产。
总之，这项研究表明脂质，特别是脂肪酸，参与了早产的发病机制。
