基于19 599例大样本的早产儿与足月儿代谢谱差异分析

Analysis of metabolic profile differences between preterm and full-term infants based on 19 599 cases

摘要

目的：通过检测新生儿血氨基酸、肉碱和琥珀酰丙酮等代谢指标，分析其相关影响因素，并寻找早产儿和足月儿之间的差异代谢物及代谢通路，为早产儿临床干预提供依据。方法：研究对象为2023年7月—2024年6月于江苏省淮安市各医疗保健机构分娩的新生儿19 599例，按出生胎龄分成两组，其中早产儿组（28周≤出生胎龄<37周）1 107例，足月儿组（37周≤出生胎龄<42周）18 492例。于新生儿出生后7 d内采集滤纸干血片，应用串联质谱技术检测血液代谢指标，使用Spearman秩相关分析性别、胎龄以及出生体重与代谢指标间的相关性，采用 t检验和偏最小二乘法判别分析鉴定组间具有显著差异的代谢物，并对两种方法获取的差异代谢物取交集，得到可能有生物学意义的潜在生物标志物。使用京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes，KEGG）数据库进行通路富集分析，获得差异代谢通路。结果：多种血氨基酸和肉碱代谢指标与新生儿性别、出生胎龄和出生体重存在显著相关性（P<0.05）。早产儿和足月儿两组间共筛选出18种显著差异代谢物，其中有8种在早产儿组表达上调，包括游离肉碱、精氨酸、苯丙氨酸等；10种代谢物下调，包括丙氨酸、甘氨酸、癸酰肉碱等。以上差异代谢物共涉及17条代谢通路，包括精氨酸和脯氨酸代谢，苯丙氨酸、酪氨酸和色氨酸的生物合成，苯丙氨酸代谢，不饱和脂肪酸的生物合成，脂肪酸降解，脂肪酸生物合成等。结论：新生儿血中氨基酸及肉碱水平与性别、胎龄、出生体重显著相关。早产儿与足月儿存在明确代谢差异，这些差异可能影响氨基酸与脂肪酸代谢过程。

Abstract

Objective：To investigate the metabolic profiles of blood amino acids，carnitines，and succinylacetone in neonates，analyze their influencing factors，and identify differential metabolites and metabolic pathways between preterm and full-term infants，thereby providing a basis for clinical intervention in preterm infants. Methods：A total of 19 599 neonates delivered at medical and healthcare institutions in Huai’an City，Jiangsu Province from July 2023 to June 2024 were enrolled. According to gestational age，they were divided into two groups：the preterm group（28 weeks≤gestational age<37 weeks， n=1 107）and the full-term group（37 weeks ≤ gestational age<42 weeks， n=18 492）. Dried blood spot samples were collected within 7 days after birth. Tandem mass spectrometry was used to measure blood metabolic parameters. Spearman rank correlation analysis was applied to examine the correlations among sex，gestational age，birth weight，and metabolic parameters. The t test and partial least squares discriminant analysis（PLS-DA）were used to identify significantly different metabolites between the two groups，and the intersection of the differential metabolites obtained by the two methods was selected as potential biologically significant biomarkers. Pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes（KEGG）database to identify differential metabolic pathways. Results：Multiple blood amino acids and carnitine metabolic parameters were significantly correlated with neonatal sex，gestational age，and birth weight（P<0.05）. A total of 18 significantly different metabolites were identified between preterm and full-term infants. Of them，8 metabolites were upregulated in the preterm group，including free carnitine（C0），arginine（Arg），and phenylalanine（Phe）；10 metabolites were downregulated，including alanine（Ala），glycine（Gly），and decanoylcarnitine（C10）. These differential metabolites were involved in 17 metabolic pathways，including arginine and proline metabolism；phenylalanine，tyrosine and tryptophan biosynthesis；phenylalanine metabolism；biosynthesis of unsaturated fatty acids；fatty acid degradation；and fatty acid biosynthesis. Conclusion：Blood amino acid and carnitine levels in neonates are significantly correlated with sex，gestational age，and birth weight. There are distinct metabolic differences between preterm and full-term infants，which may affect amino acid and fatty acid metabolic processes.

关键词

代谢组学 / 早产儿 / 氨基酸 / 肉碱 / 新生儿筛查 / 串联质谱

Key words

metabolomics / preterm infant / amino acid / carnitine / newborn screening / tandem mass spectrometry

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基金资助

江苏省卫生健康委员会妇幼保健科研项目(F202220)

淮安市科技项目（自然科学研究）(HAB2024040)