Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom; Medical Research Council-Health Protection Agency Centre for Environment and Health, Imperial College London, London, United Kingdom; Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium.
Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom; Medical Research Council-Health Protection Agency Centre for Environment and Health, Imperial College London, London, United Kingdom; Institute for Risk Assessment Sciences (IRAS), Division of Environmental Epidemiology, Utrecht University, Utrecht, the Netherlands.
Metabolism. 2020 Sep;110:154292. doi: 10.1016/j.metabol.2020.154292. Epub 2020 Jun 15.
Birthweight reflects in utero exposures and later health evolution. Despite existing studies employing high-dimensional molecular measurements, the understanding of underlying mechanisms of birthweight remains limited.
To investigate the systems biology of birthweight, we cross-sectionally integrated the methylome, the transcriptome, the metabolome and a set of inflammatory proteins measured in cord blood samples, collected from four birth-cohorts (n = 489). We focused on two sets of 68 metabolites and 903 CpGs previously related to birthweight and investigated the correlation structures existing between these two sets and all other omic features via bipartite Pearson correlations.
This dataset revealed that the set of metabolome and methylome signatures of birthweight have seven signals in common, including three metabolites [PC(34:2), plasmalogen PC(36:4)/PC(O-36:5), and a compound with m/z of 781.0545], two CpGs (on the DHCR24 and SC4MOL gene), and two proteins (periostin and CCL22). CCL22, a macrophage-derived chemokine has not been previously identified in relation to birthweight. Since the results of the omics integration indicated the central role of cholesterol metabolism, we explored the association of cholesterol levels in cord blood with birthweight in the ENVIRONAGE cohort (n = 1097), finding that higher birthweight was associated with increased high-density lipoprotein cholesterol and that high-density lipoprotein cholesterol was lower in small versus large for gestational age newborns.
Our data suggests that an integration of different omic-layers in addition to single omics studies is a useful approach to generate new hypotheses regarding biological mechanisms. CCL22 and cholesterol metabolism in cord blood play a mechanistic role in birthweight.
出生体重反映了宫内暴露和后期健康演变。尽管现有研究采用了高维分子测量方法，但对出生体重的潜在机制仍知之甚少。
为了研究出生体重的系统生物学，我们在四个出生队列（n=489）的脐带血样本中，交叉整合了甲基组、转录组、代谢组和一组炎症蛋白。我们重点关注了两组之前与出生体重相关的 68 种代谢物和 903 个 CpG，并通过二部 Pearson 相关分析，研究了这两组与所有其他组学特征之间的相关结构。
该数据集显示，出生体重的代谢组和甲基组特征集有七个共同信号，包括三种代谢物[PC(34:2)、髓鞘 PC(36:4)/PC(O-36:5)和一种分子量为 781.0545 的化合物]、两个 CpG（DHCR24 和 SC4MOL 基因）和两个蛋白质（periostin 和 CCL22）。CCL22 是一种巨噬细胞衍生的趋化因子，以前与出生体重无关。由于组学整合的结果表明胆固醇代谢的核心作用，我们在 ENVIRONAGE 队列（n=1097）中探索了脐带血中胆固醇水平与出生体重的关系，发现出生体重较高与高密度脂蛋白胆固醇升高有关，而在小胎龄儿和大胎龄儿中，高密度脂蛋白胆固醇较低。
我们的数据表明，除了单一组学研究外，整合不同的组学层是生成关于生物学机制的新假设的有用方法。脐带血中的 CCL22 和胆固醇代谢在出生体重中起机制作用。
