A multi-omic analysis of birthweight in newborn cord blood reveals new underlying mechanisms related to cholesterol metabolism.,Metabolism

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A multi-omic analysis of birthweight in newborn cord blood reveals new underlying mechanisms related to cholesterol metabolism.
Metabolism ( IF 9.8 ) Pub Date : 2020-06-15 , DOI: 10.1016/j.metabol.2020.154292
Rossella Alfano ₁ , Marc Chadeau-Hyam ₂ , Akram Ghantous ₃ , Pekka Keski-Rahkonen ₃ , Leda Chatzi ₄ , Almudena Espin Perez ₅ , Zdenko Herceg ₃ , Manolis Kogevinas ₆ , Theo M de Kok ₇ , Tim S Nawrot ₈ , Alexei Novoloaca ₃ , Chirag J Patel ₉ , Costanza Pizzi ₁₀ , Nivonirina Robinot ₃ , Franca Rusconi ₁₁ , Augustin Scalbert ₃ , Jordi Sunyer ₁₂ , Roel Vermeulen ₁₃ , Martine Vrijheid ₁₄ , Paolo Vineis ₁₅ , Oliver Robinson ₁₆ , Michelle Plusquin ₁

Affiliation

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.
International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69008 Lyon, France.
Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90007, United States; Department of Social Medicine, University of Crete, Heraklion, Crete, Greece.
Department of Biomedical Informatics Research, Stanford University, CA, United States.
Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain; ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain.
Department of Toxicogenomics, Maastricht University, Maastricht, the Netherlands.
Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium; Environment & Health Unit, Leuven University, Leuven, Belgium.
Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, United States.
Department of Medical Sciences, University of Turin and CPO-Piemonte, Torino, Italy.
Unit of Epidemiology, Anna Meyer Children's University Hospital, Florence, Italy.
ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain.
Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom; Institute for Risk Assessment Sciences (IRAS), Division of Environmental Epidemiology, Utrecht University, Utrecht, the Netherlands.
Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain; ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain.
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; Human Genetic Foundation (HuGeF), Turin, Italy.
Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom.

Background

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.

Methods

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.

Results

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.

Conclusions

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.

中文翻译：

对新生儿脐带血出生体重的多组学分析揭示了与胆固醇代谢相关的新的潜在机制。

背景

出生体重反映了子宫内暴露和后来的健康演变。尽管现有研究采用高维分子测量，但对出生体重潜在机制的理解仍然有限。

方法

为了研究出生体重的系统生物学，我们横断面整合了从四个出生队列（n  = 489）收集的脐带血样本中测量的甲基化组、转录组、代谢组和一组炎症蛋白。我们专注于先前与出生体重相关的两组 68 种代谢物和 903 个 CpG，并通过二部 Pearson 相关性研究了这两组和所有其他组学特征之间存在的相关结构。

结果

该数据集显示，出生体重的代谢组和甲基化组特征有七个共同信号，包括三种代谢物 [PC(34:2)、缩醛磷脂 PC(36:4)/PC(O-36:5) 和一种化合物m/z为781.0545]、两个 CpG（位于DHCR24和SC4MOL基因上）和两种蛋白质（periostin 和 CCL22）。CCL22 是一种巨噬细胞衍生的趋化因子，此前尚未发现其与出生体重的关系。由于组学整合的结果表明胆固醇代谢的核心作用，我们在 ENVIR ON AGE 队列（n = 1097）中探讨了脐带血中胆固醇水平与出生体重的关联， 发现较高的出生体重与高密度胆固醇增加相关。与大胎龄新生儿相比，小胎龄新生儿的脂蛋白胆固醇和高密度脂蛋白胆固醇较低。