A Co-expression Analysis of the Placental Transcriptome in Association With Maternal Pre-pregnancy BMI and Newborn Birth Weight

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Abstract

Maternal body mass index (BMI) before pregnancy is known to affect both fetal growth and later-life health of the newborn, yet the implicated molecular mechanisms remain largely unknown. As the master regulator of the fetal environment, the placenta is a valuable resource for the investigation of processes involved in the developmental programming of metabolic health. We conducted a genome-wide placental transcriptome study aiming at the identification of functional pathways representing the molecular link between maternal BMI and fetal growth. We used RNA microarray (Agilent 8 × 60 K), medical records, and questionnaire data from 183 mother-newborn pairs from the ENVIR ONAGE birth cohort study (Flanders, Belgium). Using a weighted gene co-expression network analysis, we identified 17 correlated gene modules. Three of these modules were associated with both maternal pre-pregnancy BMI and newborn birth weight. A gene cluster enriched for genes involved in immune response and myeloid cell differentiation was positively associated with maternal BMI and negatively with low birth weight. Two other gene modules, upregulated in association with maternal BMI as well as birth weight, were involved in processes related to organ and tissue development, with blood vessel morphogenesis and extracellular matrix structure as top Gene Ontology terms. In line with this, erythrocyte-, angiogenesis-, and extracellular matrix-related genes were among the identified hub genes. The association between maternal BMI and newborn weight was significantly mediated by gene expression for 5 of the hub genes ( FZD4, COL15A1, GPR124, COL6A1, and COL1A1). As some of the identified hub genes have been linked to obesity in adults, our observation in placental tissue suggests that biological processes may be affected from prenatal life onwards, thereby identifying new molecular processes linking maternal BMI and fetal metabolic programming.

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Most cited references 43

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ppcor: An R Package for a Fast Calculation to Semi-partial Correlation Coefficients.

Seongho Kim (2015)

Lack of a general matrix formula hampers implementation of the semi-partial correlation, also known as part correlation, to the higher-order coefficient. This is because the higher-order semi-partial correlation calculation using a recursive formula requires an enormous number of recursive calculations to obtain the correlation coefficients. To resolve this difficulty, we derive a general matrix formula of the semi-partial correlation for fast computation. The semi-partial correlations are then implemented on an R package ppcor along with the partial correlation. Owing to the general matrix formulas, users can readily calculate the coefficients of both partial and semi-partial correlations without computational burden. The package ppcor further provides users with the level of the statistical significance with its test statistic.

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Maternal body mass index and the risk of fetal death, stillbirth, and infant death: a systematic review and meta-analysis.

Dagfinn Aune, Ola Saugstad, Tore Henriksen … (2014)

Evidence suggests that maternal obesity increases the risk of fetal death, stillbirth, and infant death; however, the optimal body mass index (BMI) for prevention is not known. To conduct a systematic review and meta-analysis of cohort studies of maternal BMI and risk of fetal death, stillbirth, and infant death. The PubMed and Embase databases were searched from inception to January 23, 2014. Cohort studies reporting adjusted relative risk (RR) estimates for fetal death, stillbirth, or infant death by at least 3 categories of maternal BMI were included. Data were extracted by 1 reviewer and checked by the remaining reviewers for accuracy. Summary RRs were estimated using a random-effects model. Fetal death, stillbirth, and neonatal, perinatal, and infant death. Thirty eight studies (44 publications) with more than 10,147 fetal deaths, more than 16,274 stillbirths, more than 4311 perinatal deaths, 11,294 neonatal deaths, and 4983 infant deaths were included. The summary RR per 5-unit increase in maternal BMI for fetal death was 1.21 (95% CI, 1.09-1.35; I2 = 77.6%; n = 7 studies); for stillbirth, 1.24 (95% CI, 1.18-1.30; I2 = 80%; n = 18 studies); for perinatal death, 1.16 (95% CI, 1.00-1.35; I2 = 93.7%; n = 11 studies); for neonatal death, 1.15 (95% CI, 1.07-1.23; I2 = 78.5%; n = 12 studies); and for infant death, 1.18 (95% CI, 1.09-1.28; I2 = 79%; n = 4 studies). The test for nonlinearity was significant in all analyses but was most pronounced for fetal death. For women with a BMI of 20 (reference standard for all outcomes), 25, and 30, absolute risks per 10,000 pregnancies for fetal death were 76, 82 (95% CI, 76-88), and 102 (95% CI, 93-112); for stillbirth, 40, 48 (95% CI, 46-51), and 59 (95% CI, 55-63); for perinatal death, 66, 73 (95% CI, 67-81), and 86 (95% CI, 76-98); for neonatal death, 20, 21 (95% CI, 19-23), and 24 (95% CI, 22-27); and for infant death, 33, 37 (95% CI, 34-39), and 43 (95% CI, 40-47), respectively. Even modest increases in maternal BMI were associated with increased risk of fetal death, stillbirth, and neonatal, perinatal, and infant death. Weight management guidelines for women who plan pregnancies should take these findings into consideration to reduce the burden of fetal death, stillbirth, and infant death.

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Placental Origins of Chronic Disease.

Graham J. Burton, Abigail Fowden, Kent Thornburg (2016)

Epidemiological evidence links an individual's susceptibility to chronic disease in adult life to events during their intrauterine phase of development. Biologically this should not be unexpected, for organ systems are at their most plastic when progenitor cells are proliferating and differentiating. Influences operating at this time can permanently affect their structure and functional capacity, and the activity of enzyme systems and endocrine axes. It is now appreciated that such effects lay the foundations for a diverse array of diseases that become manifest many years later, often in response to secondary environmental stressors. Fetal development is underpinned by the placenta, the organ that forms the interface between the fetus and its mother. All nutrients and oxygen reaching the fetus must pass through this organ. The placenta also has major endocrine functions, orchestrating maternal adaptations to pregnancy and mobilizing resources for fetal use. In addition, it acts as a selective barrier, creating a protective milieu by minimizing exposure of the fetus to maternal hormones, such as glucocorticoids, xenobiotics, pathogens, and parasites. The placenta shows a remarkable capacity to adapt to adverse environmental cues and lessen their impact on the fetus. However, if placental function is impaired, or its capacity to adapt is exceeded, then fetal development may be compromised. Here, we explore the complex relationships between the placental phenotype and developmental programming of chronic disease in the offspring. Ensuring optimal placentation offers a new approach to the prevention of disorders such as cardiovascular disease, diabetes, and obesity, which are reaching epidemic proportions.

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Author and article information

Contributors

Bianca Cox: URI : http://loop.frontiersin.org/people/649415/overview

Maria Tsamou: URI : http://loop.frontiersin.org/people/667882/overview

Karen Vrijens: URI : http://loop.frontiersin.org/people/630370/overview

Kristof Y. Neven: URI : http://loop.frontiersin.org/people/667731/overview

Theo M. de Kok: URI : http://loop.frontiersin.org/people/411324/overview

Michelle Plusquin: URI : http://loop.frontiersin.org/people/609924/overview

Tim S. Nawrot: URI : http://loop.frontiersin.org/people/391577/overview

Journal

Journal ID (nlm-ta): Front Genet

Journal ID (iso-abbrev): Front Genet

Journal ID (publisher-id): Front. Genet.

Title: Frontiers in Genetics

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1664-8021

Publication date (Electronic): 29 April 2019

Publication date Collection: 2019

Volume: 10

Electronic Location Identifier: 354

Affiliations

[1] ¹Center for Environmental Sciences, Hasselt University , Hasselt, Belgium

[2] ²Department of Toxicogenomics, Maastricht University , Maastricht, Netherlands

[3] ³Department of Public Health, Environment and Health Unit, Leuven University (KU Leuven) , Leuven, Belgium

Author notes

Edited by: Dana C. Crawford, Case Western Reserve University, United States

Reviewed by: Signe Altmäe, University of Granada, Spain; Jacklyn Hellwege, Vanderbilt University Medical Center, United States; Ayush Giri, Vanderbilt University Medical Center, United States

*Correspondence: Tim S. Nawrot, tim.nawrot@ 123456uhasselt.be

^†These authors have contributed equally to this work

This article was submitted to Applied Genetic Epidemiology, a section of the journal Frontiers in Genetics

Article

DOI: 10.3389/fgene.2019.00354

PMC ID: 6501552

PubMed ID: 31110514

SO-VID: 8c8f618c-3f66-4039-92b8-6c7d52430e3d

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 29 November 2018

Date accepted : 02 April 2019

Page count

Figures: 3, Tables: 2, Equations: 0, References: 56, Pages: 13, Words: 0

Funding

Funded by: European Research Council 10.13039/501100000781

Funded by: Fonds Wetenschappelijk Onderzoek 10.13039/501100003130

Award ID: G073315N

Award ID: 12Q0517N

Award ID: 12D7718N

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A Co-expression Analysis of the Placental Transcriptome in Association With Maternal Pre-pregnancy BMI and Newborn Birth Weight

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G3: Genes|Genomes|Genetics

Most cited references 43

ppcor: An R Package for a Fast Calculation to Semi-partial Correlation Coefficients.

Maternal body mass index and the risk of fetal death, stillbirth, and infant death: a systematic review and meta-analysis.

Placental Origins of Chronic Disease.

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