Excessive Gestational Weight Gain Alters DNA Methylation and Influences Foetal and Neonatal Body Composition

Abstract

Background: Changes in body weight are associated with the regulation of DNA methylation (DNAm). In this study, we investigated the associations between maternal gestational weight gain-related DNAm and foetal and neonatal body composition. Methods: Brazilian pregnant women from the Araraquara Cohort Study were followed up during pregnancy, delivery, and after hospital discharge. Women with normal pre-pregnancy BMI were allocated into two groups: adequate gestational weight gain (AGWG, n = 45) and excessive gestational weight gain (EGWG, n = 30). Foetal and neonatal body composition was evaluated via ultrasound and plethysmography, respectively. DNAm was assessed in maternal blood using Illumina Infinium MethylationEPIC BeadChip arrays. Linear regression models were used to explore the associations between DNAm and foetal and neonatal body composition. Results: Maternal weight, GWG, neonatal weight, and fat mass were higher in the EGWG group. Analysis of DNAm identified 46 differentially methylated positions and 11 differentially methylated regions (DMRs) between the EGWG and AGWG groups. Nine human phenotypes were enriched for these 11 DMRs located in 13 genes (EMILIN1, HOXA5, CPT1B, CLDN9, ZFP57, BRCA1, POU5F1, ANKRD33, HLA-B, RANBP17, ZMYND11, DIP2C, TMEM232), highlighting the terms insulin resistance, and hyperglycaemia. Maternal DNAm was associated with foetal total thigh and arm tissues and subcutaneous thigh and arm fat, as well as with neonatal fat mass percentage and fat mass. Conclusion: The methylation pattern in the EGWG group indicated a risk for developing chronic diseases and involvement of maternal DNAm in foetal lean and fat mass and in neonatal fat mass.

Integrative network analysis of differentially methylated regions to study the impact of gestational weight gain on maternal metabolism and fetal-neonatal growth

“…In a previous study ( Argentato et al, 2023 ), we found subtle changes in the DNAm status of mothers with EGWG in 11 DMRs located in EMILIN1, HOXA5, CPT1B, CLDN9, ZFP57, BRCA1, POU5F1, ANKRD33, HLA-B, RANBP17, ZMYND11, DIP2C, and TMEM232. In contrast, other studies evaluating obese individuals reported denser changes ( Ling and Rönn, 2019 ).…”

“…The AC at T3 was associated with three different DMRs and HC at T3 and T4 with one DMR. In another study from our research group, maternal DNAm was associated with fetal subcutaneous thigh and arm fat and with neonatal fat mass ( Argentato et al, 2023 ). The literature had reported an association between DNAm and fetal growth ( Koukoura et al, 2012 ).…”

“…This study was conducted according to the guidelines of the Declaration of Helsinki and all procedures involving human subjects. All women and/or their legal guardian(s) signed the free informed consent form and the Research Ethics Committee of the Faculty of Public Health, University of São Paulo, approved in 12/05/2017 the study (protocol number 2.570.576), as described by Argentato et al (2023 ).…”

“…Singular value decomposition (SVD) analysis was applied to beta-values to correlate biological covariates with the principal components, as described by Argentato et al (2023 ), which led to the identification of 11 DMRs between EGWG and AGWG (DMR1 = chr6:29648161-29648756, DMR2 = chr6:31148332-31148666, DMR3 = chr7:27183133-27183816, DMR4 = chr10:530635-531584, DMR5 = chr22:51016386-51016950, DMR6 = chr16:3062296-3062975, DMR7 = chr5:110062539-110062837, DMR8 = chr17:41278135-41278906, DMR9 = chr2:27301195-27301943, DMR10 = chr5:170288671-170288788, DMR11 = chr12:52281482-52281997) were identified. The mean beta value of the DMR using the beta-value of the CpG sites that compose the DMR was calculated.…”

“…A growing number of studies using the Illumina Infinium Human MethylationEPIC BeadChip have generated data on pregnancy and fetal programming ( Sharp et al, 2015 ; Hjort et al ., 2018 ; Mas-Parés et al, 2023 ). A previous study from our research group showed that the maternal methylome of pregnant women with excessive gestational weight gain (EGWG) was altered at 46 differentially methylated positions and in 11 differentially methylated regions (DMRs) ( Argentato et al, 2023 ). However, the literature on gestational weight gain using statistical tools designed for integrative network analysis is scarce.…”