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Interplay of Placental DNA Methylation and Maternal Insulin Sensitivity in Pregnancy

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Interplay of Placental DNA Methylation and Maternal Insulin Sensitivity in Pregnancy 484 Diabetes Volume 69, March 2020 Interplay of Placental DNA Methylation and Maternal Insulin Sensitivity in Pregnancy Marie-France Hivert,1,2,3 Andres Cardenas,4 Catherine Allard,5 Myriam Doyon,5 Camille E. Powe,2 Patrick M. Catalano,6 Patrice Perron,3,5 and Luigi Bouchard5,7,8 Diabetes 2020;69:484–492 | https://doi.org/10.2337/db19-0798 The placenta participates in maternal insulin sensitivity Insulin sensitivity decreases drastically in the 2nd half of changes during pregnancy; however, mechanisms remain pregnancy to levels that are similar to those in individuals unclear. We investigated associations between maternal with early type 2 diabetes (T2D) (1). It is hypothesized that insulin sensitivity and placental DNA methylation markers this dramatic decrease in insulin sensitivity is meant to help across the genome. We analyzed data from 430 mother- provide nutrients from maternal sources to the growing offspring dyads in the Gen3G cohort. All women under- fetus. The placenta likely plays a role in this physiologic ∼ went 75-g oral glucose tolerance tests at 26 weeks of adaptation, but the exact mechanisms remain unclear. gestation; we used glucose and insulin measures to es- The placenta is a unique organ of fetal origin that lies at timate insulin sensitivity (Matsuda index). At delivery, we the maternal and fetal interface with primary roles to collected samples from placenta (fetal side) and mea- optimize fetal growth, protect the fetus against infections, sured DNA methylation using Illumina EPIC arrays. Using and produce key hormones to maintain pregnancy; these linear regression models to quantify associations at 720,077 hormones profoundly influence maternal physiology. In its cytosine-guanine dinucleotides (CpGs), with adjustment role of nutrient transfer, the placenta responds to both for maternal age, gravidity, smoking, BMI, child sex, and fetal demands and maternal availability of nutrients and gestational age at delivery, we identified 188 CpG sites further adapts to regulate resources allocation. Yet, the where placental DNA methylation was associated with “ fl ” Matsuda index (P < 6.94 3 1028). Among genes annotated maternal-fetal con ict theory posits that the mother and “ ” to these 188 CpGs, we found enrichment in targets for the fetus disagree on an optimal level of resource allo- miRNAs, in histone modifications, and in parent-of-origin cation from the mother to the fetus to allow pregnancy to DNA methylation including the H19/MIR675 locus (pater- its term and a healthy baby (2). During early embryogen- nally imprinted). We identified 12 known placenta imprinted esis, the trophectoderm develops to form the placenta with genes, including KCNQ1. Mendelian randomization analy- a distinctive epigenetic process (3). The placenta demeth- fi GENETICS/GENOMES/PROTEOMICS/METABOLOMICS ses revealed ve loci where placenta DNA methylation may ylation process in early development is characterized by causally influence maternal insulin sensitivity, including the a great number of genomic regions remaining imprinted from maternally imprinted gene DLGAP2. Our results suggest their parent of origin. Some investigators have proposed that that placental DNA methylation is fundamentally linked to the maintenance of the parental origin of imprinted regions the regulation of maternal insulin sensitivity in pregnancy. in placenta contributes to the “maternal-fetal conflict” 1Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Université de Sherbrooke, Sherbrooke, Quebec, Canada Health Care Institute, Boston, MA 8Department of Medical Biology, CIUSSS du Saguenay–Lac-Saint-Jean, Hôpital de 2Diabetes Unit, Massachusetts General Hospital, and Harvard Medical School, Chicoutimi, Saguenay, Quebec, Canada Boston, MA Corresponding author: Marie-France Hivert, [email protected] 3Department of Medicine, Faculté de médecine et des sciences de la santé, Received 10 August 2019 and accepted 24 December 2019 Université de Sherbrooke, Sherbrooke, Quebec, Canada 4Division of Environmental Health Sciences, School of Public Health, University of This article contains Supplementary Data online at https://diabetes California, Berkeley, Berkeley, CA .diabetesjournals.org/lookup/suppl/doi:10.2337/db19-0798/-/DC1. 5Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, © 2019 by the American Diabetes Association. Readers may use this article as Sherbrooke, Quebec, Canada long as the work is properly cited, the use is educational and not for profit, and the 6Mother Infant Research Institute, Department of Obstetrics and Gynecology, Tufts work is not altered. More information is available at https://www.diabetesjournals Medical Center, Tufts University School of Medicine and Friedman School of .org/content/license. Nutrition and Science Policy, Boston, MA 7Department of Biochemistry, Faculté de médecine et des sciences de la santé, diabetes.diabetesjournals.org Hivert and Associates 485 where genes that are expressed from paternal alleles act to samples based on availability of adequate tissue (high- shunt more nutrients to the fetus while expression driven quality DNA extraction) and excluded complications in late by maternal alleles helps the mother maintain her resources pregnancy or delivery (e.g., preeclampsia, chorioamnionitis, (2,4). Thus, it is plausible that specific DNA methylation stillbirth). patterns in the placenta may influence the decline in The CHUS ethics board review committee approved this maternal insulin sensitivity that leads to the transfer of study; all women provided written consent. For this study, glucose and other fuels to the fetus. we included only women of European origin (self-reported) Based on these hypotheses, we investigated associa- who had consented for genetics investigations. tions between maternal insulin sensitivity estimated in the 2nd trimester and genome-wide DNA methylation in pla- Bioassays centa collected at birth in a large prospective pregnancy We measured glucose by the glucose hexokinase method cohort. We had initially hypothesized that maternal insulin (Roche Diagnostics) immediatelyaftercollectionandinsulin sensitivity could lead to changes in placental DNA methyl- using multiplexed particle-based flow cytometric assays ation (given temporality of our measures) but also tested (Human MILLIPLEX map kits, EMD Millipore) from the possibility that placenta DNA methylation may in- plasma samples previously frozen (280°C). We estimated fluence maternal insulin sensitivity. To untangle whether insulin sensitivity using the Matsuda index, given by the placental DNA methylation is influencing maternal insulin following equation: 10,000/ (=[(fasting glucose 3 fasting sensitivity or vice versa, we tested potential causality using insulin) 3 (mean glucose during OGTT 3 mean insulin a bidirectional Mendelian randomization (MR) framework. during OGTT)]) (7). We selected the Matsuda index over Additionally, we conducted pathway analyses to deepen other measures of insulin sensitivity because it has been our understanding of our findings. validated against euglycemic-hyperinsulinemic clamps in pregnant women (7). RESEARCH DESIGN AND METHODS Description of Participants DNA Methylation Measurements This study is based on mother-child pairs in the Genetics of We purified DNA from 460 placenta samples using the Glucose regulation in Gestation and Growth (Gen3G) pro- AllPrep DNA/RNA/Protein Mini Kit (QIAGEN). After bi- spective cohort. We have previously published details of re- sulfite conversion, the Illumina Laboratory (San Diego, CA) cruitment and phenotypic measurements during pregnancy performed epigenome-wide DNA methylation measure- (5). In brief, we recruited women in the 1st trimester (V1: ments using the Infinium MethylationEPIC BeadChip. We 5–14 weeks), inviting all women presenting for their routine imported methylation data into R for preprocessing using prenatal laboratories at Centre Hospitalier Universitaire de minfi. We performed quality control (QC) at the sample Sherbrooke (CHUS). We excluded women with diabetes prior level, excluding samples that failed (n 5 5) or had mis- to pregnancy (known or discovered at 1st trimester) and matched genotype based on paired cord blood data (n 5 6) nonsingleton pregnancies. In addition to collecting blood or sex (n 5 1). Our final placenta DNA methylation data samples, our trained research staff collected demographics, set included 448 samples. We then excluded women be- medical history, and completed standardized anthropometric cause of missing data (Matsuda or key covariables). Thus, measurements. We calculated BMI using the standard our final data set for this study was composed of 430 formula (kg/m2). mother-child pairs (see Supplementary Fig. 1), which fully We followed participating women in the 2nd trimester overlap with our prior publication of maternal 2-h glucose (V2: 24–30 weeks) and completed similar measurements. associations with placenta DNA methylation (8). After overnight fasting, women completed a 75-g oral glucose We normalized our data as previously described (8). We tolerance testing (OGTT) for gestational diabetes mellitus applied functional normalization (9) (FunNorm) and Regres- (GDM) screening. We collected plasma samples at baseline sion on Correlated Probes (10) (RCP) to adjust for technical (fasting)andat1hand2hduring the OGTT. We measured variability and probe type bias, respectively. Briefly, FunNorm glucose and insulin at each OGTT time point, which allowed removes technical variability using control
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