{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:44:48Z","timestamp":1788871488530,"version":"build-2803163510"},"reference-count":52,"publisher":"American Diabetes Association","issue":"8","license":[{"start":{"date-parts":[[2018,7,20]],"date-time":"2018-07-20T00:00:00Z","timestamp":1532044800000},"content-version":"vor","delay-in-days":70,"URL":"http:\/\/www.diabetesjournals.org\/content\/license"}],"funder":[{"DOI":"10.13039\/100000041","name":"American Diabetes Association","doi-asserted-by":"publisher","award":["1-15-ACE-26"],"award-info":[{"award-number":["1-15-ACE-26"]}],"id":[{"id":"10.13039\/100000041","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000156","name":"Fonds de Recherche du Qu\u00e9bec - Sant\u00e9","doi-asserted-by":"publisher","award":["20697"],"award-info":[{"award-number":["20697"]}],"id":[{"id":"10.13039\/501100000156","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP 115071"],"award-info":[{"award-number":["MOP 115071"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008985","name":"Diabetes Qu\u00e9bec","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008985","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,8,1]]},"abstract":"<jats:p>Maternal hyperglycemia during pregnancy is associated with excess fetal growth and adverse perinatal and developmental outcomes. Placental epigenetic maladaptation may underlie these associations. We performed an epigenome-wide association study (&amp;gt;850,000 CpG sites) of term placentas and prenatal maternal glycemic response 2-h post oral glucose challenge at 24\u201330 weeks of gestation among 448 mother-infant pairs. Maternal 2-h glycemia postload was strongly associated with lower DNA methylation of four CpG sites (false discovery rate [FDR] q &amp;lt;0.05) within the phosphodiesterase 4B gene (PDE4B). Additionally, three other individual CpG sites were differentially methylated relative to maternal glucose response within the TNFRSF1B, LDLR, and BLM genes (FDR q &amp;lt;0.05). DNA methylation correlated with expression of its respective genes in placental tissue at three out of four independent identified loci: PDE4B (r = 0.31, P &amp;lt; 0.01), TNFRSF1B (r = \u22120.24, P = 0.013), and LDLR (r = 0.32, P &amp;lt; 0.001). In an independent replication cohort (N = 65\u2013108 samples), results were consistent in direction but not significantly replicated among tested CpG sites in PDE4B and TNFRSF1B. Our study provides evidence that maternal glycemic response during pregnancy is associated with placental DNA methylation of key inflammatory genes whose expression levels are partially under epigenetic control.<\/jats:p>","DOI":"10.2337\/db18-0123","type":"journal-article","created":{"date-parts":[[2018,5,11]],"date-time":"2018-05-11T10:15:15Z","timestamp":1526033715000},"page":"1673-1683","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":57,"title":["Placental DNA Methylation Adaptation to Maternal Glycemic Response in Pregnancy"],"prefix":"10.2337","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2284-3298","authenticated-orcid":false,"given":"Andres","family":"Cardenas","sequence":"first","affiliation":[{"name":"Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Gagn\u00e9-Ouellet","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Allard","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Brisson","sequence":"additional","affiliation":[{"name":"Lipidology Unit, Community Genomic Medicine Centre and ECOGENE-21, Department of Medicine, Universit\u00e9 de Montr\u00e9al, Saguenay, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrice","family":"Perron","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Bouchard","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7752-2585","authenticated-orcid":false,"given":"Marie-France","family":"Hivert","sequence":"additional","affiliation":[{"name":"Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA"},{"name":"Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada"},{"name":"Diabetes Unit, Massachusetts General Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2018,5,11]]},"reference":[{"key":"2022031211224807500_B1"},{"key":"2022031211224807500_B2"},{"key":"2022031211224807500_B3","first-page":"e1545","author":"Metzger","year":"2010"},{"key":"2022031211224807500_B4","doi-asserted-by":"crossref","first-page":"679","DOI":"10.2337\/dc16-2397","article-title":"In utero exposure to maternal hyperglycemia increases childhood cardiometabolic risk in offspring","volume":"40","author":"Tam","year":"2017","journal-title":"Diabetes Care"},{"key":"2022031211224807500_B5","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/nrendo.2009.195","article-title":"Nutritional programming of the metabolic syndrome","volume":"5","author":"Symonds","year":"2009","journal-title":"Nat Rev Endocrinol"},{"key":"2022031211224807500_B6","doi-asserted-by":"crossref","first-page":"16153","DOI":"10.3390\/ijms150916153","article-title":"Maternal-fetal nutrient transport in pregnancy pathologies: the role of the placenta","volume":"15","author":"Brett","year":"2014","journal-title":"Int J Mol Sci"},{"key":"2022031211224807500_B7","doi-asserted-by":"crossref","first-page":"2497","DOI":"10.1210\/jc.2011-1800","article-title":"Transplacental supply of mannose and inositol in uncomplicated pregnancies using stable isotopes","volume":"97","author":"Staat","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031211224807500_B8","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1053\/plac.1999.0448","article-title":"Glucose transporters in the human placenta","volume":"21","author":"Illsley","year":"2000","journal-title":"Placenta"},{"key":"2022031211224807500_B9","doi-asserted-by":"crossref","first-page":"935","DOI":"10.4161\/epi.25578","article-title":"Gestational diabetes mellitus epigenetically affects genes predominantly involved in metabolic diseases","volume":"8","author":"Ruchat","year":"2013","journal-title":"Epigenetics"},{"key":"2022031211224807500_B10","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.1093\/hmg\/ddv013","article-title":"Maternal gestational diabetes is associated with genome-wide DNA methylation variation in placenta and cord blood of exposed offspring","volume":"24","author":"Finer","year":"2015","journal-title":"Hum Mol Genet"},{"key":"2022031211224807500_B11","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1055\/s-0034-1398666","article-title":"DNA methylation profiles in placenta and its association with gestational diabetes mellitus","volume":"123","author":"Rong","year":"2015","journal-title":"Exp Clin Endocrinol Diabetes"},{"key":"2022031211224807500_B12","doi-asserted-by":"crossref","first-page":"e010031","DOI":"10.1136\/bmjopen-2015-010031","article-title":"Genetics of Glucose regulation in Gestation and Growth (Gen3G): a prospective prebirth cohort of mother-child pairs in Sherbrooke, Canada","volume":"6","author":"Guillemette","year":"2016","journal-title":"BMJ Open"},{"key":"2022031211224807500_B13","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1016\/j.ymeth.2010.01.005","article-title":"A practical approach to RT-qPCR-Publishing data that conform to the MIQE guidelines","volume":"50","author":"Taylor","year":"2010","journal-title":"Methods"},{"key":"2022031211224807500_B14","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1093\/bioinformatics\/btu049","article-title":"Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays","volume":"30","author":"Aryee","year":"2014","journal-title":"Bioinformatics"},{"key":"2022031211224807500_B15","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1186\/s13059-016-1066-1","article-title":"Critical evaluation of the Illumina MethylationEPIC BeadChip microarray for whole-genome DNA methylation profiling","volume":"17","author":"Pidsley","year":"2016","journal-title":"Genome Biol"},{"key":"2022031211224807500_B16","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1186\/s13059-014-0503-2","article-title":"Functional normalization of 450k methylation array data improves replication in large cancer studies","volume":"15","author":"Fortin","year":"2014","journal-title":"Genome Biol"},{"key":"2022031211224807500_B17","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s12864-016-3426-3","article-title":"RELIC: a novel dye-bias correction method for Illumina Methylation BeadChip","volume":"18","author":"Xu","year":"2017","journal-title":"BMC Genomics"},{"key":"2022031211224807500_B18","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1093\/biostatistics\/kxj037","article-title":"Adjusting batch effects in microarray expression data using empirical Bayes methods","volume":"8","author":"Johnson","year":"2007","journal-title":"Biostatistics"},{"key":"2022031211224807500_B19","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1186\/1471-2105-11-587","article-title":"Comparison of Beta-value and M-value methods for quantifying methylation levels by microarray analysis","volume":"11","author":"Du","year":"2010","journal-title":"BMC Bioinformatics"},{"key":"2022031211224807500_B20","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.placenta.2004.09.009","article-title":"Evaluation of housekeeping genes in placental comparative expression studies","volume":"26","author":"Meller","year":"2005","journal-title":"Placenta"},{"key":"2022031211224807500_B21"},{"key":"2022031211224807500_B22","volume-title":"An R Companion to Applied Regression: Robust Regression in R","author":"Fox","year":"2011"},{"key":"2022031211224807500_B23","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/nmeth.3809","article-title":"Sparse PCA corrects for cell type heterogeneity in epigenome-wide association studies","volume":"13","author":"Rahmani","year":"2016","journal-title":"Nat Methods"},{"key":"2022031211224807500_B24","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1164\/ajrccm.157.2.9708012","article-title":"Phosphodiesterase isozymes: molecular targets for novel antiasthma agents","volume":"157","author":"Torphy","year":"1998","journal-title":"Am J Respir Crit Care Med"},{"key":"2022031211224807500_B25","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1165\/rcmb.2008-0091TR","article-title":"Cyclic AMP: master regulator of innate immune cell function","volume":"39","author":"Serezani","year":"2008","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2022031211224807500_B26","doi-asserted-by":"crossref","first-page":"7628","DOI":"10.1073\/pnas.122041599","article-title":"Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-\u03b1 responses","volume":"99","author":"Jin","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031211224807500_B27","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1093\/rheumatology\/keq031","article-title":"Transmembrane TNF-\u03b1: structure, function and interaction with anti-TNF agents","volume":"49","author":"Horiuchi","year":"2010","journal-title":"Rheumatology (Oxford)"},{"key":"2022031211224807500_B28","doi-asserted-by":"crossref","first-page":"S12","DOI":"10.1186\/1471-2393-7-S1-S12","article-title":"PDE4 as a target in preterm labour","volume":"7","author":"M\u00e9hats","year":"2007","journal-title":"BMC Pregnancy Childbirth"},{"key":"2022031211224807500_B29","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.4049\/jimmunol.178.2.1115","article-title":"PDE4 inhibition prevents preterm delivery induced by an intrauterine inflammation","volume":"178","author":"Schmitz","year":"2007","journal-title":"J Immunol"},{"key":"2022031211224807500_B30","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/oby.2010.215","article-title":"Pregravid obesity associates with increased maternal endotoxemia and metabolic inflammation","volume":"19","author":"Basu","year":"2011","journal-title":"Obesity (Silver Spring)"},{"key":"2022031211224807500_B31","doi-asserted-by":"crossref","first-page":"2207","DOI":"10.2337\/diabetes.51.7.2207","article-title":"TNF-\u03b1 is a predictor of insulin resistance in human pregnancy","volume":"51","author":"Kirwan","year":"2002","journal-title":"Diabetes"},{"key":"2022031211224807500_B32","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1210\/jc.2013-4016","article-title":"TNF\u03b1 dynamics during the oral glucose tolerance test vary according to the level of insulin resistance in pregnant women","volume":"99","author":"Guillemette","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031211224807500_B33","doi-asserted-by":"crossref","first-page":"3076","DOI":"10.1210\/en.2009-0108","article-title":"Reduced adiposity and high-fat diet-induced adipose inflammation in mice deficient for phosphodiesterase 4B","volume":"150","author":"Zhang","year":"2009","journal-title":"Endocrinology"},{"key":"2022031211224807500_B34","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1111\/dom.12839","article-title":"The PDE4 inhibitor roflumilast reduces weight gain by increasing energy expenditure and leads to improved glucose metabolism","volume":"19","author":"M\u00f6llmann","year":"2017","journal-title":"Diabetes Obes Metab"},{"key":"2022031211224807500_B35","doi-asserted-by":"crossref","first-page":"2779","DOI":"10.1007\/s00125-012-2632-z","article-title":"The glucose-lowering effects of the PDE4 inhibitors roflumilast and roflumilast-N-oxide in db\/db mice","volume":"55","author":"Vollert","year":"2012","journal-title":"Diabetologia"},{"key":"2022031211224807500_B36","doi-asserted-by":"crossref","first-page":"E1720","DOI":"10.1210\/jc.2011-2886","article-title":"Effect of the phosphodiesterase 4 inhibitor roflumilast on glucose metabolism in patients with treatment-naive, newly diagnosed type 2 diabetes mellitus","volume":"97","author":"Wouters","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031211224807500_B37","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1111\/cts.12436","article-title":"Pharmacokinetic\/pharmacodynamic modeling of the PDE4 inhibitor TAK-648 in type 2 diabetes: early translational approaches for human dose prediction","volume":"10","author":"Plock","year":"2017","journal-title":"Clin Transl Sci"},{"key":"2022031211224807500_B38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0021-9150(00)00375-0","article-title":"Soluble receptors for tumor necrosis factor-\u03b1 (TNF-R p55 and TNF-R p75) in familial combined hyperlipidemia","volume":"153","author":"van Greevenbroek","year":"2000","journal-title":"Atherosclerosis"},{"key":"2022031211224807500_B39","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/39335","article-title":"Protection from obesity-induced insulin resistance in mice lacking TNF-\u03b1 function","volume":"389","author":"Uysal","year":"1997","journal-title":"Nature"},{"key":"2022031211224807500_B40","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.placenta.2008.10.012","article-title":"Human tumour necrosis factor: physiological and pathological roles in placenta and endometrium","volume":"30","author":"Haider","year":"2009","journal-title":"Placenta"},{"key":"2022031211224807500_B41","doi-asserted-by":"crossref","first-page":"E146","DOI":"10.1210\/jc.2010-1170","article-title":"TNF-\u03b1 antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome","volume":"96","author":"Stanley","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031211224807500_B42","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.metabol.2009.08.017","article-title":"The association of TNFr2 and TNF\u03b1 with insulin resistance and the influence of adipose tissue biomarkers in humans","volume":"59","author":"Hivert","year":"2010","journal-title":"Metabolism"},{"key":"2022031211224807500_B43","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.2337\/diacare.25.10.1824","article-title":"Increased plasma-soluble tumor necrosis factor-\u03b1 receptor 2 level in lean nondiabetic offspring of type 2 diabetic subjects","volume":"25","author":"Straczkowski","year":"2002","journal-title":"Diabetes Care"},{"key":"2022031211224807500_B44","doi-asserted-by":"crossref","first-page":"875","DOI":"10.2337\/diacare.26.3.875","article-title":"Soluble tumor necrosis factor-\u03b1 receptors in young obese subjects with normal and impaired glucose tolerance","volume":"26","author":"Dzienis-Straczkowska","year":"2003","journal-title":"Diabetes Care"},{"key":"2022031211224807500_B45","first-page":"859","article-title":"Serum levels of tumor necrosis factor-\u03b1 are increased in obese patients with noninsulin-dependent diabetes mellitus","volume":"83","author":"Katsuki","year":"1998","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031211224807500_B46","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1007\/s001250051000","article-title":"Elevated serum tumour necrosis factor-alpha levels can contribute to the insulin resistance in type II (non-insulin-dependent) diabetes and in obesity","volume":"41","author":"Winkler","year":"1998","journal-title":"Diabetologia"},{"key":"2022031211224807500_B47","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1095\/biolreprod.112.105619","article-title":"Modulation of cholesterol transport by insulin-treated gestational diabetes mellitus in human full-term placenta","volume":"88","author":"Dub\u00e9","year":"2013","journal-title":"Biol Reprod"},{"key":"2022031211224807500_B48","doi-asserted-by":"crossref","first-page":"E476","DOI":"10.1152\/ajpendo.00547.2005","article-title":"Intrauterine growth restriction is associated with alterations in placental lipoprotein receptors and maternal lipoprotein composition","volume":"292","author":"Wadsack","year":"2007","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2022031211224807500_B49","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1111\/j.1471-0528.1999.tb08153.x","article-title":"Expression of low density lipoprotein receptor messenger ribonuclein acid in placentas from pregnancies with preterm delivery and pregnancies with intrauterine growth retardation","volume":"106","author":"Stepan","year":"1999","journal-title":"BJOG"},{"key":"2022031211224807500_B50","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.ghir.2007.09.001","article-title":"Differential regulation of pregnancy associated plasma protein-A in human coronary artery endothelial cells and smooth muscle cells","volume":"18","author":"Conover","year":"2008","journal-title":"Growth Horm IGF Res"},{"key":"2022031211224807500_B51","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/S0065-227X(04)80061-3","article-title":"The function of RecQ helicase gene family (especially BLM) in DNA recombination and joining","volume":"38","author":"Kaneko","year":"2004","journal-title":"Adv Biophys"},{"key":"2022031211224807500_B52","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/nmeth.4190","article-title":"Correcting for cell-type heterogeneity in DNA methylation: a comprehensive evaluation","volume":"14","author":"Rahmani","year":"2017","journal-title":"Nat Methods"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/diabetes.diabetesjournals.org\/syndication\/doi\/10.2337\/db18-0123","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/67\/8\/1673\/539373\/db180123.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/67\/8\/1673\/539373\/db180123.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T12:35:37Z","timestamp":1667392537000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/67\/8\/1673\/17297\/Placental-DNA-Methylation-Adaptation-to-Maternal"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,11]]},"references-count":52,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2018,5,11]]},"published-print":{"date-parts":[[2018,8,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db18-0123","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/224139","asserted-by":"object"}]},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,11]]}}}