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Title: | Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies | Authors: | Tobi, Elmar W Juvinao-Quintero, Diana L. Ronkainen, Justiina Ott, Raffael ALFANO, Rossella Canouil, Mickaël Geurtsen, Madelon L. Khamis, Amna Küpers, Leanne K. Lim, Ives Y. Perron, Patrice Pesce, Giancarlo Tuhkanen, Johanna Starling, Anne P. Andrew, Toby Binder, Elisabeth Caiazzo, Robert Chan, Jerry K.Y. Gaillard, Romy Gluckman, Peter D. Keikkala, Elina Karnani, Neerja Mustaniemi, Sanna NAWROT, Tim Pattou, François Plusquin, Michelle Raverdy, Violeta Hian Tan, Kok Tzala, Evangelia Raikkonen, Katri Winkler, Christiane Ziegler, Anette-G. Annesi-Maesano, Isabella Bouchard, Luigi Seng Chong, Yap Dabelea, Dana Felix, Janine F. Heude, Barbara Jaddoe, Vincent W.V. Lahti, Jari REIMANN, Brigitte Vääräsmäki, Marja Bonnefond, Amélie Froguel, Philippe Hummel, Sandra Kajantie, Eero Jarvelin, Marjo-Riita Steegers-Theunissen, Regine P.M. Howe, Caitlin G. Hivert, Marie-France Sebert, Sylvain |
Issue Date: | 2022 | Publisher: | Source: | DIABETES CARE, 45 (3) , p. 614 -623 | Abstract: | OBJECTIVE Maternal glycemic dysregulation during pregnancy increases the risk of adverse health outcomes in her offspring, a risk thought to be linearly related to maternal hyperglycemia. It is hypothesized that changes in offspring DNA methylation (DNAm) underline these associations. RESEARCH DESIGN AND METHODS To address this hypothesis, we conducted fixed-effects meta-analyses of epigenome-wide association study (EWAS) results from eight birth cohorts investigating relationships between cord blood DNAm and fetal exposure to maternal glucose (Nmaximum = 3,503), insulin (Nmaximum = 2,062), and area under the curve of glucose (AUCgluc) following oral glucose tolerance tests (Nmaximum = 1,505). We performed lookup analyses for identified cytosine-guanine dinucleotides (CpGs) in independent observational cohorts to examine associations between DNAm and cardiometabolic traits as well as tissue-specific gene expression. RESULTS Greater maternal AUCgluc was associated with lower cord blood DNAm at neighboring CpGs cg26974062 (β [SE] −0.013 [2.1 × 10−3], P value corrected for false discovery rate [PFDR] = 5.1 × 10−3) and cg02988288 (β [SE]−0.013 [2.3 × 10−3], PFDR = 0.031) in TXNIP. These associations were attenuated in women with GDM. Lower blood DNAm at these two CpGs near TXNIP was associated with multiple metabolic traits later in life, including type 2 diabetes. TXNIP DNAm in liver biopsies was associated with hepatic expression of TXNIP. We observed little evidence of associations between either maternal glucose or insulin and cord blood DNAm. CONCLUSIONS Maternal hyperglycemia, as reflected by AUCgluc, was associated with lower cord blood DNAm at TXNIP. Associations between DNAm at these CpGs and metabolic traits in subsequent lookup analyses suggest that these may be candidate loci to investigate in future causal and mediation analyses. | Document URI: | http://hdl.handle.net/1942/37752 | ISSN: | 0149-5992 | e-ISSN: | 1935-5548 | DOI: | 10.2337/dc21-1701 | ISI #: | 000834050800028 | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2023 |
Appears in Collections: | Research publications |
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