Maternal glycemic dysregulation during pregnancy and neonatal blood DNA methylation : meta-analyses of epigenome-wide association studies
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 S.; Pattou, François; Plusquin, Michelle; Raverdy, Violeta; Tan, Kok Hian; Tzala, Evangelia; Räikkönen, Katri; Winkler, Christiane; Ziegler, Anette-G.; Annesi-Maesano, Isabella; Bouchard, Luigi; Chong, Yap Seng; 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; Järvelin, Marjo-Riita; Steegers-Theunissen, Regine P.M.; Howe, Caitlin G.; Hivert, Marie-France; Sebert, Sylvain
Elmar W. Tobi, Diana L. Juvinao-Quintero, Justiina Ronkainen, Raffael Ott, Rossella Alfano, Mickaël Canouil, Madelon L. Geurtsen, Amna Khamis, Leanne K. Küpers, Ives Y. Lim, Patrice Perron, Giancarlo Pesce, Johanna Tuhkanen, Anne P. Starling, Toby Andrew, Elisabeth Binder, Robert Caiazzo, Jerry K.Y. Chan, Romy Gaillard, Peter D. Gluckman, Elina Keikkala, Neerja Karnani, Sanna Mustaniemi, Tim S. Nawrot, François Pattou, Michelle Plusquin, Violeta Raverdy, Kok Hian Tan, Evangelia Tzala, Katri Raikkonen, Christiane Winkler, Anette-G. Ziegler, Isabella Annesi-Maesano, Luigi Bouchard, Yap Seng Chong, Dana Dabelea, Janine F. Felix, Barbara Heude, Vincent W.V. Jaddoe, Jari Lahti, Brigitte Reimann, Marja Vääräsmäki, Amélie Bonnefond, Philippe Froguel, Sandra Hummel, Eero Kajantie, Marjo-Riita Jarvelin, Regine P.M. Steegers-Theunissen, Caitlin G. Howe, Marie-France Hivert, Sylvain Sebert; Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies. Diabetes Care 1 March 2022; 45 (3): 614–623. https://doi.org/10.2337/dc21-1701
© 2022 by the American Diabetes Association. This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes Care. The American Diabetes Association (ADA), publisher of Diabetes Care, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes Care in print and online at http://care.diabetesjournals.org.
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https://urn.fi/URN:NBN:fi-fe2022042831107
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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.
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