Maternal Glycemic Dysregulation During Pregnancy and Neonatal Blood DNA Methylation: Meta-analyses of Epigenome-Wide Association Studies
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posted on 2022-02-01, 20:12 authored by 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 Mustamiemi, 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, M.F. Hivert, Sylvain Sebert<b>OBJECTIVE</b>
<p>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. </p>
<p><b>RESEARCH DESIGN
AND METHODS</b></p>
<p>To
address this hypothesis, we conducted fixed-effect 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 (N<sub>max</sub>=
3,503), insulin (N<sub>max</sub>= 2,062), and the area under the curve of
glucose (AUC<sub>gluc</sub>) following oral glucose tolerance tests (OGTT, N<sub>max</sub>=
1,505). We performed look-up analyses for identified CpG dinucleotides (CpGs)
in independent observational cohorts to examine associations between DNAm and
cardiometabolic traits as well as tissue-specific gene expression.</p>
<p><b>RESULTS</b></p>
<p>Greater
maternal AUC<sub>gluc</sub> was associated with lower cord blood DNAm at neighboring
CpGs cg26974062 (β= -0.013 [SE=2.1x10<sup>-3</sup>], P<sub>FDR</sub>= 5.1x10<sup>-3</sup>)
and cg02988288 (β= -0.013 [SE=2.3x10<sup>-3</sup>], P<sub>FDR</sub> =0.031) in <i>TXNIP</i>.
These associations were attenuated in women with GDM. Lower blood DNAm at these
two CpGs near <i>TXNIP</i> was associated with multiple metabolic traits later
in life, including type 2 diabetes. <i>TXNIP</i> DNAm in liver biopsies was
associated with hepatic expression<i> </i>of <i>TXNIP</i>. We observed little
evidence of associations between either maternal glucose or insulin and cord blood
DNAm.</p>
<p><b>CONCLUSION</b></p>
<p>Maternal
hyperglycemia, as reflected by AUC<sub>gluc</sub>, was associated with lower
cord blood DNAm at <i>TXNIP</i>. <a>Associations between
DNAm at these CpGs and metabolic traits in subsequent look-up analyses suggest
that these may be candidate loci to investigate in future causal and mediation
analyses</a>.</p>
Funding
E.W.T. was supported by a VENI grant from the Netherlands Organization for Scientific Research (91617128). This work was funded by the Joint Programming Initiative – A Healthy Diet for a Healthy Life (JPI HDHL) (proposal number 655). In the UK it is jointly funded by the Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC) [grant reference: MR/S03658X/1]; in Spain by Instituto de Salud Carlos III [PCI2018-093147], in Germany by the German Federal Ministry of Education and Research [FKZ 01EA1905]; ZonMw in the Netherlands [529051023]; and in France by French National Research Agency [ANR18-HDHL-0003-05]. JR and SS received funding from the Healthy Diet for a Healthy Life (JPI HDHL) (PREcisE proposal number 655) and the European Union's Horizon 2020 research and innovation program under grant agreement No. 733206 (LifeCycle), 824989 EUCAN-Connect, 874739 Longitools, 848158 EarlyCause.
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