Hypertensive Disorders of Pregnancy and DNA Methylation in Newborns.

Nabila Kazmi,Dawn L Demeo,John W Holloway,Ivana V Yang,Quaker E Harmon,Wenche Nystad,Kimberley Burrows,Faisal I Rezwan,Janine F Felix,Wilfried Karmaus,Diana L Santos Ferreira,Debbie A Lawlor,Anne P Starling,Sarah E Reese,Emily Oken,Christian M Page,Darina Czamara,Shanshan Zhao,Dana Dabelea,Elisabeth B Binder,Augusto A Litonjua,Stephanie J London,Hannele Laivuori,Abigail Fraser,Jari Lahti,Tom R Gaunt,Marie‐France Hivert ,Florianne O L Vehmeijer ,Tom G Richardson,Syed Hasan Arshad ,Maria C Magnus,Andrea A Baccarelli ,Ellen Aagaard Nøhr ,Thorkild I A Sørensen,Katri Räikkönen ,Siri Eldevik Håberg ,Gemma C Sharp,Andrew Simpkin ,Katerina Kechris ,Sheryl L Rifas‐Shiman ,Weimin Zhang ,Vincent W V Jaddoe ,Caroline L Relton

doi:10.1161/hypertensionaha.119.12634

Abstract

Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]) and epigenome-wide DNA methylation in cord blood using the Illumina HumanMethylation450 BeadChip. In models adjusted for confounders, and with Bonferroni correction, HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites, respectively. HDP was associated with higher methylation at 27 (63%) of the 43 sites, and across all 43 sites, the mean absolute difference in methylation was between 0.6% and 2.6%. Epigenome-wide associations of HDP with offspring DNA methylation were modestly consistent with the equivalent epigenome-wide associations of preeclampsia with offspring DNA methylation (R2=0.26). In longitudinal analyses conducted in 1 study (n=108 HDP cases; 550 controls), there were similar changes in DNA methylation in offspring of those with and without HDP up to adolescence. Pathway analysis suggested that genes located at/near HDP-associated sites may be involved in developmental, embryogenesis, or neurological pathways. HDP is associated with offspring DNA methylation with potential relevance to development.

Highlights

In the EWAS meta-analysis evaluating the association between Hypertensive disorders of pregnancy (HDP) and differential DNA methylation in cord blood, after adjustment for confounders, estimated cell counts, and technical covariates, we found 43 differentially methylated sites that passed the Bonferroni-corrected P (P
HDPs were associated with higher methylation levels at 27 (63%) of the CpG sites (CpGs), and across all CpGs, associations were relatively weak with the range of mean difference in methylation being 0.6% to 2.6%
These findings suggest that the known association of HDP with lower birth weight may be mediated through DNA methylation at these CpGs

Summary

Methods

Our a priori primary analysis was of the association of HDP with epigenome-wide DNA methylation in cord blood. This provided maximal statistical power by enabling us to include all studies, including those that did not have sufficient numbers of preeclampsia for meaningful analyses or had not collected data that could differentiate GH from preeclampsia. These cohorts listed in alphabetic order were the following: the ALSPAC (Avon Longitudinal Study of Parents and Children),[20,21,22] the GenR (Generation R) study,[23,24] the GOYA (Genetics of Overweight Young Adults) study (a genome-wide population-based association study nested in the Danish National Birth Cohort),[25,26] healthy start (Hispanic and non-Hispanic),[27,28] the Isle of Wight cohort,[29 2] independent datasets from the MoBa (Norwegian Mother and Child Cohort Study; MoBa1 and MoBa2),[30,31] The PREDO (Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction),[32] and Project Viva.[33]

Results

Discussion

Conclusion