Early Pregnancy Dyslipidemia is Associated with Placental DNA Methylation at Loci Relevant for Cardiometabolic Diseases

Abstract

Aim: To identify placental DNA methylation changes that are associated with early pregnancy maternal dyslipidemia. Materials & methods: We analyzed placental genome-wide DNA methylation (n=262). Genes annotating differentially methylated CpGs were evaluated for gene expression in placenta (n=64). Results: We found 11 novel significant differentially methylated CpGs associated with high total cholesterol, low-density lipoprotein cholesterol and triglycerides, and low high-density lipoprotein cholesterol. High triglycerides were associated with decreased methylation of cg02785814 (ALX4) and decreased expression of ALX4 in placenta. Genes annotating the differentially methylated CpGs play key roles in lipid metabolism and were enriched in dyslipidemia pathways. Functional annotation foundcis-methylation quantitative trait loci for genetic loci in ALX4 and EXT2. Conclusion: Our findings lend novel insights into potential placental epigenetic mechanisms linked with maternal dyslipidemia.

Trial Registration: ClinicalTrials.gov, NCT00912132.

Keywords::

• cardiometabolic diseases
• dyslipidemia
• epigenome-wide association study
• lipids
• placental DNA methylation
• placental gene expression

Supplementary data

To view the supplementary data that accompany this article please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2019-0293

Acknowledgements

The authors acknowledge the study participants of the NICHD Fetal Growth Studies. The authors thank research teams at all participating clinical centers (which include Christina Care Health Systems, Columbia University, Fountain Valley Hospital, California, Long Beach Memorial Medical Center, New York Hospital, Queens, Northwestern University, University of Alabama at Birmingham, University of California, Irvine, Medical University of South Carolina, Saint Peters University Hospital, Tufts University and Women and Infants Hospital of Rhode Island). The authors also acknowledge the Wadsworth Center, C-TASC and the EMMES Corporations in providing data and imaging support. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov).

Financial & competing interest disclosure

This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health including American Recovery and Reinvestment Act funding via contract numbers HHSN275200800013C; HHSN275200800002I; HHSN27500006; HHSN275200800003IC; HHSN275200800014C; HHSN275200800012C; HHSN275200800028C; HHSN275201000009C and HHSN27500008. Additional support was obtained from the NIH Office of the Director, the National Institute on Minority Health and Health Disparities and the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health including American Recovery and Reinvestment Act funding via contract numbers HHSN275200800013C; HHSN275200800002I; HHSN27500006; HHSN275200800003IC; HHSN275200800014C;HHSN275200800012C; HHSN275200800028C; HHSN275201000009C and HHSN27500008. Additional support was obtained from the NIH Office of the Director, the National Institute on Minority Health and Health Disparities and the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.