Abnormal placental DNA methylation variation in spontaneous preterm birth

Abstract

Objective

Preterm birth (PTB) has become a major public health concern as the leading cause of neonatal death, but little is understood about its etiology. Children born preterm are also at increased risk of long-term consequences such as neurodevelopmental disorders, adulthood hypertension and diabetes. Recent studies have indicated that DNA methylation may be involved in the occurrence of PTB as well as related adverse outcomes. The latest Infinium EPIC BeadChip extends the coverage of the genome and provides a better tool to help investigate the involvement of DNA methylation in these conditions.

Methods

We conducted this case-control study in three Women and Children’s hospitals in South China, and enrolled 32 spontaneous preterm births and 16 term births. We assessed placental DNA methylation profiling of these participants with the Infinium EPIC BeadChip. We identified PTB and gestational age (GA)-associated CpG sites with limma regression model, and applied seqlm to identify PTB-associated regions. We performed gene ontology analysis to further interpret functional enrichment of the identified differentially methylated genes in PTB.

Results

We identified a total of 8 differentially methylated positions (DMPs) that were significantly associated with PTB (FDR < 0.1) and a total of 15 DMPs that were associated with GA (FDR < 0.1). In the regional analysis, one differentially methylated region in the SLC23A1 gene overlapped with PTB-associated CpG site. The differentially methylated CpG sites in PTB were mapped to the genes involving in biological processes mainly regarding neurodevelopment, regulation of inflammation and metabolism.

Conclusion

Our findings suggested that preterm placenta have distinct DNA methylation alterations, and these alteration patterns established at birth provide insight into the long-term consequences of preterm birth.

Keywords:

• DNA methylation
• placenta
• spontaneous preterm birth
• gestational age
• epigenome-wide association study

Acknowledgements

We acknowledge the support from Foshan and Shenzhen Women’s and Children’s Hospitals. Xi-Meng Wang would like to personally thank Ms. Chang Liu (The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China) for her support during this study.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Availability of data and materials

The datasets generated and/or analyzed during the current study are not publicly available due to privacy protection of the participants, but are available from the corresponding author on reasonable request.

Authors’ contributions

XMW and WQC designed the study, XMW also processed the bio-samples, analyzed the data and drafted the manuscript, FYT and WQC revised the manuscript critically for important intellectual content. CBX collected the data and bio-samples, ZZN contributed data analysis support. All authors have given final approval of the version to be published. WQC takes final responsibility for this article.

Additional information

Funding

The study was funded by Guangdong Science and Technology Program Project [2016A020218014 and 2017B020227006] and Guangzhou Science and Technology Project [201804020049]. Xi-Meng Wang was supported by International Program for Ph.D. Candidates, Sun Yat-Sen University. The funding sources were nonprofit scientific research management and academic institutions, they had no role in the design of this study, and did not have any role during its execution, analyses, interpretation of the data, or decision to submit results.