DNA methylation profiling in recurrent miscarriage.

Li Pi,Jing Du,Jianhua Xu,Xinyue Wang,Junwei Liu,Yan Gu,Xuan Zhang,Zhaofeng Zhang,Jianmei Wang

doi:10.7717/peerj.8196

Abstract

Recurrent miscarriage (RM) is a complex clinical problem. However, specific diagnostic biomarkers and candidate regulatory targets have not yet been identified. To explore RM-related biological markers and processes, we performed a genome-wide DNA methylation analysis using the Illumina Infinium HumanMethylation450 array platform. Methylation variable positions and differentially methylated regions (DMRs) were selected using the Limma package in R language. Thereafter, gene ontology (GO) enrichment analysis and pathway enrichment analysis were performed on these DMRs. A total of 1,799 DMRs were filtered out between patients with RM and healthy pregnant women. The GO terms were mainly related to system development, plasma membrane part, and sequence-specific DNA binding, while the enriched pathways included cell adhesion molecules, type I diabetes mellitus, and ECM–receptor interactions. In addition, genes, including ABR, ALCAM, HLA-E, HLA-G, and ISG15, were obtained. These genes may be potential candidates for diagnostic biomarkers and possible regulatory targets in RM. We then detected the mRNA expression levels of the candidate genes. The mRNA expression levels of the candidate genes in the RM group were significantly higher than those in the control group. However, additional research is still required to confirm their potential roles in the occurrence of RM.

Highlights

Recurrent miscarriage (RM), defined as two or more consecutive clinically recognized spontaneous pregnancy losses before 20 weeks of gestation (Rai & Regan, 2006), affects 1–5% of women within the reproductive age (Kim et al, 2004; Pildner & Ktm, 2009)
We screened ALCAM (P = 3.00E−08), HLA-G (P = 3.00E−08), and HLA-E (P = 3.00E−08), which are closely related to embryonic development, as candidate genes of RM (Cizelsky & Tata, 2014; Gelmini et al, 2016; Verloes et al, 2017)
The analysis showed that the mRNA expression levels of ISG15, ABR, HLA-E, and HLA-G were higher in the RM group than in the control group (P < 0.05)

Summary

Introduction

Recurrent miscarriage (RM), defined as two or more consecutive clinically recognized spontaneous pregnancy losses before 20 weeks of gestation (Rai & Regan, 2006), affects 1–5% of women within the reproductive age (Kim et al, 2004; Pildner & Ktm, 2009). Multiple causes have been found to contribute to the pathogenesis of RM, including chromosomal abnormalities, cervical incompetence, uterine anomalies, autoimmune diseases, endocrinological abnormalities, antiphospholipid antibodies, thrombophilic disorders, low progesterone levels, and microbial infections (Hou et al, 2016; Rai & Regan, 2006). 40–50% of cases remain unexplained (Li et al, 2002); the molecular mechanisms have not been fully identified (Griebel et al, 2005).

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