Elevated methylation of the vault RNA2-1 promoter in maternal blood is associated with preterm birth

Abstract

Background: Preterm birth, defined as parturition before 37 completed weeks of gestation, is associated with an increased risk of neonatal complications and death, as well as poor health and disease later in life. Epigenetics could contribute to the mechanism underlying preterm birth. Results: Genome-wide DNA methylation analysis of whole blood cells from 10 women (5 term and 5 preterm deliveries) was performed using an Illumina Infinium HumanMethylation450 BeadChips array. We identified 1,581 differentially methylated CpG sites in promoter regions between term and preterm birth. Although the differences were not significant after correcting for multiple tests, seven CpGs on the genomically imprinted vault RNA2-1 (VTRNA2-1; also known as non-coding RNA, nc886 or miR-886) showed the largest differences (range: 26–39 %). Pyrosequencing verification was performed with blood samples from pregnant women recruited additionally (39 term and 43 preterm deliveries). In total, 28 (34.1 %) samples showed hypomethylation of the VTRNA2-1 promoter (< 13 % methylation), while 54 (65.9 %) samples showed elevated methylation levels between 30 and 60 %. Elevated methylation of VTRNA2-1 promoter was associated with an increased risk of preterm birth after adjusting for maternal age, season of delivery, parity and white blood cell count. The mRNA expression of VTRNA2-1 was 0.51-fold lower in women with preterm deliveries (n = 20) compared with women with term deliveries (n = 20). Conclusions: VTRNA2-1 is a noncoding transcript to environmentally responsive epialleles. Our results suggest that elevated methylation of the VTRNA2-1 promoter may result in increased risk of PTB caused by the pro-inflammatory cytokines. Further studies are needed to confirm the association of VTRNA2-1 methylation with preterm birth in a large population, and to elucidate the underlying mechanism.