Abstract
BackgroundPreterm birth is a leading cause of perinatal mortality and long-term health consequences. Epigenetic mechanisms may have been at play in preterm birth survivors, and these could be persistent and detrimental to health later in life.MethodsWe performed a genome-wide DNA methylation profiling in adult twins of premature birth to identify genomic regions under differential epigenetic regulation in 144 twins with a median age of 33 years (age range 30–36).ResultsAssociation analysis detected three genomic regions annotated to the SDHAP3, TAGLN3 and GSTT1 genes on chromosomes 5, 3 and 22 (FWER: 0.01, 0.02 and 0.04) respectively. These genes display strong involvement in neurodevelopmental disorders, cancer susceptibility and premature delivery. The three identified significant regions were successfully replicated in an independent sample of twins of even older age (median age 66, range 56–80) with similar regulatory patterns and nominal p values < 5.05e−04. Biological pathway analysis detected five significantly enriched pathways all explicitly involved in immune responses.ConclusionWe have found novel evidence associating premature delivery with epigenetic modification of important genes/pathways and revealed that preterm birth, as an early life event, could be related to differential methylation regulation patterns observable in adults and even at high ages which could potentially mediate susceptibility to age-related diseases and adult health.
Highlights
Preterm birth is a leading cause of perinatal mortality and long-term health consequences
Multiple-CpG-based analysis On top of the single-CpG-based analysis, we further extended our analysis to multiple CpGs to look for differentially methylated genomic regions (DMRs) in association with Preterm birth (PTB)
By focusing on regions with a mean methylation difference of over 10% between PTB and term births, we found a list of 16,508 regions (Additional file 3: Figure S2) and among them 2651 regions with p value < 0.05 (Additional file 4: Table S2)
Summary
Preterm birth is a leading cause of perinatal mortality and long-term health consequences. Epigenetic mechanisms may have been at play in preterm birth survivors, and these could be persistent and detrimental to health later in life. With a prevalence estimated from 5 to 18% in singleton pregnancies across 184 countries according to the World Health Organization and over 50% in twin pregnancies in the USA [1], PTB is a leading cause of perinatal mortality as well as long-term morbidity and health consequences. Relatively large numbers of CpG sites were found significantly differentially methylated in association with PTB at birth, they are largely resolved in adolescents in both studies. Persistent methylation differences were identified at ten CpG sites in the study by Cruickshank et al [14] reflecting a lasting epigenetic effect of PTB
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