Characterization of DNA Methylation in African Americans with Spontaneous Preterm Birth Open Access
Parets, Sasha Erin (2015)
Published
Abstract
African Americans are at increased risk for spontaneous preterm birth (PTB), but the biological mechanisms underlying PTB are not yet known. Epigenetic factors, such as DNA methylation, may provide insight into the genes that are being actively regulated in those that deliver or are delivered preterm. The objective of this study was to evaluate DNA methylation in paired maternal blood and umbilical cord blood (fetal) samples to identify patterns specific to PTB. Peripheral blood from African American women who delivered preterm (24-34 weeks) or at term (39-41weeks) was assessed for DNA methylation across the genome using the HumanMethylation450 BeadChip. In maternal samples, no sites associated after correction for multiple comparisons though 17,829 CpG sites associated with PTB (p<.05). Examination of paired samples, irrespective of PTB status, identified 5,171 CpG sites in which methylation of maternal samples predicted methylation of her respective neonate (false discovery rate (FDR)<.05). The majority of correlated CpG sites could be attributed to one or more nearby genetic variants. However, correlated CpG sites were significantly more likely to be in genes involved in metabolic, cardiovascular and immune pathways, suggesting a role for genetic and environmental contributions to PTB risk. The observation that maternal epigenetic differences predict fetal methylation may provide insight into the heritability of PTB. In umbilical cord blood samples, we identified ~10,000 CpG sites that associate with gestational age (GA), only 29 of which associated with PTB when controlling for GA, suggesting that the majority of CpG sites primarily reflect developmental differences between preterm and term samples. In order to assess the association of DNA methylation with childhood outcomes, we investigated DNA methylation of calcitonin (CALCA), which associated with GA in cord blood and PTB in maternal blood. DNA methylation of CALCA did not associate with or mediate the relationship between maternal depressive symptoms, a known risk factor for PTB and internalizing behavioral in childhood. These finding show the importance of DNA methylation in understanding the risk and consequences of PTB in African Americans.
Table of Contents
Chapter 1: Preterm Birth and Its Long-Term Effects: Methylation to Mechanisms 1
Introduction 2
Overview of Pregnancy 3
Types of Preterm Birth 4
Proposed Mechanisms of PTB 6
Consequences of PTB 9
DNA Methylation Studies of PTB 10
DNA Methylation Studies of Long Term Outcomes of PTB 13
Opportunities for Epigenetic Studies of PTB 14
Chapter 2: DNA Methylation Provides Insight into Intergenerational Risk for Preterm Birth in African Americans 34
Introduction 35
Methods 37
Results 41
Discussion 45
References 57
Chapter 3: Fetal DNA Methylation Associates with Early Spontaneous Preterm Birth and Gestational Age 67
Introduction 68
Methods 69
Results 73
Discussion 77
References 89
Chapter 4: Fetal DNA Methylation of Calcitonin (CALCA) Does Not Associate with Behavioral and Cognitive Outcomes in Childhood 97
Introduction 98
Methods 100
Results 103
Discussion 105
References 111
Chapter 5: A Pilot Study of DNA Methylation in Spontaneous Preterm Birth: Conclusions & Recommendations for Future Studies 116
References 123
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