Graduation Year

2010

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Epidemiology and Biostatistics

Major Professor

Hamisu Salihu, M.D.,Ph.D.

Committee Member

Kathleen O’Rourke, Ph.D.

Committee Member

Erin M. Siegel, Ph.D.

Committee Member

Getachew Dagne, Ph.D.

Committee Member

Terry Ashmeade, M.D.

Keywords

prenatal smoking, intrauterine growth restriction, epigenetics, small for gestational age, birthweight, cotinine

Abstract

Altered DNA methylation may lead to suboptimal fetal programming, increasing the risk of adverse pregnancy outcomes such as small for gestational age (SGA); however, few studies have examined the associations between DNA methylation, prenatal exposures, and fetal outcomes. Cross-sectional data from a larger, ongoing study were used to assess the impact of prenatal smoking on gene specific methylation of umbilical cord blood derived DNA and to investigate the association between gene-specific methylation and risk of SGA. The association between gene-specific DNA methylation and birthweight was also assessed. Maternal and infant covariates were abstracted from medical records, cigarette smoke exposure was determined by measuring cotinine in umbilical cord blood plasma, and the Illumina Infinium Methylation27 assay was used to assess CpG site specific methylation. Methylation was represented by a beta value ranging from 0 to 1. Gene-level methylation was calculated by averaging the methylation levels over the CpG sites interrogated in that gene. Logistic regression was used to generate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association between SGA and methylation of CYP1A1, HIF1A, GSTT1, and GSTM1 and the association between cotinine level and hypermethylation of CYP1A1, HIF1A, GSTT1, and GSTM1. DNA was considered hypermethylated if the beta value was greater than or equal to the 75th percentile. Univariate and multivariable linear regression were used to examine the association between birthweight and methylation of the IGF1 and IGF2 gene. The analyses included 90 singleton births. A 0.10 unit increase in methylation of GSTT1 increased the risk of SGA almost 3-fold (OR=2.69, 95%CI=1.34, 5.43). A 5ng/ml increase in cotinine level increased the risk of hypermethylation of GSTT1 (OR=1.18, 95%CI=1.02, 1.37). Birthweight did not appear to be impacted by methylation of IGF2 (β=0.07, 95%CI=-2.91, 3.05), but a one standard deviation increase in methylation of IGF1 was associated with a 3.63% decrease in birthweight (95%CI= -6.49, -0.78). No differences in DNA methylation by prenatal vitamin intake were detected. These findings suggest that DNA methylation plays a critical role in fetal growth and may mediate the risk of SGA and low birthweight.

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