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Molecular profiling of acute chorioamnionitis-affected placentas : insights into genomic variation underlying a common preterm birth condition

University of British Columbia

Acute chorioamnionitis (aCA), a preterm birth (PTB) associated inflammatory condition, can have adverse effects on the health of the baby. This condition is characterized by inflammatory lesions in the fetal membranes and can also involve the chorionic plate in the placenta. Histologic examination of the placenta is the gold standard for diagnosing aCA, but is only possible after delivery; thus, this method is not suitable for prenatal diagnosis of aCA. This necessitates the development of non-invasive biomarkers to allow effective management of the disease and hence, reduce the incidence of PTB. Additionally, genetic variation in immune-system genes may contribute to the placenta’s inflammatory responses, thus influencing susceptibility to aCA. The overarching objective of this dissertation is to understand how genetic, epigenetic, and miRNA variation in the placenta is associated with the disruption of immune balance in aCA. To achieve this, I first examined the association of single nucleotide polymorphisms (SNPs) in innate immune system genes and aCA status. I observed that differences in IL6 (rs1800796) placental allele frequencies were associated with the presence of aCA. Further, I showed the IL6 SNP may regulate IL6 gene expression and DNA methylation (DNAme) in the placenta, and alter disease risk to aCA. Secondly, using the Illumina HumanMethylation850 BeadChip, I characterized epigenetic variation associated with aCA in placenta and fetal membranes. Specifically, I observed that aCA-affected placentas showed a unique DNAme profile that may reflect an increase in immune cell number as a response to inflammation and/or represent activation of the innate immune response in the placenta. Lastly, I investigated whether altered miRNA profiles were associated with aCA-affected placentas. Expression was quantified for six inflammation-related miRNAs using quantitative real-time PCR. I observed that expression of miR-518b and miR-338-3p were differentially expressed in aCA-affected placentas. I also showed that miR-518b expression in placenta was associated with IL6 (rs1800796) genotype, where carriers of the C allele exhibited decreased miR-518b expression compared to the carriers of the G allele. In summary, this research uniquely investigated genetic alterations, DNAme, and miRNA expression patterns in aCA-affected placentas, adding insights into the processes likely impacting immune function during aCA.

Text

2019-06-05

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/70534

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/