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Genetic and epigenetic profiling of placental insufficiency : identifying biomarkers of preeclampsia and intrauterine growth restriction

University of British Columbia

Preeclampsia (PE), characterized by maternal hypertension and proteinuria, is the leading cause of maternal and perinatal morbidity and mortality worldwide. PE can be subdivided into early-onset PE (EOPE), diagnosis <34 weeks, and late-onset PE (LOPE), diagnosis ≤34 weeks. Intrauterine growth restriction (IUGR), pathologically poor fetal growth, often co-occurs with PE. Both conditions are thought to be due to the placenta, the organ responsible for oxygen and nutrient transport to the fetus, not functioning adequately; this is referred to as placental insufficiency (PI). Currently there is no consistent clinical test to predict pregnancies at risk of these conditions. This dissertation investigated placental genetic and epigenetic profiles to assess their utility to identify novel protein biomarkers in maternal blood and to subclassify PE and IUGR placentas. DNA methylation (DNAm) in the placenta at delivery correlated to second trimester Inhibin alpha and third trimester fibronectin levels in maternal blood, indicating that DNAm alterations may be useful to identify novel biomarkers. Widespread DNAm alterations were identified in EOPE placentas, many of which validated in an independent cohort. These changes can be used to refine clinical diagnoses. Placental DNAm signatures can help to refine clinical diagnoses to create more homogenous pathological groups, aiding in more robust predictive algorithms for PI conditions. Telomere length (TL) was also assessed as a potential biomarker, as it has been reported altered in placentas of PE and IUGR pregnancies. This is thought to be due to the hypoxic environment iii associated with PI which results in DNA damage, and shortened TL. However, correcting for placental gestational age and fetal sex, TL was not shorter in LOPE or IUGR in our population. EOPE placentas trended towards shorter TL (p=0.1). Overall, these studies found that TL is not likely to be an informative marker of PI. These studies show the potential utility of DNAm in identifying novel protein biomarkers in maternal blood, refining clinical diagnoses to create more homogenous subtypes of PI, or as a potential biomarker itself for identifying pregnancies at risk of PI conditions.

Text

2018-06-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/63939

Medical Genetics

University of British Columbia

UBCV

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