Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/95878
Type: Thesis
Title: Angiogenesis regulating gene polymorphisms in adverse pregnancy outcomes.
Author: Andraweera, Prabha Hemamali
Issue Date: 2012
School/Discipline: School of Paediatrics and Reproductive Health
Abstract: Introduction: Both placental vascular defects and a genetic contribution are documented in pregnancies complicated by preeclampsia, small-for-gestational-age infants (SGA) and spontaneous preterm birth (sPTB). Our primary aim was to investigate the association between polymorphisms in genes regulating placental vascular integrity including vascular endothelial growth factor (VEGFA), placenta growth factor (PGF), kinase insert domain receptor (KDR), fms-like tyrosine kinase 1 receptor (FLT1), angiopoietin 1 (ANGPT1) and thrombospondin 1 (TSP1) and these pregnancy complications in a Caucasian cohort. The secondary aims were to investigate the association between these polymorphisms and (1) preeclampsia in Sri Lankan women (2) first trimester placental gene expression (3) abnormal uterine and umbilical artery Doppler (4) environment and lifestyle interactions that modify the risk of pregnancy complications and to (5) compare term placental angiogenic gene mRNA expression in complicated pregnancy with uncomplicated pregnancy. Methods: Nulliparous pregnant women, their partners and infants (3234 trios) were recruited to a prospective multicenter cohort study (SCOPE study) in Adelaide, Australia and Auckland, New Zealand. Pregnancy outcomes were classified using international guidelines. Uterine and umbilical artery Doppler was performed at 20 weeks gestation. Mean uterine or umbilical artery resistance indices (RI) above the 90th percentile or the presence of bilateral notching of the uterine artery waveform were considered abnormal. A second Sri Lankan cohort comprised 175 nulliparous preeclamptic women and 171 matched controls. The polymorphisms in the Caucasian parent-infant trios, Sri Lankan women and first trimester placental tissue from elective pregnancy terminations (n = 74) were genotyped using the Sequenom Mass ARRAY system. Term placentae were collected from women with preeclampsia (n = 18), gestational hypertension (n = 15), normotensive SGA infants (n = 13), spontaneous preterm birth (n = 10) and uncomplicated pregnancy (n = 30). Placental mRNA expression was analysed by quantitative RT-PCR. Results: In the Caucasian cohort, maternal ANGPT1 1414T/A and paternal and infant KDR -604T/C polymorphisms were associated with preeclampsia; maternal ANGPT1 1414T/A, paternal and infant KDR -604T/C, paternal and infant TSP1 2210A/G and infant VEGFA+936C/T were associated with SGA. In the Sri Lankan cohort, PGF 642C/A was associated with preeclampsia. The ANGPT1 1414T/A was associated with abnormal uterine Doppler and the VEGFA +936C/T was associated with abnormal uterine and umbilical artery Doppler and reduced first trimester placental VEGFA mRNA expression suggesting that these polymorphisms may have a role in the pathogenesis of pregnancy complications. We also found that the maternal ANGPT1 1414T/A and VEGFA -2578C/A polymorphisms interact with maternal BMI to modify the risk of sPTB and that the maternal KDR -604T/C interacts with smoking to influence the risk of preeclampsia and SGA. In all these polymorphisms, genotypes associated with pro-angiogenic phenotypes reduced the risk and genotypes associated with anti-angiogenic phenotypes increased the risk of pregnancy complications. We were also able to demonstrate that term placental expression of VEGFA, PGF, KDR and FLT1 mRNA were reduced in pregnancy complications compared to uncomplicated pregnancy. Conclusion: This project demonstrates that inherited susceptibility to altered angiogenic gene expression in the placenta contributes to the risk of pregnancy complications.
Advisor: Roberts, Claire Trelford
Dekker, Gustaaf Albert
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Paediatrics and Reproductive Health, 2012
Keywords: polymorphisms; angiogenesis; preeclampsia; SGA infants; preterm birth
Provenance: This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals
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