Inherited factors in pre-eclampsia: Molecular genetic and epidemiological studies in a Sri Lankan population

Dissanayake, Vajira Harshadeva Weerabaddana (2004) Inherited factors in pre-eclampsia: Molecular genetic and epidemiological studies in a Sri Lankan population. PhD thesis, University of Nottingham.

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Abstract

Pre-eclampsia is a disorder of unknown aetiology that affects about 5% of Sri Lankan women during their pregnancy. It is most likely a multifactorial disorder that is caused by the interaction of genetic and environmental factors. Recent advances in genetics have resulted in a surge of investigations into genetic factors underlying pre-eclampsia. These studies have been conducted mainly in the white Caucasians in the West and the Japanese in the East.

The investigations described in this thesis therefore were undertaken in a genetically distinct South Asian Sinhalese population in Sri Lanka and replicated in a white Caucasian population in Nottingham, UK. Four candidate genes; Epidermal Growth Factor (EGF) and Transforming Growth Factor Alpha (TGFA), which may play a role in placentation; Angiotensinogen (ANG), which is involved in blood pressure regulation; and 5,10-Methylenetetrahydrofolate reductase (MTHFR), which is an enzyme involved in folate metabolism, were examined.

These investigations consisted of the following: Recruitment of 80 population volunteers each from the Sinhala, Sri Lankan Tamil and Moor racial groups in Sri Lanka, establishing the allele/haplotype frequency for the candidate genes in those volunteers and in 80 white Caucasian population volunteers, and comparing their allele/haplotype frequencies; recruitment of 180 Sinhalese women with pre-eclampsia and 180 normotensive pregnant Sinhalese women, establishing the allele/haplotype frequencies of the candidate genes in these women and in 74 white Caucasian women with pre-eclampsia and 81 normotensive pregnant white Caucasian women, comparing the pre-eclampsia phenotype of the Sinhalese with that of the white Caucasians, examining the association of the candidate genes with pre-eclampsia, and examining the association of the candidate genes with quantitative traits such as birth weight and blood pressure in normotensive pregnant women; and examining the functional effects of polymorphisms in the angiotensinogen gene on gene expression.

The phenotyping results of the Sinhalese women reflect the severe morbidity associated with pre-eclampsia elsewhere, and highlight the severe perinatal mortality associated with pre-eclampsia in the Sinhalese. The population genetic results show considerable similarity between allele/haplotype frequencies of the Sri Lankan racial groups and considerable variation between them and the white Caucasians. The EGF gene was associated with pre-eclampsia in the Sinhalese and with the weight of babies at birth in both the Sinhalese and the white Caucasians. The TGFA, ANG and MTHFR genes were not associated with either pre-eclampsia or any quantitative trait. The angiotensinogen reporter gene expression studies revealed the possible existence of a repressor element in the 3' untranslated region of the angiotensinogen gene, but this finding needs confirmation by further investigations.

Item Type:Thesis (PhD)
Supervisors:Broughton Pipkin, Fiona
Morgan, Linda
Uncontrolled Keywords:pre-eclampsia, eclampsia,gestational hypertension,sinhalese, sri lankan,genetic association study, quantitrative trait, MTHFR, EGF, angiotensinogen, TGFA, candidate gene
Faculties/Schools:UK Campuses > Faculty of Medicine and Health Sciences > School of Molecular Medical Sciences
UK Campuses > Faculty of Medicine and Health Sciences > School of Clinical Sciences > Former School of Human Development
ID Code:66
Deposited By:Vajira Harshadeva Weerabaddana Dissanayake
Deposited On:03 Nov 2004
Last Modified:06 Feb 2009 14:44

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