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Title: Investigating genetic factors associated with complications of pregnancy
Author: Demetriou, Charalambos
ISNI:       0000 0004 5922 6979
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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This PhD project sets out to investigate the role of genetic factors associated with fetal growth restriction and recurrent miscarriage (RM), two of the most common complications of pregnancy. This work studied large cohorts of patients collected from specialist clinics in West London with the aim of better understanding their underlying molecular aetiology. The first part of this project focused on the paternally expressed, maternally imprinted gene, IGF2, which is a key growth hormone critical for in utero growth in mice. Its role in human fetal growth has remained ambiguous, as it has only been studied in term tissues. mRNA expression levels of IGF2 and other genes were investigated in 260 chorionic villus samples collected at 11-13 weeks' gestation. Transcript levels of IGF2 revealed a significant positive correlation with birth weight (P=0.009). Critically, small for gestational age neonates had significantly lower IGF2 levels than appropriate for gestational age neonates (P=3.6x10-7). Next a study was undertaken to investigate a potential role for disturbed imprinting in products of conception (POC). This work first involved a detailed analysis of the POC DNA to establish levels of maternal cell contamination. POCs could then be more accurately evaluated to investigate the status of known imprinted genes. Interestingly, in a number of POCs, known maternally expressed genes were found to be paternally expressed and vice versa. This suggested that some miscarriages might be associated with or even caused by abnormal imprinting. Two approaches were then used to study genetic factors associated with RM. The first involved a genetic association study with a placental anti-coagulant protein Annexin A5 that contains four nucleotide substitutions (M2 haplotype) in its promoter. Patient and control haplotypes were determined and compared in 500 White European pairs that had RMs and 250 control trios. Carriers of the M2 haplotype were found to exhibit higher RM risk than non-carriers, which was in agreement with previous studies. However, this is only true for the patients who suffered with early miscarriages. The second study involved analysis of a single family where the patient had experienced a total of 29 miscarriages but had no successful pregnancies. Next-generation exome sequencing was carried on family members to search for a potential rare genetic variant gene causative of the RM phenotype. Two candidate genes with potentially damaging mutations were investigated in more depth by sequencing them in cohorts of Asian RM patients (n=100) and White European RM patients (n=120). In one of the genes, three novel variants and one very rare SNP, which were all predicted to be damaging by different prediction programs, were identified in a total of four Asian patients. Future studies to further investigate these potential mutations, involves functional analysis of each variant such as site-directed mutagenesis and protein-protein interactions.
Supervisor: Regan, Lesley ; Moore, Gudrun Sponsor: Imperial College Healthcare NHS Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available