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Title: Epigenetic variation associated with genetic and environmental factors in the aetiology of Type 2 diabetes
Author: Finer, Sarah
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2013
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Type 2 diabetes, as a complex disease, has a range of genetic and environmental factors that underpin its aetiology. It is hoped that the emerging study of epigenetic processes will provide the necessary mechanistic insight into the genetic and environmental interactions that, to date, are poorly understood. This thesis considers the role of DNA methylation, an epigenetic modification, in the aetiology of type 2 diabetes. A range of different genome-wide and whole genome techniques are applied to a study of established type 2 diabetes and experimental models (human and animal) of fetal programming. Samples from a recent genome-wide association study of type 2 diabetes were used to identify DNA methylation patterns at areas of genetic variation associated with disease risk. Analysis of data from methylated DNA immunoprecipitation and microarray identified a genetic-epigenetic interaction in the FTO gene. At this locus, the presence or absence of a SNP created or abrogated a CpG site capable of methylation and further analyses highlighted possible functional relevance via enhancer activity. Models of fetal programming were then used to identify whether variation in DNA methylation may underlie the ‘programmed’ phenotype of diabetes and related cardiometabolic disease. Pre-existing human models of programming via maternal vitamin B12 deficiency and maternal famine exposure have been used to generate exploratory evidence of such mechanisms. Whole genome-based techniques (Medip-seq and Illumina 450k methylation array) were used to profile DNA methylation in whole blood samples from the offspring born to each of these studies. Custom bioinformatic analysis was performed to identify differences in methylation between offspring exposed versus unexposed to the in utero environmental insult. Technical replication and validation studies are ongoing to confirm or refute the presence of regions of differential methylation. Finally, this thesis considers whether a state of ‘over nutrition’ gestational diabetes, may play a role in fetal programming. This condition is of increasing prevalence across the world and is characterised by maternal hyperglycaemia and insulin resistance, often resulting in fetal overgrowth. A mouse model using an inbred strain (Lepr) of mice induced a programmed phenotype of glucose intolerance and obesity in aged offspring born to mothers with gestational diabetes. Medip-seq performed on the livers of late gestation mouse embryos identified differential methylation in cases vs. controls, located at genomic regions with potential functional relevance. A human cohort of women with gestational diabetes was collected to develop further hypothesis around the multiple environmental factors that could interact in pregnancy. Prevalent nutritional deficiencies of vitamin D, iron and one-carbon metabolites were found in women with and without gestational diabetes recruited from a local antenatal clinic. This thesis presents preliminary findings that variation in DNA methylation may be involved in the genetic and environmental risk of type 2 diabetes. The work presented highlights how future studies must incorporate integrated genetic, epigenetic and functional analysis with sufficient sample size if their results are to be translatable to diverse populations at risk of diabetes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medicine ; Diabetes