Hillman, SL; (2014) The Role of Genes and Environment on Fetal Growth. Doctoral thesis , UCL (University College London).

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Abstract

Fetal growth is influenced by the in utero environment and genetic factors inherited from both parents. Poor fetal growth leading to low birth weight is associated with insulin resistance and type-2 diabetes in later life. The fetal programming of adult disease hypothesis suggests that growth-restricted fetuses make enduring physiological adaptations that predispose to diabetes in later life. The fetal insulin hypothesis suggests that poor fetal growth and diabetes are two phenotypes of genetically determined insulin resistance. Under these circumstances, an insulin resistant fetus cannot optimise insulin-mediated growth and is predisposed to diabetes in later life. Environmental and genetic influences come together through epigenetic modifications, for example DNA methylation, that alter gene expression without altering the nucleotide sequence. The first aim of this thesis was to investigate whether men who fathered pregnancies complicated by fetal growth restriction had an insulin resistant phenotype at the time of the index pregnancy. A case-control study showed that men who fathered growth-restricted offspring have pre-clinical insulin resistance and are more likely to smoke than fathers of normal grown offspring. This observation supports the concept that an insulin resistant genotype inherited from a father could manifest as poor fetal growth in offspring. I then investigated the mechanisms through which paternal insulin resistance might be inherited by a growth-restricted fetus. I studied DNA extracted from the cord blood of growth-restricted offspring using whole exome sequencing to identify novel gene variants and those known to be associated with type-2 diabetes. I validated findings with Sanger sequencing and Taqman genotyping in all family members. Using the Illumina Human 450 BeadChip, I found marked differences in genome wide DNA methylation of fetal cord blood and placental samples from growth restricted compared with normal grown offspring. Future work is aimed at investigating the functional consequences of genetic and epigenetic differences to identify targets for treatment and prophylaxis against fetal growth restriction and diabetes.

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