Genetic determinants of oxidative stress in diabetes mellitus

Increased oxidative stress has been implicated in the pathogenesis of atherosclerosis and coronary heart disease, and is a key feature of diabetes mellitus. Increased oxidative stress has numerous adverse effects on the vascular system, including the altered expression of cell adhesion molecules, induction of pro-inflammatory mediators and more specifically the oxidation of low density lipoprotein (LDL) to form oxidised LDL (Ox-LDL). As well as measuring the total degree of oxidative stress in plasma, specific measures may also be recorded, such as the degree of LDL-oxidation. This thesis focuses on the association between plasma markers of oxidative stress and LDL-oxidation with other biochemical intermediate risk factors and common gene variants, in subjects with diabetes mellitus. Analysis focused on three candidate genes: a cellular anti-oxidant, glutathione-s-transferase; a plasma lipoprotein, apolipoprotein E; and a mitochondrial protein, uncoupling protein-2 (UCP2). The effect of common variants in these genes was explored in relation to plasma markers of oxidative stress, along with gene-environment interaction in the pro-oxidant environment of cigarette smoking. Initially a cohort of approximately 1000 subjects with diabetes, were recruited from the diabetes clinic at University College London Hospitals. Routine biochemical and clinical data was gathered, as well as plasma and blood for DNA extraction. Further in vitro functional studies were performed in respect to the UCP2 gene, to further our understanding of the role of this gene in the generation of oxidative stress and in the pathogenesis of coronary heart disease