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Steroidogenic acute regulatory (StAR) related-lipid transfer (START) proteins (STARD1-STARD15) are suggested to play a role in cholesterol homeostasis and atherosclerosis, and are potential drug targets by virtue of their lipid binding domains. Members of the STARD1 subfamily (STARD1, STARD3) of lipid trafficking 'START' proteins can reduce macrophage lipid content and inflammatory status (STARD1; StAR), and traffic cholesterol from the endosomes (STARD3/MLN64) All of the 'START' family members were found to be expressed in human heart aorta, peripheral blood monocytes and human THP-1 monocytes, except testis-specific STARD6. Phorbol ester-Induced differentiation of THP-1 monocytes to macrophages (7 days) induced two-fold or greater Increases in gene expression of STARD4, STARDd, STARD9 and STARD14, whereas levels of STARD3 mRNA declined. Treatment with acetylated LDL increased gene expression of STARD4, STARD10, STARD12 more than two-fold, but levels of STARDl STARD2, STARD7, STARDd, STARD9 and STARD14 mRNA declined significantly.

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This thesis provides an empirical investigation of the geneticisation thesis. Geneticisation is one of the most prominent critiques of the social and cultural implications of developments in genetics. It incorporates a set of claims and expectations about the way genetic knowledge and technologies are transforming or will transform ideas about health and illness, and health care practices. This research aims to explore the empirical basis of these claims, by looking at the place of genetic discourses and practices in one specific area. The thesis focuses on familial hypercholesterolaemia (FH), a treatable hereditary cholesterol condition associated with high rates of coronary heart disease (CHD). It asks how much and in what ways patients with FH and professionals involved with the condition construct FH and CHD as genetic conditions. The thesis draws on three main areas of data - biomedical literature concerning CHD and FH; ethnographic work concerning the activities of HEART UK, the main UK health charity involved with inherited lipid disorders and cholesterol; and interviews with patients with FH and with staff and members of HEART UK. The analysis suggests that FH is not understood or managed within a strong genetic frame, and that neither professionals involved in HEART UK, nor patients with FH, provided or contributed to radically new or geneticised accounts of CHD. In short, the research suggests that geneticisation overstates the transformatory potential of genetics, and that factors such as the availability of effective therapeutics, the sites where care takes place, the disciplines involved, and existing lay and professional models of disease are important for the construction of a particular field. Furthermore, in arguing that FH is not associated with a strong specific disease identity or community, the analysis questions the notion of biosociality, suggesting that is may be less relevant to some biological states or conditions than to others.

Background: Abnormalities in postprandial lipid metabolism may explain, in part, the 2 to 4 fold increased risk of coronary heart disease (CHD) in diabetic individuals compared with the general population. Aims: To develop an Oral Triglyceride Tolerance Test (OTTT) to evaluate reliably post challenge metabolism and to determine whether more physiologic insulin profiles can improve lipid responses in diabetic subjects. Methods: Post 50g fat and 50g carbohydrate challenge triglyceride and glucose profiles were measured 2 hourly for 8 hours on 2 occasions to establish test reproducibility and to characterise responses in type 2 diabetic and non diabetic subjects. The potential effects on post challenge lipid and glucose metabolism of modifying endogenous insulin delivery via the portal system or augmenting post challenge systemic insulin levels were assessed using the OTTT. Results: Reproducible post challenge triglyceride, NEFA, glycerol, glucose, insulin and C peptide responses were obtained in non diabetic and type 2 diabetic subjects. In type 2 diabetic subjects both ultra rapid endogenous and exogenous insulin delivery decreased post challenge hyperglycaemia and improved NEFA-glycerol suppression, relative to placebo and soluble insulin respectively. Enhancing portal insulin secretion had no effect on triglyceride levels. Increasing peripheral insulin levels showed no difference in triglyceride profiles between insulins tested although 6 hour triglyceride excursions were less than endogenous enhancement. Type 1 diabetic subjects displayed triglyceride profiles similar to non diabetic subjects, and reduced triglyceride excursion was seen with soluble than analogue insulin replacement. Conclusion: Increasing the peripheral to portal insulin ratio may relieve hepatic exposure to chronic hyperinsulinaemia characteristic of type 2 diabetes thus reducing post challenge triglyceride excursions. Improving postprandial metabolism, by delaying atherogenesis, may help decrease the risk of CHD.

The integration of biological and genetic data has established that diverse biological processes, involving multiple effectors, influence circulating levels of triglyceride and cholesterol. This diversity may underlie the genetic complexity of human dyslipidemias, including the common and highly atherogenic condition, Familial Combined Hyperlipidemia (FCHL). The aetiologies of FCHL are currently undetermined. In this thesis, a multi-pronged approach was employed to identify genes/variants contributing to the linkage observed between the chromosome 21q22.2-22.3 interval and lipid traits, in white-British FCHL families. Additionally GPIHBP1, which encodes glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1, was studied. GPIHBP1 represents a strong FCHL candidate gene due to its role in the lipolytic processing of triglyceride-rich lipoproteins. Combined genetic and gene expression analyses, focussed upon a refined 3.8Mb interval on chromosome 21q22.3 that was linked to lipid abnormalities in subsets of FCHL families, identified two genes (COL18A1 and PKNOX1 ) that warrant further investigation with regard to their contribution to FCHL. Promising results were also obtained for C21orf57, which resides just outside the 3.8Mb interval. Genetic association analyses in 1725 members of 239 FCHL families identified nominal association (P=0.0009) between a TSPEAR variant, rs34163868, and plasma triglyceride levels. Furthermore, transcript levels of CBS and TRPM2 were significantly altered by treatment with the PPAR-agonist bezafibrate in a rat hepatoma cell line, thus implicating these genes in triglyceride/fatty acid metabolism. In combined analysis of five independent cohorts, the minor allele of the GPIHBP1 variant, rs11538388 was protective against hypertriglyceridemia (P=2.98x10-4). The same allele was associated with decreased risk of coronary heart disease in the prospective Northwick Park Heart Study II (hazard ratio for carriers=0.76, P=0.0480) and delayed age of onset in the Southampton Atherosclerosis Study (odds ratio=0.76, P=0.0146). Collectively, these data demonstrate that the rs11538388 minor allele, or variant in linkage disequilibrium, is associated with more favourable processing of atherogenic lipoproteins.