Lane, Anne; (1993) Genetic and environmental influences on the control of expression of fibrinogen and factor VII genes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Raised levels of plasma fibrinogen and factor VII coagulant activity (FVIIc), both involved in blood coagulation, have been shown in a number of prospective epidemiological studies to be independent risk factors for coronary heart disease (CHD). Lipid-loaded macrophages, or 'foam cells', form a large proportion of the advanced atherosclerotic plaque. Cytokine production by lipid-loaded human peripheral macrophages was investigated in vitro to determine a possible effect on plasma fibrinogen levels. Conditioned medium from these cells after 3 days in culture produced a slight stimulation of fibrinogen synthesis in HepG2 cells, but contained little apoE protein. This stimulation was blocked by an anti-IL-6 antibody. Conditioned medium from 17-day-old-cultured monocyte-macrophages treated with acetylated low density lipoprotein (AcLDL) caused no stimulation of fibrinogen synthesis in HepG2 cells, contained no IL-1, TNEα or IL-6, but did contain increased levels of apoE protein. These results suggest that it is unlikely that cytokine production by foam cells in the atherosclerotic lesion is a major contributing factor in determining the raised fibrinogen levels associated with ischaemic heart disease (IHD). IL-6 induced expression of β fibrinogen mRNA in HepG2 cells was inhibited in a dose-dependent fashion by TGF-β. A C to T polymorphism at position -148 in the promoter region of the β-fibrinogen gene, near to an IL-6 responsive element and previously shown to be associated with plasma fibrinogen levels, was found to be within a TGF-β inhibitory consensus sequence. The single base change appeared to alter the strength of binding of a number of hepatoma cell nuclear proteins in 'bandshift' assays both under basal and cytokine-stimulated conditions. It did not alter promoter strength of the β-fibrinogen gene in transient expression assays. The association between a common polymorphism in the coding region of the FVII gene which alters an amino acid from an arginine to a glutamine at position 353 (Arg/Gln353) was investigated in a number of different population samples. These were population samples from white European men and women from north-west London, Gujarati indian men and women, Afro-Caribbean men and women, and from our different centres in Europe (Belfast, Lille, Strasbourg and Toulouse). There was a statistically significant association in all the population samples studied between plasma FVIIc levels and genotype, and in one study between FVIIag levels and genotype, with the Gln353 allele associated with a 20% reduction in FVIIc and FVIIag levels. There was also evidence for an interaction between genotype and plasma triglyceride level in determining FVIIc level. Carriers of the Gln353 allele showed no correlation between FVIIc and triglyceride level while in Arg353 homozygotes there was a positive correlation. These results suggest that the Arg/Gln353 polymorphism may be affecting the interaction of FVII with triglycerides and also the production and/or secretion of FVII rather than being a marker for another functional polymorphism elsewhere in the FVII gene. In conclusion, this study provides evidence that genetic variation at the fibrinogen and FVII gene loci may determine plasma levels of the respective gene products and their and response to 'environmental' factors such as acute-phase stimuli and plasma triglyceride level.

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