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Genetic and Environmental Mechanisms Underlying Hypercoagulability and Impaired Fibrinolytic Function Predisposing to Coronary Artery Disease

Objective

- To elucidate gene-environment interactions for the haemostatic proteins fibrinogen, coagulation factor VII and plasminogen activator inhibitor-1 (PAI- 1) determining the risk of atherothrombosis and coronary heart disease.
- To establish whether there are cross-cultural differences between countries in Europe in these respects.

The project has three parts: I) A large-scale cross-cultural study of gene-environment interactions influencing the three major haemostatic risk factors for CHD (fibrinogen, factor VII and PAI-1) in individuals with and without manifest CHD in four countries in Europe with a different incidence of CHD; II) Detailed clinical and biochemical studies in individuals with specific single gene genotypes or multiple gene genotypes selected from the populations recruited to the cross-cultural study; and III) Molecular biological and molecular genetic studies of mechanisms regulating the plasma levels of fibrinogen, factor VII and PAI-1 and their relationships to CHD. Genotyping will be performed at 4 loci in all participants in the cross-cultural study: beta-fibrinogen promoter (G453-A), factor VII (Arg353-Gln), PAI-1 promoter (4G/5G) and factor V (Arg506-Gln). The associations between genotypes and levels of the
relevant haemostatic proteins will be examined to address the following questions: i) Is the effect of genotype on determining the plasma levels of the relevant protein larger in patients than in controls? ii) Is the effect of genotype on determining the plasma levels of the relevant protein larger in individuals selected from countries with a higher incidence of premature CHD? iii) Do significant gene-environment interactions exist, i.e. are there allele-specific differences in the influence of various environmental factors on the expression of the three haemostatic proteins? In the second part of the programme, "bottom-up" comparisons will be carried out under different genetic and environmental backgrounds. First, the association of three "high-risk" genotypes with severity of carotid atherosclerosis will be examined. Secondly, the effect of genotype on within-individual variability of plasma fibrinogen and PAI-1 levels will be addressed. Simultaneously with the epidemiological and clinical studies, molecular genetic studies will aim at identifying new polymorphisms in the three candidate genes under study. Regulation at polymorphic sites will be examined using molecular biological techniques. The
emphasis will be placed on promoter regions.

Funding Scheme

CON - Coordination of research actions

Coordinator

KAROLINSKA INSTITUTE
Address
Karolinska Hospital
17116 Stockholm
Sweden