|dc.description.abstract||INTRODUCTION AND AIM - The prevalence of cardiovascular disease (CVD) has increased significantly in the black South African population in recent years. Early in the development of CVD, atherosclerotic plaques form in the vessel wall. When this plaque becomes unstable and ruptures, the coagulation cascade is activated and a blood clot forms. The function of this clot is to stop bleeding. However, it cannot remain in the vasculature indefinitely and has to be lysed again. The ability of the body to lyse clots can be measured with global fibrinolytic potential (GFP) assays and expressed as lysis time. Increased clot lysis time (CLT) has been shown to be significantly associated with various CVD risk factors and CVD events in Caucasian populations while very little information is available for other ethnicities. In this study we investigated plasma GFP and its relation to CVD risk factors in a large black African population. We also determined the effect of three polymorphisms in the promoter area of the plasminogen activator inhibitor-1 (PAI-1) gene on PAI-1act (activity) levels (a main determinant of CLT) and CLT, together with gene-environment interactions and the effect of urbanisation on these interactions. PARTICIPANTS AND METHODS
Apparently healthy men and women between the ages of 35 and 65 years were recruited to take part in the South African arm of the Prospective Urban and Rural Epidemiology (PURE) study. Approximately 1000 rural and 1000 urban black African individuals participated. Data and samples were collected during a 12-week collection period in 2005 for cross-sectional analysis.
RESULTS - Increased PAI-1act levels, body mass index (BMI), glycosylated haemoglobin (HbA1c), triglycerides, fibrinogen concentration, C-reactive protein, female sex, positive HIV-status and the metabolic syndrome were all associated with prolonged CLTs, while increased habitual alcohol consumption was associated with shorter CLTs. Urban-rural differences for CLT existed in women only. This is likely due to the larger extent of rural-urban differences in other CVD risk factors observed in women compared to what was observed in men. Of the CVD risk factors measured, PAI-1 explained the largest proportion of the variance in CLT (27%). Owing to the important role PAI-1act plays in CLT, we investigated three polymorphisms in the PAI-1 gene promoter area (the 4G/5G polymorphism, the novel SNP C428T and SNP G429A (previously identified)), and the influence of these polymorphisms on PAI-1act levels and CLT. The frequency of the 5G allele was high (0.85) in comparison with previously reported literature. PAI-1act increased significantly across genotypes in the urban (5G/5G: 3.84 U/ml; 4G/5G: 4.85 U/ml; 4G/4G: 5.96 U/ml p=0.009) but not the rural subgroup, while CLT did not differ. We found significant interactions between the 4G/5G polymorphism and BMI, waist circumference and triglycerides in determining PAI-1act, and between the 4G/5G polymorphism and fibrinogen and fibrinogen gamma prime in determining CLT. Direct relationships with PAI-1act or CLT were not found for the C428T and G429A polymorphisms; they did, however, influence associations of other environmental factors with PAI-1act and CLT. Several of these interactions differed significantly between rural and urban subgroups, particularly in individuals harbouring the mutant alleles.
CONCLUSION - CLT associated with many of the same CVD risk factors described in the literature for Caucasian populations, but also with other risk factors. Rural-urban differences in CLT are dependent on the association of CLT with other CVD risk factors in the rural-urban setting. Genetic polymorphisms of the PAI-1 gene did not directly influence CLT, despite influencing PAI-1act. The main contributor to PAI-1act variance, however, was (central) obesity. The effect of the 4G/5G polymorphism on PAI-1act, as well as gene–environment interactions for the C428T and G429A genotypes in determining PAI-1act and CLT, were significantly influenced by urbanisation.||en_US