Genes Encoding Fibrinogen and Cardiovascular Risk

Abstract

Abstract-The role of fibrinogen in cardiovascular disease has been extensively studied, and meta-analyses have definitively confirmed that high levels of fibrinogen are associated with an increased risk of the disease. In recent years, several polymorphisms have been identified in the fibrinogen chain genes that contribute to determine the levels of fibrinogen in the general population. The fibrinogen ␤-chain gene has been more extensively studied because the ␤-chain synthesis is the limiting step in the production of mature fibrinogen. Overall, the studies show an association between ␤-fibrinogen chain polymorphisms and the levels of fibrinogen. In contrast, the majority of the studies did not find any relation with the risk of cardiovascular disease. The individual responses to gender or to environmental stimuli such as smoking, physical exercise, or infections may be genetically determined, and genetic variability underlies changes in biological reactions that contribute to differences in cardiovascular risk. In the future, gene-environment interactions should be considered in evaluating the relevance of genetic variations on the risk of cardiovascular disease. Key Words: fibrinogen Ⅲ polymorphisms Ⅲ gene-environment interactions Ⅲ risk factors Ⅲ cardiovascular disease A fter the first evidence made in the early 1980s by Meade et al 1 in the Northwick Park Heart Study (NPHS), the role of fibrinogen as a predictor of primary and secondary ischemic coronary events has been demonstrated by several epidemiological studies. [2][3][4][5] Three meta-analyses have been published on the association between fibrinogen and cardiovascular disease: all agree on the finding that high fibrinogen levels are associated with an increased risk of disease. 6 -8 The last of them 8 reviewed 18 prospective studies on Ϸ4000 cases of coronary heart disease followed for a mean of 8 years: fibrinogen levels in the top third were associated with an odds ratio of 1.8 (95% confidence interval [CI], 1.6 to 2.0). These results definitively confirmed the importance of fibrinogen, because they assemble a large number of prospective studies, weighed for possible confounders.Many pieces of evidence make plausible a causal contribution of fibrinogen to cardiovascular disease. This protein is crucial in the process of thrombus formation and evolution, and its levels are influenced by several conventional risk factors. Fibrinogen is the last target of coagulation: its lysis by thrombin produces soluble fibrin fragments that are then stabilized in a clot by factor XIII. It is a mediator of platelet aggregation and a determinant of plasma viscosity. Fibrinogen is an acute phase protein, synthesized in the liver, the plasma levels of which acutely rise during inflammatory conditions. Fibrinogen levels increase with age, pregnancy, use of oral contraceptives, menopause, and obesity. Smoking habits, infections, hypertension, and diabetes are associated with increased levels of fibrinogen, whereas physical activity, moderate alcohol consumption, and fi...

Palmitate-Induced Interleukin-6 Expression in Human Coronary Artery Endothelial Cells

“…Therefore, in our opinion, two other probably synergistic functions of vasculature-derived IL-6 (rev. in 8) seem to be more conceivable: 1) endocrine activation of the hepatic acute-phase response provoking the release of strong risk factors for cardiovascular disease, such as C-reactive protein (30,31) and fibrinogen (32,33); and 2) local paracrine activation of monocytes and platelets favoring fibrinogen deposition and thrombus formation in the vessel wall. In the case of an endocrine function, it could be postulated that palmitate-induced vascular IL-6 secretion influences plasma IL-6 concentrations, but this remains to be shown.…”

Prevalence of the fibrinogen β‐chain, angiotensin‐converting enzyme and plasminogen activator inhibitor‐1 polymorphisms in Costa Rican young adults with thrombotic disease

“…6,26,27 The other explanation is that the age of our group is younger (less than 40 years), because the À455A allele has been associated with the progression of atheroma, that is associated with the elderly population studies. The H2H2 homozygote genotype (À455G/A) was not found in all the groups studied.…”

“…But was not found between MI and Stroke group, which did not agrees total with numerous epidemiological studies where plasma FG has been associated with thrombotic disease, atherosclerotic disease, and an increased risk of cardiovascular disorders, including ischemic heart disease and stroke. 6,7 That could be explained on the basis of the results that was found dealing with the b-chain polymorphisms À455G/A and À48C > T. In special, the À455G/A has been the most extensively studied clinically and the À455HH genotype is present in %10-20% of the population and is correlated with FG levels that are 10% higher than in individuals with the H1H1 genotype. 6,9,26 The influence of the b-FG chain gene has been more extensively studied, because the synthesis of this chain is the limiting step for the production of the mature protein.…”

“…Experimental studies have shown an upregulation of the b-chain gene transcription which has therefore been related with higher FG levels in plasma. 6,7 Polymorphism À148 C > T is related to an increased stimulus exerted by IL-6 on the gene transcription. 8 This factor joins specific promoting region sequences between approximately À150 and À82 base pairs (bp) and increases the levels of FG in plasma.…”

Association between Beta-Fibrinogen C148T Gene Polymorphism and Risk of Ischemic Stroke in a North Indian Population: A Case-Control Study

“…G-A substitution in the promoter region of β-fibrinogen has been found to be associated with an increase in plasma fibrinogen levels [17,18]. One study demonstrated that the β-fibrinogen 148 TT genotype was associated with genetic risk factors for carotid atherosclerosis [19].…”