β-fibrinogen gene G/A-455 polymorphism in relation to fibrinogen concentrations and ischaemic heart disease in Chinese patients with Type II diabetes

Abstract

It has been increasingly recognised that the excess cardiovascular risk in Type II (non-insulin-dependent) diabetes mellitus could be partly contributed by an increased prothrombotic tendency, including increased fibrinogen concentrations [1], a strong predictor of ischaemic heart disease and stroke in various large epidemiological studies [2]. Fibrinogen and fibrin accumulate in the atherosclerotic plaque at a rate proportional to the plasma fibrinogen concentration [2,3]. Genetic factors which affect the production or circulating concentrations of fibrinogen could therefore be causally related to the development of atherosclerosis.Of the known fibrinogen gene polymorphisms, the G/A-455 polymorphism at the 5 ¢-flanking region of the b-fibrinogen gene is the most important independent genetic determinant of plasma fibrinogen concentrations in Caucasian populations [4], with the highest concentrations found in subjects with the AA Diabetologia (1999) Abstract Aims/hypothesis. We investigated the relation between the G/A-455 (Hae III) b-fibrinogen gene polymorphism and plasma fibrinogen concentration and its role in ischaemic heart disease in 264 Chinese patients with Type II (non-insulin-dependent) diabetes mellitus and 182 non-diabetic control subjects. Methods. The G/A-455 polymorphism was determined in genomic DNA using polymerase chain reaction and Hae III restriction enzyme digestion. Fibrinogen was measured with the Claus method. Results. Fibrinogen concentrations were higher in diabetic patients (3.3 ± 0.5 vs 2.5 ± 0.9 g/l in controls, p < 0.0001) and in women (p < 0.03 vs men). Allele frequency of the variant A allele was 27 % in both diabetic patients and control subjects' similar to findings in Caucasians. In control subjects, the AA genotype was associated with higher fibrinogen concentrations (2.8 ± 0.38 g/l vs 2.5 ± 0.5 in GG or GA, p < 0.03), contributing to 4 % of the variance in plasma fibrinogen. The genotype effect was smaller and not significant among non-smokers, women and diabetic patients. Higher fibrinogen concentrations and AA genotype frequency were found in diabetic patients with ischaemic heart disease (p < 0.05 and p < 0.005, respectively vs unaffected patients). In a multiple logistic regression model, AA genotype, age and mean arterial pressure were associated with ischaemic heart disease, with odds ratios of 4.19 (p < 0.01), 1.05 (p < 0.0001) and 1.03 (p < 0.03), respectively. Conclusion/interpretation. The G/A-455 polymorphism is a genetic determinant of fibrinogen concentrations and ischaemic heart disease in this Chinese cohort. It also interacts with environmental influences associated with smoking, the female sex and Type II diabetes in determining plasma fibrinogen concentrations. [Diabetologia (1999)

The association of beta-fibrinogen 455 G/A gene polymorphism with left atrial thrombus and severe spontaneous echo contrast in atrial fibrillation

“…Although it did not reach statistical significance, MR score was lower in patients with left atrial thrombus. This study confirmed the higher prevalence of SEC in patients with LA thrombus (17,31).…”

“…However, these markers may change instantaneously, and they may also be affected by many other conditions. Recent studies revealed the relationship between beta-fibrinogen 455G/A polymorphism and stroke or myocardial infarction (17)(18)(19). Beta-fibrinogen 455G/A polymorphism was also shown to be associated with the increased erythrocyte aggregation and predisposing the development of stasis (28).…”

“…Previous study revealed the increased fibrinogen activity in the presence of homozygote A/A allele (14)(15)(16). It was determined that the increased A/A allele is associated with increased cardiovascular events (17,18) and increased prevalence of lacunar infarct in brain (19). However, conflicting results were also reported (20) Glycoprotein PLA1/A2 polymorphism is another gene mutation, which is responsible for predisposition to thrombosis through change in the activity of a glycoprotein IIIa receptor located on the surface of a thrombocyte.…”

Genes Encoding Fibrinogen and Cardiovascular Risk

“…None of the latter were related to thrombosis in coronary arteries. However, 2 groups showed an association with the risk of cardiovascular disease in patients with non-insulindependent diabetes, 26,35 one with peripheral arterial disease, 32 one with deep venous thrombosis, 25 and the last one with large vessel cerebrovascular disease. 36 An additional study documented that the Ϫ455 G/A polymorphism was related to the progression of cardiovascular disease, in patients with hypercholesterolemia.…”

“…15,16 Only few studies have found an association between Ϫ455 G/A polymorphism and the risk of ischemic vascular disease (Table). 25,26,32,35,36 In particular, out of 14 studies in which the relation between Ϫ455 G/A polymorphism and the risk was evaluated, only 5 reported the presence of an association. None of the latter were related to thrombosis in coronary arteries.…”