Genetic variation at the beta-fibrinogen locus in relation to plasma fibrinogen concentrations and risk of myocardial infarction. The ECTIM Study.

Abstract

Increased plasma fibrinogen concentration is a major cardiovascular risk factor. Conflicting results on genetic variations in plasma fibrinogen levels have been reported. Furthermore, whether flbrinogen genotype is associated with the risk of ischemic heart disease has not been studied so far. An HaelU restriction fragment length polymorphism of the ^-fibrinogen gene was used in a case-control study to investigate the genetic variation at this locus in relation to plasma fibrinogen concentrations and the risk of myocardial infarction (MI). Five hundred thirty-three male patients aged 27-66 years and 648 control subjects were recruited from four World Health Organization MONICA centers in Northern Ireland and in France. The absence of the HaeWl cutting site (H2 allele) was associated with a significant rise in fibrinogen concentrations in both patients and control subjects. The effect of the HaelU polymorphism on plasma fibrinogen levels did not significantly differ between centers. Fibrinogen levels were higher in smokers than in nonsmokers. The difference between the two groups was larger in subjects with the genotype H2H2 than in those with either genotype H1H1 or H1H2, regardless of the case-control status. However, there was no significant interaction between smoking status and genotype in their effects on fibrinogen levels. HaelU genotype accounted for «1% of the total variance in fibrinogen levels, whereas smoking and age together explained 7% and 5% in control subjects and patients, respectively. The frequency of the H2 allele was 0.21 in control subjects and 0.19 in patients. The relative risk estimate of MI associated with the presence of the H2 allele was 0.89 (95% confidence interval, 0.69-1.13). The results were consistent with respect to the centers. Multiple regression analysis showed that smoking and raised plasma fibrinogen made independent contributions to the increase in MI risk. There was no significant interaction between HaelU genotype and the effect of smoking on MI risk. These data provide further evidence for a role of the genetic variation at the /3-fibrinogen locus in the determination of plasma fibrinogen concentrations. However, this study failed to detect an association between this genetic variation and MI risk. Further investigations are needed to assess the relative contribution of genetic and environmental determinants of plasma fibrinogen to the prediction of atherothrombotic diseases.

Two Common, Functional Polymorphisms in the Promoter Region of the β-Fibrinogen Gene Contribute to Regulation of Plasma Fibrinogen Concentration

“…13,21,23,[37][38][39][40][41][42] It appears from these studies that the overall impact of the Ϫ455G/A polymorphism on the plasma fibrinogen concentration is rather small. For instance, investigators from the Copenhagen City Heart Study 13 reported that the Ϫ455G/A polymorphism explained only 1% of the variation in plasma fibrinogen level.…”

A common mutation (G-455--> A) in the beta-fibrinogen promoter is an independent predictor of plasma fibrinogen, but not of ischemic heart disease. A study of 9,127 individuals based on the Copenhagen City Heart Study.

“…Because several studies have suggested variable effects of ␤-fibrinogen genotype on plasma fibrinogen levels in cases with IHD and in controls within the same study (9)(10)(11)19), the effect of ␤-fibrinogen genotype on plasma fibrinogen was examined in women and men with and without IHD. The A-allele was associated with significant increases in plasma fibrinogen in women and men both with and without IHD (Fig.…”

“…Of the polymorphisms studied to date, the ( G Ϫ 455 → A ) substitution in the 5 Ј flanking region of the ␤ -fibrinogen gene is associated with the most consistent differences in plasma fibrinogen levels in both casecontrol studies, and in selected groups of healthy individuals (9)(10)(11)(12). Whether fibrinogen genotype actually affects plasma fibrinogen levels and risk of IHD in the general population has not yet been studied.…”

Genetic factors associated with endothelial dysfunction affect the early onset of coronary artery disease in Korean males

“…Plasma fibrinogen levels were determined using methods described by Scarabin et al 27 and are reported in mg/dl.…”