GENETIC-VARIATION AT THE BETA-FIBRINOGEN LOCUS IN RELATION TO PLASMA-FIBRINOGEN CONCENTRATIONS AND RISK OF MYOCARDIAL-INFARCTION - THE ECTIM STUDY

Increased plasma fibrinogen concentration is a major cardiovascular risk factor. Conflicting results on genetic variations in plasma fibrinogen levels have been reported. Furthermore, whether fibrinogen genotype is associated with the risk of ischemic heart disease has not been studied so far. An HaeIII restriction fragment length polymorphism of the beta-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 HaeIII cutting site (H2 allele) was associated with a significant rise in fibrinogen concentrations in both patients and control subjects. The effect of the HaeIII 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. HaeIII genotype accounted for almost-equal-to 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 R2 allele was 0.21 in control subjects and 0.19 in patients. The relative risk estimate of MI associated with the presence of the R2 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 HaeIII genotype and the effect of smoking on MI risk. These data provide further evidence for a role of the genetic variation at the beta-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.