Positive Association of the β Fibrinogen H1/H2 Gene Variation to Basal Fibrinogen Levels and to the Increase in Fibrinogen Concentration during Acute Phase Reaction but not to Coronary Artery Disease and Myocardial Infarction

Abstract

Summary Background: Fibrinogen has been demonstrated to be an independent risk factor of cardiovascular disease. The absence of the Haelll cutting site (H2 allele) of an H1/H2 gene variation in the promoter region of the (β fibrinogen gene was associated with increased levels of fibrinogen. Methods and Results: In the present study, the effects of the H1/H2 gene variation not only on plasma fibrinogen concentrations but also on coronary artery disease (CAD) and myocardial infarction (MI) were investigated in 923 individuals who underwent coronary angiography for diagnostic purposes. Relation of the H1/H2 genotype to fibrinogen plasma levels: A strong association was observed between the H1/H2 gene variation and fibrinogen levels. The differences in fibrinogen plasma levels between H2H2 and H1H1 homozygotes were almost threefold more pronounced within subjects with clinical chemical signs of an acute phase reaction (CRP ≥ 7.5 mg/1) than within a subgroup of subjects without these signs (CRP < 7.5 mg/1) (median of CRP distribution: 7.5 mg/1). In 207 patients who underwent aortocoronary bypass surgery plasma fibrinogen levels were almost identical directly after surgery. Two days after operation fibrinogen increased to clearly higher levels in H2H2 homozygotes than in H1H2 and H1H1 genotypes, whereas almost the same maximal increases in fibrinogen concentrations were reached 3-4 days after surgery in all individuals. Relation of the H1/H2 genotype to CAD and MI. Whereas in the total population the plasma fibrinogen concentrations were strongly associated with smoking, CAD and MI, an association of the H1/H2 gene variation to CAD and MI was not detected. However, mean age at first MI of H2H2 individuals (62.9 years) was clearly higher than of H1H2 genotypes (56.9 years) and of H1H1 subjects (56.4 years). In addition, in a subgroup of individuals with a higher risk of MI by either high apoB and/or low apoAl plasma levels the portion of MI patients was clearly smaller within H2H2 homozygotes than within H1H2 or H1H1 genotypes, although – also in these high risk groups – mean age at first MI of H2H2 individuals were higher than of the other two genotypes. Conclusions: Obviously, the H2 allele of the fibrinogen H1/H2 genotype does not only influence basal fibrinogen concentrations, but particularly also the extent of fibrinogen level increase during acute phase reaction. Whereas the fibrinogen plasma level is positively associated with coronary artery disease and myocardial infarction, the H2 allele - although exhibiting an association with elevated fibrinogen levels - was not positively associated with CAD and MI.

Interleukin-6 Gene −174G>C and −572G>C Promoter Polymorphisms Are Strong Predictors of Plasma Interleukin-6 Levels After Coronary Artery Bypass Surgery

“…This is the first suggestion that genotype might influence the dynamic profile of the IL-6 response, although a similar genotype effect has been observed on post-CABG fibrinogen levels. 42,43 However, these observations require further and more detailed investigation in this and other clinical models. More detailed in vitro studies of the time-course response are also required.…”

Genetic Variation in Coagulation and Fibrinolytic Proteins and Their Relation With Acute Myocardial Infarction

“…32,33 The recessive model indicated a significant association between AA genotype and a lower risk of myocardial infarction (OR 0.67, 95% CI 0.45 to 0.98, Pϭ0.04; Figure 3) …”

“…32,33 The recessive model indicated a significant association between AA genotype and a lower risk of myocardial infarction (OR 0.67, 95% CI 0.45 to 0.98, Pϭ0.04; Figure 3). The dominant model indicated a nonsignificant association between carriership of at least 1 A allele and the risk of myocardial infarction (OR 0.91, 95% CI 0.76 to 1.09, Pϭ0.3).…”

“…3,[31][32][33][34] From those, 3 studies were excluded because no solid diagnostic criteria for myocardial infarction were used 3,31 or because of an inadequate spectrum of cases, 34 leaving 2 studies in the analysis.…”

“…Three studies investigating patients with myocardial infarction occurring before the age of 55 years were identified. 32,33,50 One study was excluded because of inadequate delineation of cases. 50 …”