Bcl I Polymorphism in the Fibrinogen β-Chain Gene Is Associated With the Risk of Familial Myocardial Infarction by Increasing Plasma Fibrinogen Levels

Abstract

The aim of this study was to investigate the association of the Bcl I beta-chain fibrinogen polymorphism with the risk of acute myocardial infarction (AMI) and its relationship with fibrinogen levels in the Italian population. We studied 102 AMI patients, selected within the framework of the GISSI-2 trial, who had a familial history of arterial thrombosis (at least one first-degree relative suffering from AMI or stroke before 65 years) and 173 control subjects (with neither AMI nor personal or familial history of arterial thrombosis). All subjects were Italian. Patients showed fibrinogen levels higher than control subjects. There was a highly significant difference in allele frequency in cases versus control subjects, the B2 allele frequencies being respectively 0.28 versus 0.17 (P = .002). In multivariate analysis, adjusted for sex, age, smoking habits, and history of hyperlipidemia, hypertension, or diabetes, the (B1B2 + B2B2) genotype was associated with a higher risk of AMI (odds ratio 2.4, 95% confidence interval, 1.2 to 4.6). The Bcl I genotype was also associated with fibrinogen levels, independently of gender and smoking habits, the (B1B2 + B2B2) subjects showing the highest levels in both cases and control subjects. The difference in fibrinogen levels between cases and control subjects was significantly influenced by the genotype (significant interaction, P = .042). The B2 allele of the Bcl I polymorphism in the beta-chain of the fibrinogen gene is a new factor associated with the risk of familial AMI through its association with fibrinogen levels. These data provide evidence for a causal role of fibrinogen in familial AMI.

Genetic and Environmental Determinants of Fibrin Structure and Function

“…49 The BclI polymorphism has been shown to associate with increased fibrinogen levels and is more common in subjects with severe coronary artery disease. 50,51 The Ϫ455G/A substitution in the B␤ gene occurs in an IL-6 -responsive HNF1 element and has been associated with increased fibrinogen levels 52 in a manner that is environment-dependent. 53,54 In vitro studies of the B␤-455 A/G polymorphism have indicated that the substitution alters nuclear protein binding profiles, reporter luciferase gene expression, and that it may explain up to Ϸ11% of the variation in fibrinogen levels.…”

“…Increases fibrinogen level 50 More common in CAD [50][51] Fibrinogen B␤-148C/T --Fibrinogen B␤-448G/A Alters nuclear protein binding 55 More common in CAD [56][57][58] Coding polymorphisms…”

Population variability in some genes involving the haemostatic system: data on the general population of Corsica (France), Sardinia and Sicily (Italy)

“…This might be explained by the reciprocal exchange that has taken place between the two populations ever since prehistoric times. For instance, during the late Neolithic period, north Sardinia saw the «Megalithic Circle» culture, that was in strong correspondence with the Haemostasis genes in Mediterranean populations 143 Zito et al, 1997;Dell'Acqua et.al., 1997;Iacoviello et al, 1998 North Italy 0.019 0.658 0.323 0.000 Girelli et al, 2000 Italy ( Peyruchaud et al, 1995;Ruan et al, 1993 England 0.730 0.850 0.810 0.883 0.046 0.672 0.282 0.000 Thomas et al, 1994;Humphries et al, 1996;de Knijff et al, 1994Netherland 0.710 0.830 0.861 de Maat et al, 1997de Knijff et al, 1994;Doggen et al, 2000 contemporaneous «Torreana» culture in Corsica. The contact between the two islands continued throughout both the Bronze and Iron Ages.…”

“…This allele variant has shown to be associated with an increased plasma fibrinogen level, which is an independent risk indicator for cardiovascular disease (de Maat et al, 1995;Iso et al, 1995;Zito et al, 1997;Donati et al, 2000).…”

“…Allele variants of these markers have shown to be associated with an increased plasma fibrinogen level, which is an independent risk indicator for cardiovascular disease (de Maat et al, 1995;Iso et al, 1995;Zito et al, 1997, Donati et al, 2000. Genetic variation of the Factor VII gene (F7) was tested by means of the Insertion/Deletion (at the -323 site in the promoter region) and the HVR4 (VNTR of 37bp repeat core next to intron G) markers.…”