A functional haplotype in the 5′ flanking region of the factor VII gene is associated with an increased risk of coronary heart disease

Abstract

Summary. Aims: The aim of this study was to investigate associations between coronary heart disease risk and polymorphisms in the coagulation factor (F)VII gene in participants of a large prospective study. Methods: One thousand nine hundred and ®fty-seven men were genotyped for four FVII polymorphisms, À670A3C, À402G3A, a 10 base pair insertion at À323 (0 > 10) in the promoter, and R353Q in the structural gene. Associations among genotypes and estimated haplotypes, plasma FVII levels, and coronary heart disease risk were evaluated, and the function of the promoter polymorphisms was assessed in reporter gene assays. Results: The À670A3C and À402G3A polymorphisms were in complete allelic association. The haplotype containing À670C and À402A (frequency 0.23) was associated with signi®cantly increased plasma FVII coagulant activity and increased risk of an initial coronary event, particularly acute myocardial infarction, which remained after correction for conventional risk factors. In contrast, the À323 insertion and Q353 alleles (frequency 0.11 and 0.10, respectively) were associated with decreased plasma FVII levels, but hazard ratios for coronary events in carriers of these alleles were not signi®cantly different from unity. In transiently transfected hepatoma cells, increased basal expression of the reporter gene was directed by a promoter fragment with rare haplotype À670C/À630G/À402A rather than by a promoter fragment with common haplotype À670A/À630A/À402G; À402A was not responsible for this effect. Conclusions: The promoter haplotype, À670C/À630G/ 402A, was associated with signi®cantly increased plasma FVII coagulant activity, risk of an initial coronary event, particularly acute myocardial infarction, and reporter gene expression.

Reduction in coagulation factor VII plasma levels by R353Q but not the −323P0/10 promoter polymorphism in healthy Tunisians

“…In addition, the interaction between genetic markers associated with FVII coagulant activity and the risk of CHD pathogenesis remains to be established [24,35]. The positive association of the R353Q polymorphism (though not the À323P0/10) with FVII prompts the speculation as to whether the Q allele might confer some protection against thrombosis and coronary artery disease among Tunisians, as previously described [31,36].…”

“…While epidemiological evidence suggests that FVII coagulant activity is a marker of coronary heart diseases (CHD), the exact link between plasma FVII levels and CHD is controversial [35]. In addition, the interaction between genetic markers associated with FVII coagulant activity and the risk of CHD pathogenesis remains to be established [24,35].…”

The Association of Blood Biochemical Parameters with Myocardial Infarction

“…7,[14][15][16] Previous reports suggested that hypertriglyceridemia predisposes to thrombosis by increasing factor VII coagulant activity. [17][18][19] Therefore, the relationship between hypertriglyceridemia, factor VII coagulant activity and myocardial infarction should be considered in future studies. On the contrary, there were no significant differences in total cholesterol concentration between patients with myocardial infarction (5.8 ± 1.3 mmol/l) and control group (5.2 ± 1.2 mmol/l).…”

Factor VII Gene Haplotypes and Risk of Ischemic Stroke

“…Previously, the Ϫ402A allele had been reported to be associated with both increased FVII plasma concentrations and increased transcriptional activity in vitro (10 ). Recently, this sequence variant has been reported to represent a risk factor for myocardial infarction (19,20 ), but its role had not been tested in stroke patients. In our study we report for the first time an association of the Ϫ402A allele with the occurrence of acute ischemic cerebrovascular events before the age of 60 years by showing that individuals carrying the Ϫ402A allele have an increased risk for developing transient ischemic attack or ischemic stroke.…”