Genotype-specific increase in plasma concentrations of activated coagulation factor VII in response to experimental inflammation. A link between infection and acute myocardial infarction?

Recent studies have provided evidence for associations between common polymorphic markers in the coagulation factor VII (FVII) gene and plasma FVII levels. Here we describe two common, nonrelated, functional polymorphisms in the promoter region of the FVII gene, a G to T substitution at position −401 and a novel G to A substitution at position −402. Both polymorphisms strongly influence the binding properties of nuclear protein(s). The rare −401T allele is associated with a reduced basal rate of transcription of the FVII gene in human hepatoblastoma cells and with reduced plasma concentrations of total FVII (VIIag) and fully activated FVII molecules (VIIa). In contrast, the rare −402A allele confers increased transcriptional activity and is associated with increased plasma FVII levels. Together, the two polymorphisms explained 18% and 28% of the variation in VIIag and VIIa, respectively, in a group of 183 healthy, middle-aged men. It is concluded that these polymorphisms are important for the regulation of the plasma levels of FVII and that they are likely to be useful genetic markers to resolve the issue of whether a causal relationship exists between FVII levels and risk of coronary heart disease.

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Influence of factor VII gene polymorphisms and environmental factors on plasma coagulation factor VII concentrations in middleaged women with and without manifest coronary heart disease

Thrombosis and Haemostasis ◽

10.1160/th04-09-0616 ◽

2005 ◽

Vol 93 (02) ◽

pp. 351-358 ◽

Cited By ~ 14

Author(s):

Margita Eriksson-Berg ◽

Hiroyuki Deguchi ◽

Emma Hawe ◽

Daniela Scanavini ◽

Kristina Orth-Gomér ◽

...

Keyword(s):

Coronary Heart Disease ◽

Heart Disease ◽

Large Scale ◽

Plasma Concentrations ◽

Coagulation Factor ◽

Factor Vii ◽

Major Influence ◽

Serum Triglycerides ◽

Coagulation Factor Vii ◽

Functional Polymorphisms

SummaryPlasma concentrations of coagulation factorVII (FVII) are determined by environmental and genetic factors. The influence of functional polymorphisms in the FVII gene (-670A>C, –402G>A, –401G>T and R353Q) and of established cardiovascular risk factors on plasma concentrations of FVII were investigated in a representative sample of middle-aged women with (n=238) and without (n=220) coronary heart disease (CHD). Specific and sensitive assays were used to measure FVII antigen (VIIag) and activated factorVII (VIIa).The effect of genotypes was markedly stronger on VIIa than on VIIag, with the percentage variation in FVII levels accounted for by genotypes being greater in controls than in patients. Of the four polymorphisms examined, only the R353Q contributed to the variation inVIIa (24.1% in patients and 30.3% in controls). The –401G>T and –670A>C promoter polymorphisms together accounted for 12.2% of the variation in VIIag amongst patients whereas the –401G>T polymorphism alone contributed 19.7% of the variation in VIIag in controls. Serum triglycerides exerted a major influence onVIIag in both patients (13.0%) and controls (7.2%).Three main haplotypes emerged from the four polymorphisms which accounted for 98% of all haplotypes. Large-scale prospective studies of CHD including FVII haplotypes and sensitive and specific FVII measurements are needed in women.

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