The Arg ³⁵³ Gln Polymorphism Reduces the Level of Coagulation Factor VII

Abstract

Factor VII levels are regulated by environmental and genetic factors. Two polymorphisms, a G-to-A transversion at nucleotide 10,976 resulting in Arg353Gln and a decanucleotide insert at position -323 in the 5'-flanking region of the factor VII gene, have been associated with a 20% to 25% reduction in plasma factor VII levels. However Arg353Gln almost always segregates on alleles containing the insert in UK and Italian populations, thereby making it impossible to independently evaluate the impact of Arg353Gln on factor VII levels in these ethnic groups. We have evaluated the influence of genotype on factor VII levels in 99 healthy Polish blood donors and observed that Arg353Gln frequently occurs in the absence of the insert. In univariate analysis, the mean levels of factor VII coagulant activity (VII:C) and factor VII antigen (VII:Ag) were significantly lower in 16 people who were heterozygous for Arg353Gln and the insert compared with 72 normal subjects who had neither Arg353Gln nor the insert (88.8% of normal and 83.1% versus 102% and 100%, P = .019 and P = .0003, respectively). In nine subjects heterozygous for Arg353Gln alone, VII:C and VII:Ag were significantly decreased compared with the normal subjects (81.9% and 83%, respectively, P = .007 and P = .004). In multivariate analysis, Arg353Gln but not the insert significantly reduced VII:C and VII:Ag after adjustment for age and plasma triglycerides (P < .05 and P = .02, respectively). To evaluate the mechanism responsible for reduced factor VII levels in individuals with Arg353Gln, we performed transient transfection assays with factor VII cDNA containing the base substitution resulting in Gln353 and wild-type factor VII cDNA in COS-1 cells. The levels of VII:Ag in the cell lysates were similar, but the amino acid substitution significantly reduced factor VII secretion into the media to 74.9% of wild-type (P = .0001). Based on these in vivo and in vitro studies, we conclude that the Arg353Gln polymorphism alone can decrease plasma factor VII levels.

Association Between Factor VII Polymorphisms and Blood Pressure

“…31 In our study, the well-known association between the rarer alleles and decreased FVII levels was observed. [17][18][19][20]32 Furthermore, we observed a positive correlation between FVII and BP as previously reported. 14 -16 Despite the high disequilibrium found between the 2 polymorphisms in several populations, data suggest that it is possible that both polymorphisms are functionally relevant: the 2 polymorphisms may be responsible for as much as one third of the variation in FVII levels.…”

“…14 -16 Despite the high disequilibrium found between the 2 polymorphisms in several populations, data suggest that it is possible that both polymorphisms are functionally relevant: the 2 polymorphisms may be responsible for as much as one third of the variation in FVII levels. 33 In vitro, the Arg353Gln amino acid substitution reduced FVII secretion, 19 possibly arising from a conformational alteration. The presence of the Ϫ323 decanucleotide insert was shown to reduce promoter activity compared with the absence of the decanucleotide.…”

“…14 -16 Genetic variations in the FVII gene, the Arg353Gln and the Ϫ323Del/Ins polymorphisms, have been related to FVII levels and coagulant activity. [17][18][19][20] An association between BP and the Arg353Gln polymorphism was described in a genetic isolate. 21 Therefore, the purpose of this study was to investigate the association of these 2 polymorphisms with BP levels and hypertension in a large, family-based population.…”

Thrombin generation in different cohorts: Evaluation of the haemostatic potential

“…The Arg353Gln polymorphism, which was found in 90% of the patients in this cohort, is rather common; Hunault et al reported a prevalence of about 13.1% in a population of Polish blood donors (n=99) [181]. Its prevalence in the Swedish population is unknown.…”

Genes, coagulation and cardiovascular risk

“…However, a direct effect of this polymorphism on F VII antigen levels could also be proposed as a working hypothesis; recently, in transient transfection assays with F VII cDNA containing the base substitution, it has been shown that the Q allele determined a defective secretion of the molecule from the cells. 16 Beside the R353Q polymorphism, the −323 0/10 bp promoter has also been demonstrated to be functionally relevant; the rare insertion allele 10/bp, indeed, reduced the promoter activity, as compared to the common allele, in transfection experiments. 17 Therefore, it is conceivable that the promoter polymorphism, due to its functionality and strong linkage disequilibrium with the R353Q polymorphism, could also contribute to the effect of FVII genotype on the risk of MI, or even be the main determinant of the effect.…”