Published online before print September 27, 2004, doi: 10.1161/01.HYP.0000144799.41945.a5
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(Hypertension. 2004;44:674.)
© 2004 American Heart Association, Inc.
Scientific Contributions |
Association Between Factor VII Polymorphisms and Blood Pressure
The Stanislas Cohort
From the Unité INSERM U525 (C.S., M.P., S.V.-S.), Centre de Médecine Préventive, and Université Henri Poincaré, Nancy; Fournier Pharma (C.B.) Dijon, France; and the Hematology Laboratory (P.-E.M.), CHU Timone, INSERM U626, Faculty of Medicine, Marseille, France.
Correspondence to Sophie Visvikis-Siest, Unité INSERM U525, Faculté de Pharmacie, Université Henri Poincaré Nancy I, 30 rue Lionnois, 54000 Nancy, France. E-mail Sophie.Visvikis{at}cmp.u-nancy.fr
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Abstract |
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The purpose this study was to determine whether Arg353Gln and –323Del/Ins polymorphisms of factor VII (FVII) are related to blood pressure levels and hypertension. Subjects were drawn from the Stanislas Cohort, a longitudinal, familial French cohort examined twice since 1994. The "blood pressure study" included 1342 subjects free of medication use that could affect blood pressure. The "hypertension study" included 645 normotensive and 77 hypertensive adult subjects. Association with hypertension was also studied in 547 hypertensives enrolled in a clinical trial and in 624 normotensives drawn from the Stanislas Cohort. In the "blood pressure study," parents with the 353Gln or –323Ins allele had lower blood pressures than did noncarriers at each examination, independent of covariates (0.01
P0.05, except for diastolic blood pressure [DBP] at baseline, where P=0.103). Similarly significant relations were observed in their offspring (P0.05, except for systolic blood pressure [SBP] at 5 years, where P=0.186). In a representative subgroup of 267 individuals, the –323Del/Ins polymorphism was significantly associated with plasma FVII levels in both parents and offspring (P<0.001). FVII levels in plasma were significantly correlated with SBP and DBP in parents but not in offspring. After inclusion of both FVII levels and the –223Del/Ins in the same model in parents, only FVII levels remained significantly associated with SBP and DBP. The "hypertension study" revealed that the 353Gln and –323Ins alleles were related to decreased risk (odds ratio [OR]=0.554, 95% confidence interval [CI], 0.362 to 0.848, and OR=0.475, 95% CI, 0.299 to 0.755, respectively). These results suggest that the FVII gene may be a susceptibility locus for hypertension.
Key Words: rheology • thrombin • blood pressure • hypertension • genetics
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Introduction |
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Associations between rheologic and hemostatic factors1–4 and blood pressure (BP) and/or hypertension have been described. Association studies cannot establish whether abnormalities of rheology and coagulation occur as a consequence of the higher BP or whether these could be factors that contribute to high BP. However, data suggest that hemorheologic factors may be implicated in BP homeostasis. Thrombin, in addition to converting fibrinogen to fibrin, can interact with cell-surface receptors and induce several intracellular pathways.5,6 Proangiogenic activities of thrombin have been described,5 and thrombin can also modulate vascular tone7 and have proinflammatory properties.8 All of these factors can play a role in initiating and maintaining an elevation in BP.
Factor VII (FVII) is a key factor in the coagulation cascade leading to the production of thrombin. FVII also elicits several cellular responses, such as angiogenesis9–11 and inflammation,12,13 that may be related to hypertension, and associations between FVII and BP have been found.14–16 Genetic variations in the FVII gene, the Arg353Gln and the –323Del/Ins polymorphisms, have been related to FVII levels and coagulant activity.17–20 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.
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Methods |
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BP Study
The study population was selected from the Stanislas Cohort22 For the present study, 1342 individuals (657 men and 686 women from 424 families) were selected on the basis of the following criteria: (1) subjects were present at both the first (T0) and second (T+5) examinations; (2) data from both examinations and information on FVII Arg353Gln and –323Del/Ins genotypes were available; and (3) at each visit, there was no indication of antihypertensive, lipid-lowering, or anti-inflammatory drug use.
Hypertension Studies
Sample Group 1
The normotensive subjects were drawn from the "blood pressure levels study" sample population. There were 295 fathers and 350 mothers with a systolic blood pressure (SBP)/diastolic blood pressure (DBP) <140/90 mm Hg at both examinations. The hypertensive subjects included parents from the Stanislas Cohort with an SBP 
140 mm Hg or a DBP 90 mm Hg or who were taking antihypertensive drugs at both examinations (49 fathers and 28 mothers). Consistency of the results was checked after inclusion of the prehypertensive subjects with the hypertensive subjects according to the Joint National Committee VII guidelines.23
Sample Group 2
The normotensive subjects were drawn from the previous group. There were 287 men and 347 women <56 years old at the second examination and with an SBP/DBP <140/90 mm Hg at both examinations. The hypertensive population (278 men and 269 women) was selected from French subjects enrolled in a clinical trial. The clinical inclusion criteria were (1) Caucasian origin; (2) absence of cardiovascular disease, stroke; or diabetes; and (3) an SBP between 140 and 180 mm Hg and a DBP between 90 and 110 mm Hg. Only subjects <56 years old were included to match the normotensive age distribution more closely.
Clinical and Biological Data: Stanislas Cohort
BP was measured under standardized conditions (supine position) with a sphygmomanometer. The values reported for SBP and DBP are the means of 3 readings at each examination. Biologic measurements and DNA extraction were performed with standardized methods.22 FVII Arg353Gln and –323Del/Ins genotyping was performed by using a multilocus genotyping assay24 modified to also include genotyping capability for FVII Arg353Gln and –323Del/Ins polymorphisms. Plasma FVII antigen (FVII:Ag) was measured with a commercially available ELISA kit from Diagnostica Stago. The interassay coefficient of variation was 7%.
Clinical Trial
Characteristics of the hypertensive subjects were obtained after the wash-out period. DNA extraction and FVII genotyping were performed as described for the Stanislas Cohort.
Statistical Analysis
Statistical analyses were performed with SAS statistical software (SAS Institute, Inc). Plasma levels of FVII:Ag were logarithmically transformed. Pairwise disequilibrium between the 2 FVII polymorphisms was tested with ARLEQUIN. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by means of logistic regression analysis, which was adjusted for sex, age, body mass index, smoking status, alcohol consumption, contraceptive use, and triglyceride level.
In the BP levels study, because individuals within a family are not independent, statistical analyses were based on the estimating equation technique25 by using the SAS GENMOD procedure with a repeated statement. Analyses were done in the whole sample and in subgroups according to relative status (parents or offspring).
ANOVA and ANCOVA adjusted for sex, age, body mass index, smoking status, alcohol consumption, contraceptive use, and triglyceride level in each relative were performed to compare BP levels among FVII genotypes. Homogeneity of the association for relatives (parents vs offspring) or sex was tested by introducing a cross-product term, FVII genotypexparents or genotypexsex. A 2-sided probability value <0.05 was considered statistically significant.
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Results |
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BP Levels Study
Distribution of FVII Polymorphisms (Arg353Gln and –323Del/Ins)
The genotype frequencies for the –323Del/Ins polymorphism were 68.2%, 29.0%, and 2.8% for Del/Del, Del/Ins, and Ins/Ins, respectively in the parents. The allele frequency was 17.3% for the Ins allele. The genotype frequencies for the Arg353Gln polymorphism were 72.1%, 25.6%, and 2.3% for Arg/Arg, Arg/Gln, and Gln/Gln, respectively, in the parents. The allele frequency was 15.1% for the Gln allele. These results are consistent with Hardy-Weinberg equilibrium (
2=0.099, P=0.751 for –323Del/Ins and 2=0.016, P=0.897, for Arg353Gln). The 2 polymorphisms were in strong linkage disequilibrium (D'=0.912, 2=1112.6, P<0.00001). For this reason, only results concerning the –323Del/Ins polymorphism are shown in the following sections.
Biological and Clinical Characteristics and Lifestyle Factors According to FVII Polymorphisms
Primary biologic and clinical characteristics and lifestyle factors at each examination according to FVII –323Del/Ins are shown in Table 1. The percentage of smokers and triglyceride levels were slightly lower in offspring with the –323Ins allele than in the Del/Del genotype (P<0.05 at the second visit), and the percentage of mothers taking contraceptive pills was about twice that in Del allele carriers than in Del/Del carriers (0.01<P<0.05). Similar results were observed with the Arg353Gln polymorphism (data not shown).
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Association Between BP Levels and FVII Polymorphisms
Table 2 shows the relation between BP levels and the FVII –323Del/Ins polymorphism. In the whole population, the less frequent allele was related to lower SBP and DBP at each visit, with a decrease of 
2 mm Hg (0.01<P<0.05). Adjustment for BP covariates (age, body mass index, smoking status, alcohol consumption, contraceptive pill use, and triglyceride level) did not change the results. Neither heterogeneity according to relative status (parents versus offspring) nor sex was significant. Among parents, the relation between the –323Del/Ins polymorphism and BP levels was significant at both visits for SBP (0.01<P<0.05) and at the second visit for DBP (P<0.05); the relation between genotype and DBP at T0 had borderline significance (P=0.103). In offspring, DBP at both visits and SBP at the first visit were significantly related to the –323Del/Ins polymorphism (P<0.05). Similar results were obtained with the Arg353Gln polymorphism (data not shown).
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Association Between Plasma FVII, BP Levels, and FVII Polymorphisms
Because it had been previously shown that both FVII polymorphisms are related to plasma FVII levels, we measured FVII:Ag concentrations in 267 individuals from the cohort. This subgroup consisted of 114 parents (46 fathers and 68 mother) and 153 offspring (83 sons and 70 daughters) who were not significantly different from those whose FVII levels were not measured with respect to the relation between FVII polymorphisms and BP and other parameters evaluated in the study.
The –323Del/Ins polymorphism was significantly associated with FVII:Ag levels. Ins carriers exhibited lower levels than did homozygotes in both parents (mean±SD, 83.8±2.5 and 101.0±2.3 IU/dL; P<0.0001) and offspring (74.5±2.1 and 94.3±2.4 IU/dL; P<0.0001). After adjustment for sex and age, FVII levels were correlated with SBP and DBP in parents (ß=38.77 and ß=25.25, respectively; P<0.001) but not in offspring (ß=2.66, P=0.68, and ß=2.75, P=0.71 for SBP and DBP, respectively).
We then explored whether the relation between FVII polymorphisms and BP was caused by modifications of FVII levels. After inclusion of these 3 variables in the same model in parents, the FVII level but not the –323Del/Ins polymorphism remained significantly associated with SBP and DBP (Table 3). Similar results were obtained with the Arg353Gln polymorphism (data not shown).
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Hypertension Studies
Table 4 shows baseline clinical and biologic characteristics of subjects who were hypertensive and of those who where normotensives at both visits within the parents of the Stanislas Cohort. As would be expected, aside from BP levels, age; body mass index; cholesterol, triglyceride, and glucose levels; and alcohol consumption were higher in hypertensives than in normotensives (P<0.0001), and there were more male than female hypertensive subjects. No significant differences were observed for smoking status and contraceptive pill use.
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As shown in Table 5, the FVII genotype distribution for the –323Ins/Del polymorphism was significantly different among normotensive and hypertensive subjects (P<0.01). Hypertensive subjects had reduced carrier rates for the –323Ins allele (P=0.0033). Thus, the estimated OR for hypertension associated with the –323Ins allele was 0.432 (95% CI, 0.237 to 0.789). In a multivariate model (Table 6) adjusted for sex, age, body mass index, smoking status, alcohol consumption, contraceptive pill use, and triglyceride level, the estimated OR of hypertension associated with the –323Ins allele remained significant (OR=0.465, 95% CI, 0.241 to 0.889, P=0.021). Similar results were observed for the Gln353 allele (OR=0.442, 95% CI, 0.218 to 0.896, P=0.024).
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To strengthen our results, we verified the association between FVII polymorphisms and hypertension by comparing normotensives from the Stanislas Cohort with hypertensive subjects enrolled in a clinical trial. Characteristics of the subjects are given in Table 7.
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The less frequent allele of the –323Del/Ins polymorphism was again found to be associated with a lower risk of hypertension (OR=0.525, 95% CI, 0.403 to 0.682 for the –323Ins allele). The protective effect remained after controlling for sex; age; body mass index; and glucose, cholesterol, and triglyceride levels (OR=0.547, 95% CI, 0.411 to 0.772 for the –323Ins allele). Similar results were obtained for the Arg353Gln polymorphism (OR=0.507, 95% CI, 0.375 to 0.686 for the Gln allele).
Furthermore, allele and genotype frequencies of both polymorphisms were not significantly different (0.387P0.576) between hypertensive subjects from the clinical trial and hypertensive subjects from the Stanislas Cohort.
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Discussion |
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In this study, we reveal an association between BP and FVII polymorphisms. This was observed in 3 different ways involving 2 different sample populations: (1) with the BP phenotype considered as a quantitative trait in a French family-based cohort, free of medications that could influence BP levels; (2) with BP as a dichotomous variable (normotensives vs hypertensives) in a sample population selected from the same Stanislas Cohort; and (3) in a case/control study for hypertension, with controls from the Stanislas Cohort and French cases from an antihypertensive clinical trial. Our results are strengthened by several other points: (1) The Stanislas Cohort is an ethnically homogeneous population, thus limiting the possibility that the observed association is because of population admixture and stratification. (2) It seems unlikely that the difference in allele frequencies between normotensives and hypertensives observed in the Stanislas Cohort may be due to some particularity of this cohort. An association with hypertension was also observed when French hypertensives enrolled in a clinical trial were compared with hypertensives from the Stanislas Cohort and from the clinical trial. Allele frequencies in the Stanislas Cohort are similar to those observed among the ECTIM (Etude Cas Témoin sur L’Infartus du Myocarde)26 study controls recruited from the eastern part of France, as was the Stanislas Cohort. (3) Misclassification between normotensive and hypertensive subjects was limited, because classification in the Stanislas Cohort was based on 2 health examinations performed at a 5-year interval. (4) Associations were observed for both SBP and DBP, and these persisted after adjustment for potential confounding variables. (5) Similar associations were found in both adult subjects and among children, suggesting a continuous impact during life, at least across the age range studied. (6) In a genetic isolate of Canadian Hutterites, the 353Arg/Gln polymorphism was also found to be related to BP.21
The less frequent alleles of the –323Del/Ins and of the 353Arg/Gln polymorphisms were related to a decreased risk of hypertension and to lower BP levels, for both DBP and SBP. The benefits of a decrease of 2 mm Hg with the less frequent alleles may appear small, but a decrease of 6 mm Hg in DBP is related to a reduction of 40% in stroke risk and 25% in coronary artery disease risk.27 Furthermore, it is widely acknowledged that BP variation is most likely the result of a combination of many genetic and environmental factors, and the effect of any 1 gene is expected to be relatively small.
The lowering effect of the less frequent allele of both FVII polymorphisms is consistent first, with the reported association between the rarer allele and a lower risk of cardiovascular diseases,26,28–30 even though this was not found in all studies.31 In our study, the well-known association between the rarer alleles and decreased FVII levels was observed.17–20,32 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.33 In vitro, the Arg353Gln amino acid substitution reduced FVII secretion,19 possibly arising from a conformational alteration. The presence of the –323 decanucleotide insert was shown to reduce promoter activity compared with the absence of the decanucleotide.34 Owing to the relatively low frequencies of both polymorphisms and the strong linkage disequilibrium between them, it was not possible in this study to evaluate haplotype effects.
Our study does not address the physiologic significance of the observed association between the FVII polymorphisms and BP, but some hypothesis can be inferred from the literature. After including –323Del/Ins polymorphism and plasma FVII level in the same model, only the latter remained significantly associated with BP. This suggests that the influence of FVII polymorphism on BP is mediated by modifications of plasma FVII levels.
Data suggest that FVII by itself or through the generation of thrombin may affect BP levels. Recent data have shown that injection of recombinant activated FVII into swine increases mean arterial pressure.35 FVII itself can also elicit cellular responses, such as angiogenesis9–11 and inflammation.12,13,36 The blood coagulation cascade is initiated when cryptic tissue factor is expressed and exposed to circulating blood and binds plasma activated FVII. The resulting activated FVII-tissue factor complex activates the serine protease zymogens factors IX and X, leading to the generation of thrombin, the key enzyme of the hemostatic system. Thrombin, in addition to converting fibrinogen to fibrin, can interact with cell-surface receptors and induce several intracellular pathways.5,6 Thrombin can modulate vascular tone7,8 in part through its stimulation of endothelin-1 synthesis, 1 of the most important vasoconstrictor peptides in the human vascular system.37 Moreover, thrombin can have proinflammatory properties8,38 and proangiogenic activities.5 Vascular tone, blood viscosity,2,3,39 inflammation,40–43 and angiogenesis44–46 can play roles in initiating and maintaining an elevation in BP and therefore, are potential mechanisms contributing to the association between BP and FVII.
Perspectives
By showing an association between both BP levels and hypertension and FVII polymorphisms, this work provides new insight on the relation between coagulation factors and BP. Our study suggesting that FVII polymorphisms may contribute to BP regulation should be viewed as a hypothesis-generating work that requires further confirmation in other populations. Finally, our findings may gain insight into novel pathophysiologic mechanisms underlying hypertension and potential therapeutic targets.
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Acknowledgments |
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This work was supported by grants from the Institut National de Santé et de Recherche Médicale (INSERM) contract IDS 1999 (Interactions between health determinants), the Société Francaise d’Hypertension (SFTA), the Pôle Européen de Santé de Nancy, the Région Lorraine, and the Communauté Urbaine of Nancy. The Stanislas Cohort is supported by grants from Bayer, Roche Molecular Systems Inc, Beckman Coulter, Biomérieux, and Daiichi Pure Chemicals. We thank the management, reception, and preclinical and clinical staffs of the Centre de Médecine Préventive de Vandoeuvre-lès-Nancy for their help in this study. We would like also to thank Dominique Aguillon and Gérard Pottier for technical assistance and Roche Molecular Systems for developing and providing us with genotyping reagents.
Received November 12, 2003; first decision December 13, 2003; accepted September 1, 2004.
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