The Journal of Nutrition Vol. 128 No. 5 May 1998, pp. 870-874

Dietary Effects on Coagulation Factor VII Vary across Genotypes of the R/Q353 Polymorphism in Elderly People^1,2

Louise I. Mennen^{*, , 3}, Moniek P. M. de Maat^**, Evert G. Schouten, Cornelis Kluft^**, Jacqueline C. M. Witteman^*, Albert Hofman^*, and Diederick E. Grobbee^*,

^* Department of Epidemiology and Biostatistics, Erasmus University, Rotterdam, 3000 DR Rotterdam, The Netherlands;  Division of Human Nutrition and Epidemiology, Agricultural University Wageningen, 6700 EV Wageningen, The Netherlands; ^** Gaubius Laboratory, TNO-PG, 2300 AK Leiden, The Netherlands; and  Julius Center for Patient Oriented Research, Utrecht University, 3508 TA Utrecht, The Netherlands

	ABSTRACT

Abstract Introduction Methods Results Discussion References

The objective of this study was to evaluate the association of factor VII with dietary factors while also considering the R/Q353 polymorphism. Nutrition is an important determinant of coagulation factor VII, which is also genetically determined by the R/Q353 polymorphism. High levels of coagulation factor VII clotting activity (FVII:C) are associated with the risk of myocardial infarction; nutrition may have an effect on these levels if people are genetically susceptible to dietary changes. FVII:C was measured in 3005 elderly subjects, and the extreme quintiles of the FVII:C distribution were selected for measurement of the R/Q353 genotype and FVII:Chr (reflects total factor VII). In these 1158 subjects, habitual diet was assessed with a semiquantitative food-frequency questionnaire. The frequency of the Q353 allele was 0.24 in the lowest and 0.09 in the highest quintile. The quintiles were combined for linear regression analyses. FVII:C was inversely associated with fiber [ = 0.64 %pooled plasma (PP)/g, confidence interval (CI): 1.07,0.21] and protein intake ( = 0.16 %PP/g, CI: 0.31,0.01) and positively with saturated fat intake ( = 0.19 %PP/g, CI: 0.10,0.48). FVII:Chr was inversely associated with fiber ( = 0.38 %PP/g, CI: 0.71,0.05). No other associations with diet were observed. The inverse association of FVII:C with fiber was stronger in subjects with the RR genotype ( = 0.76 %PP/g, CI: 1.23,0.29), than in those with the RQ/QQ genotypes ( = 0.19 %PP/g, CI: 0.97,0.59). The same was found for FVII:Chr. The association of FVII:C with saturated fat was positive in those with the RR allele and inverse in those carrying the Q allele. These findings suggest that the strength of the association between coagulation factor VII and diet varies across the genotypes of the R/Q353 polymorphism.

	INTRODUCTION

Abstract Introduction Methods Results Discussion References

Intake of specific nutrients is related to cardiovascular disease. Prospective studies have shown that an increased intake of saturated fat or a decreased intake of dietary fiber is associated with the development of coronary heart disease (Khaw and Barrett-Connor 1987, Kromhout et al. 1982, Kushi et al. 1985, McGee et al. 1984). Many cardiovascular risk indicators exist for which nutrition has a potential effect. Factor VII, a vitamin K-dependent coagulation factor, is one of those indicators highly influenced by nutrition. Factor VII clotting activity (FVII:C)⁴ and total factor VII were found to be positively associated with intake of dietary fat in a cross-sectional study (Miller et al. 1995). Results from several experiments showed an increase of FVII:C in subjects when they consumed a high fat diet, whereas a decrease was noted when subjects consumed a low fat diet (Marckmann et al. 1990, Miller et al. 1986). The effects of a high fat diet on total factor VII are less clear (Mennen et al. 1996). In one intervention study and two cross-sectional studies, an inverse association of FVII:C with dietary fiber was reported (Mutanen et al. 1995, Rankinen et al. 1994b, Simpson et al. 1982). Finally, a change in protein intake was associated with a change in FVII:C and total factor VII (Miller et al. 1986).

In addition to its relation to nutrition, the level of factor VII is also genetically determined. In the gene coding for factor VII, the R/Q353 polymorphism is the result of a single base change in the codon for amino acid 353, which leads to the replacement of arginine (R) by glutamine (Q) (Green et al. 1991). The Q353 allele is associated with lower levels of FVII:C and total factor VII (Green et al. 1991).

In two prospective studies, high levels of FVII:C were associated with an increased risk for (fatal) ischemic heart disease (Assmann et al. 1996, Junker et al. 1997, Meade et al. 1986, Ruddock and Meade 1994). To lower this risk, dietary changes may be used to lower factor VII. Because the R/Q353 polymorphism substantially influences the level of both FVII:C and total factor VII (Bernardi et al. 1996), the effect of dietary changes may differ among people on the basis of their genetic susceptibility. Therefore, in this study the association of dietary factors with FVII:C and total factor VII, according to genotype of the R/Q353 polymorphism, was evaluated in cross-sectional data from the Rotterdam Study.

	SUBJECTS AND METHODS

Abstract Introduction Methods Results Discussion References

Population.  The Rotterdam Study is a single-center, population-based prospective cohort study of 7983 persons. All inhabitants 55 y of age from a suburb of Rotterdam were asked to participate in the study, with a response rate of 78%. In short, the objective of the study is to clarify determinants of occurrence of chronic disabling cardiovascular, neurogeriatric, locomotor and ophthalmologic diseases. The rationale and design of the Rotterdam Study have been published elsewhere (Hofman et al. 1991). The study was approved by the Medical Ethics Committee of the Erasmus University, Rotterdam, and written informed consent was obtained from all participants. Dietary data and blood samples were not available for 2548 and 993 persons, respectively. The following characteristics may affect the factor VII level and were therefore used as exclusion criteria: myocardial infarction in the year before the investigation (n = 574), diabetes mellitus (n = 779 ), use of anticoagulants (n = 1349) or stasis during venipuncture (n = 1513). None of the women used hormone replacement therapy. Because some subjects were excluded for multiple reasons, 4978 people were not eligible for this study. FVII:C was measured in blood samples of the 3005 people who remained after exclusions. Individuals in the two extreme quintiles of the distribution of FVII:C were selected, with the expectation of an enrichment for the Q353 allele in the lowest quintile. This analysis is therefore based on cross sectionally obtained information from 1158 subjects.

Examination procedures.  The participants came to the research center between 0800 and 1630 h. At the research center, a brief clinical examination was performed and height and weight were measured. Body mass index was calculated by dividing weight by the square of height (kg/m²). Blood samples were taken from nonfasting subjects using a 21-gauge butterfly needle after minimal stasis. Time between last meal and blood sampling was recorded.

Dietary assessment.  The habitual diet was assessed by a semiquantitative food-frequency questionnaire. The questionnaire was a modification of a validated self-administered semiquantitative food-frequency questionnaire that was previously used in a large-scale prospective cohort study, involving a younger population. Measures of the validity and repeatability of the original questionnaire for several nutrients have been reported (Goldbohm et al. 1993 and 1994). The questionnaire was adapted to allow an easy and time-efficient dietary assessment in a population of older people. Modification consisted mainly of inclusion of additional items (ice cream, corn flakes and linseed); collection of more detailed information on vegetable, fruit and meat consumption; and a different mode of administration, which was undertaken in two consecutive phases. The modified questionnaire contained 170 food items in 13 food groups and general questions about dietary habits. Its aim was to assess habitual food intake during the past year.

In the first phase, a self-administered questionnaire was handed out and explained to each participant during a home visit by trained research assistants. Participants had to mark the foods that they consumed at least once a month. In addition, the amounts of several foods they used were weighed and the content of cups and bowls was measured. In the second phase, a dietary interview was conducted by trained dietitians on the basis of the already completed dietary questionnaire. During the dietary interview, the dieticians concentrated on obtaining accurate information on amount and frequency of food items noted by participants as consumed at least once a month. General questions to check the consistency of the completed dietary questionnaire were asked. The modified questionnaire was validated by comparison with multiple food records. The correlation coefficients were corrected for within-person variation in food records and adjusted for age, sex and energy intake. For the different types of fat and fiber, these varied between 0.50 and 0.65 (Klipstein, K., personal communication).

All data were entered into a self-made interactive computer program, which included automatic checks for inconsistencies in the answers of the participants. A computer application was developed to calculate the frequency and amounts of foods consumed. Questionnaires were checked for completeness by an interactive data entry program and automatically coded for later conversion into nutrients. The program checked further for consistency, range and other response errors. The conversion from foods to energy and nutrient intake was established with a computerized version of the Dutch Food Composition Table (NEVO 1993), and percentages of total energy (en%) delivered by macronutrients were calculated.

Laboratory measurements.  Blood samples. Blood was collected in siliconized vacutainer tubes containing 0.129 mol/L sodium citrate (Becton Dickinson, Leuven, Belgium). Samples were centrifuged for 10 min at 1600 × g and 4°C. Citrated plasma was snap frozen and stored at 80° C until laboratory analysis. FVII:C was measured with a one-stage clotting assay with the use of human thromboplastin (Tromborel S, Behringwerke, Germany) and factor VII-deficient plasma (Ortho Diagnostic System, Beerse, Belgium). The results are expressed as percentages of pooled plasma (% PP). The total concentration of factor VII (FVII:Chr) was estimated by a two-stage amidolytic microtiter assay (Chromogenix, Mölndal, Sweden) (Avvisati 1980). For 36 subjects, no sample was available for measurement of FVII:Chr. For the measurements of FVII:C and FVII:Chr, different pooled plasmas were used.

DNA-procedures. DNA was extracted from buffy-coats by a small scale method (Droog et al. 1996). Each polymerase chain reaction (PCR) (25 µL) contained 50-100 ng of the DNA extract, 50 ng of each appropriate primer, 10 mmol/L Tris/HCL (pH 9.0), 50 mmol/L KCl, 0.1 g/L gelatin, 1.55 mmol/L Triton X-100, 1 mmol/L MgCl₂, 0.2 mmol/L dNTP and 0.1 unit of SuperTaq polymerase (HT Biotechnology, Cambridge, UK).

Oligonucleotide primers were as described by Lane et al. (1992). The reaction components were incubated at 94°C for 4 min, followed by 32 cycles of 94°C for 1 min, 59°C for 1.5 min and 72°C for 2 min.

PCR product (10 µL) was digested with 5 units of MspI (Gibco BRL, Gaithersburg, MD) at 37°C overnight. The digestion products were separated by electrophoresis through a 20 g/L agarose gel in 44 mmol/L Tris/borate, 1 mmol/L EDTA, containing 0.4 mg/L etidiumbromide and visualized using UV light.

MspI digestion yielded a constant band of 40 bp. The common R353 allele gave bands of 205 and 67 bp, and the Q353 allele gave a band of 282 bp as described previously (Green et al. 1991).

Data analysis.  The association of FVII:C and FVII:Chr with dietary factors was examined by means of multiple linear regression analysis using the BMDP-statistical package (Dixon 1990). For these analyses, the quintile groups were combined. Adjustments were made for age and energy intake by including them as an independent variable in the regression model.

If an association between a dietary factor and FVII:C or FVII/Chr was found, this was investigated further to evaluate whether these associations varied across the genotypes. This was done by conducting the same analyses separately in those with the RR genotype and those with RQ/QQ genotypes. Because there were only 32 people with the QQ genotype, they were combined with those with the RQ genotype for this analysis.

	RESULTS

Abstract Introduction Methods Results Discussion References

General characteristics and dietary intake of the study population are presented in Table 1, with the lowest and the highest quintiles presented separately. The characteristics that were also measured in the source population of 3005 people (i.e., age, body mass index and FVII:C) were very similar to those of the study population of 1158 subjects (data not shown). In the lowest quintile, 249 individuals (Q allele frequency 0.24) carried the Q353 allele and in the highest quintile, 51 (Q allele frequency 0.05). In the total group, FVII:C was 35% lower (80.6 %PP vs. 125.3 %PP) and FVII:Chr 48% lower (49.6 %PP vs. 95.7 %PP) in individuals with the QQ genotype compared with those with the RR genotype (Table 2). The FVII:C and FVII:Chr levels for those with the RQ genotype were intermediate.

Table 3 shows the regression coefficients of factor VII and dietary factors for the total population. FVII:C was inversely related to fiber intake [= 0.64 %PP/g, 95% confidence interval (CI): 1.07,0.21] and protein intake ( = 0.16 %PP/g, CI: 0.31,0.01). Adjustment for fat intake did not change these results. Saturated fat intake was positively associated with FVII:C ( = 0.19 %PP/g, CI: 0.10,0.48). FVII:C was not associated with total energy intake, total fat intake and mono- or polyunsaturated fat intake. FVII:Chr was inversely related to fiber intake ( = 0.38 %PP/g, CI: 0.71,0.05). No associations with any of the other dietary factors were found.

View this table: [in this window] [in a new window]   Table 3. Regression coefficients () and 95% confidence intervals (CI) with several dietary factors as independent variable and factor VII as dependent variable in elderly subjects

To explore these relationships further, we examined the associations of the three dietary factors with factor VII separately for the genotype groups. Because the association of diet with factor VII was in a similar direction in individuals with the RQ and QQ genotypes (data not shown) and because the group of individuals with the QQ genotype was too small for meaningful regression analysis, the group with the QQ genotype was combined with the group with the RQ genotype. In individuals with the RQ/QQ genotype the associations of FVII:C with the dietary factors were weaker than in those with the RR genotype (Table 4). For fiber and protein, there was no association in individuals with the Q353 allele; for saturated fat, the association was reversed.

View this table: [in this window] [in a new window]   Table 4. Regression coefficients () and 95% confidence intervals (CI) with protein, saturated fat and fiber intake as independent variable and factor VII as dependent variable according to genotype of the elderly subjects

For FVII:Chr, there was a positive association with fiber in subjects homozygous for the R allele and no association in those with the RQ/QQ genotype. Although there was a negligible association between saturated fat and FVII:Chr in the total group, a positive association was observed in individuals with the RR genotype, whereas an inverse association was found in individuals with the RQ/QQ genotype. When we adjusted the regression models for belonging to the lowest or highest quintile, the results were similar.

	DISCUSSION

Abstract Introduction Methods Results Discussion References

In this study, in the total group, FVII:C was inversely associated with fiber and protein intake and positively with saturated fat. In subjects with the RQ/QQ genotype, these associations were weaker, and for saturated fat, the association was inverse. FVII:Chr was inversely associated with fiber intake and, in subjects with the RR genotype, also positively with saturated fat.

In an unselected population, the frequency of the Q353 allele is expected to be 0.10 (Green et al. 1991, de Maat et al. 1997). If there is a direct relation between the R/Q353 polymorphism and the level of FVII:C, a similar frequency would be expected in our population of extreme quintiles of the distribution of FVII:C. The frequency in total population of 1158 subjects was, however, 0.14. This suggests that another factor, linked to the R/Q353 polymorphism, is associated with FVII:C.

There have been several intervention studies in which the effect of diet on factor VII was studied. Marckmann and colleagues (1993 and 1994) reported a reduction in FVII:C after consumption of a low fat/high fiber diet compared with a high fat/low fiber diet by young and middle-aged subjects. No difference in factor VII-antigen (FVII:Ag, reflects total factor VII) between the two diets was observed. In one intervention study among diabetic patients, FVII:C was almost 23% lower in subjects fed a high fiber diet than in those fed a low fiber diet. The results from our study suggest that dietary fiber in older men and women is related to FVII:C as well as FVII:Chr; an increase in fiber intake of 10 g [an increase that would raise the mean fiber intake toward the level of at least 3 g/MJ as indicated by the current Dutch Guidelines for Healthy Eating (Voedingsraad 1986)] would result in a decrease of FVII:C by 6.4 %PP and of FVII:Chr by 3.8 %PP.

In several studies, FVII:C decreased in subjects consuming a low fat diet compared with those consuming a high fat diet (Brace et al. 1991, Marckmann et al. 1990, Miller et al. 1986). No difference in FVII:C was observed among subjects eating diets with different fatty acid composition (Foley et al. 1992, Heinrich et al. 1990, Marckmann et al. 1990, Rankinen et al. 1994a). In our study, only an association with saturated fat was found. One explanation may be that in intervention studies, the intake of different fatty acids is usually much higher than it would be in a diet consumed by subjects in their daily life. Another difference is that in our study, blood samples were collected from nonfasting subjects at a nonstandardized time, whereas in intervention studies, samples were collected from fasting subjects. However, when we adjusted the associations for the time since the last meal before blood sampling, the results were similar.

The associations of factor VII with the three dietary factors all varied among the genotype groups of the R/Q353 polymorphism. A possible explanation for the effect of the R/Q353 polymorphism on these associations may be that the change in charge ensuing from the substitution of the positively charged arginine with a neutral glutamine affects the interaction of factor VII with lipid surfaces (Green and Humphries 1994). Factor VII is strongly associated with serum triglycerides (Mennen et al. 1996), and some evidence is available that the association between factor VII and serum triglycerides is influenced by the R/Q353 polymorphism (Humphries et al. 1994, Lane et al. 1992, Mennen et al. 1997). Because the associations of factor VII with dietary fat and with dietary fiber may both be mediated through serum triglycerides, it could be expected that the influence of the R/Q353 polymorphism is also found in the association of factor VII with diet. This is supported by a small study of Silveira et al. (1994), who showed that the absolute increase in factor VII after a high fat meal is higher in subjects with the RR genotype than in those with the RQ genotype. It is important to note, however, that the numbers in that study were very small (n = 8 for RQ) and that the increase relative to the fasting factor VII level did not differ between genotype groups. Furthermore, adjustment of the associations of dietary factors with FVII:C or FVII:Chr for serum triglyceride level did not change our results. Finally, the R/Q353 polymorphism is strongly linked to the -323Ins10 polymorphism, which is suggested to be the functional polymorphism (Humphries et al. 1996, de Maat et al. 1997).

In combination with tissue factor, factor VII is a very potent procoagulant, and high levels may increase the risk of a thrombotic event. The RR genotype of the R/Q353 polymorphism of factor VII is a risk indicator for myocardial infarction through increased factor VII levels. This risk may be especially important in an environment of a diet high in saturated fat and low in fiber and protein.

	ACKNOWLEDGMENTS

We are grateful to the participants of the Rotterdam Study. We thank all field workers and dieticians in the Ommoord research center for their enthusiasm and skillful contributions to the data collection. We also thank Linda Huisman for carrying out the DNA procedures and the FVII:Chr analysis, and Hanneke den Breeijen for her help with the dietary data.

	FOOTNOTES

Manuscript received 7 August 1997. Initial reviews completed 25 November 1997. Revision accepted 24 January 1998.

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