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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:887-892.)
© 1999 American Heart Association, Inc.

Original Contributions

Fibrinogen

A Possible Link Between Alcohol Consumption and Cardiovascular Disease?

Louise I. Mennen; Beverley Balkau; Sylviane Vol; Emile Cacès; Evelyn Eschwège; for the DESIR Study Group

From INSERM Unit 21 and the Faculty of Medicine Paris-Sud, Villejuif (L.I.M., B.B., E.E.), and IRSA, La Riche (S.V., E.C.), France.

Correspondence to L.I. Mennen, INSERM Unit 21, 16 Avenue Paul Vaillant Couturier, 94807 Villejuif cedex, France. E-mail mennen{at}vjf.inserm.fr

	Abstract

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Abstract—The relation between alcohol consumption and fibrinogen concentration was evaluated in a French population to investigate whether fibrinogen could explain part of the relation between alcohol consumption and cardiovascular disease. Cross-sectional data on self-reported alcohol consumption and fibrinogen, measured by the immunonephelometric method, of 4967 men and women aged 30 to 64 years were used. These subjects were volunteers for a free health checkup in the western central part of France from 1994 to 1996 and participated in the DESIR Study (Data from an Epidemiological Study on the Insulin Resistance syndrome). Alcohol consumption was strongly associated with fibrinogen concentration, with higher concentrations in those who were nondrinkers or who drank >60 g of alcohol per day. This U-shaped association was stronger among men than women. Consumption of wine and spirits was associated with fibrinogen, whereas consumption of beer or cider was not. Furthermore, smoking was positively associated with fibrinogen concentration, and in men the difference between nondrinkers and drinkers with the lowest fibrinogen level was higher in nonsmokers and ex-smokers than in current smokers. We conclude that moderate drinking may lower fibrinogen concentration. If fibrinogen is a causal risk factor for cardiovascular disease, it may be 1 of the variables that explain the protective effect of moderate alcohol consumption on cardiovascular disease.

Key Words: fibrinogen • alcohol consumption • epidemiology

	Introduction

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It is known from many prospective studies that fibrinogen is a risk indicator for cardiovascular disease, including coronary heart disease, stroke, and peripheral arterial disease.^{1 2 3 4 5} Fibrinogen is also associated with major cardiovascular risk factors, such as smoking, hypertension, and total cholesterol.^{6 7 8 9 10 11} Furthermore, 1 prospective, 1 interventional, and several cross-sectional studies showed an inverse association between fibrinogen and alcohol consumption,^{6 7 8 10 12 13 14 15 16 17} although others were not able to show a relation.^{9 18 19 20} Krobot et al⁸ showed that the association between alcohol intake and fibrinogen was U-shaped, but Lee et al¹⁴ could not confirm this observation. Alcohol seems to be related to cardiovascular disease in a U-shaped fashion,^{21 22 23 24 25} and fibrinogen may be 1 of the mediators for its effect on cardiovascular disease. The drinking of wine has been suggested to be 1 of the reasons for the existence of "the French paradox" (a low incidence of cardiovascular disease, despite a high consumption of saturated fat), and it has been hypothesized that this may be due to lower levels of hemostatic factors.^{26 27} To evaluate this hypothesis, we investigated whether there was a U-shaped relation between fibrinogen concentration and alcohol consumption in a population of French men and women.

	Methods

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The study population consisted of men and women, aged 30 to 64 years, who participated in the DESIR (Data from an Epidemiological Study on the Insulin Resistance syndrome) study, a 9-year follow-up study that aims to clarify the development of the insulin resistance syndrome.²⁸ Participants were recruited from volunteers insured by the French Social Security system, which offers periodic health examinations free of charge. Subjects came from 10 Health Examination Centers in the western central part of France. All subjects signed an informed consent form. Data on alcohol consumption and fibrinogen were available for 2499 women and 2468 men, who accounted for 4967 of the 5214 subjects participating in this study.

Smoking habits and alcohol consumption were assessed by means of a self-administered questionnaire. Three questions were asked on the subjects' daily intake of wine, beer/cider, and spirits. Total alcohol consumption was calculated in grams per day.²⁹ Venous blood samples were collected in the morning after the subjects had fasted for 12 hours. Fibrinogen was measured in tripotassium EDTA–plasma with the immunonephelometric method (BNA Behring). The CV was 3.3%.

To evaluate the association with fibrinogen, alcohol consumption was divided into the following 6 groups: nondrinkers and those who consumed 0 to 19, 20 to 39, 40 to 59, 60 to 79, and 80 g/d of alcohol. ANCOVAs were used to calculate means of fibrinogen for each category of alcohol consumption after adjustment for smoking status and age, separately for men and women. Similar analyses were carried out for the type of alcoholic beverage. For wine and beer/cider consumption, the classes were as follows: nondrinkers and those consuming <0.5 L/d, 0.5 to 1 L/d, and >1 L/d; and for the consumption of spirits, nondrinkers and those consuming 1 glass per day, 2 glasses per day, and >2 glasses per day. To investigate the possibility of a nonlinear relationship between alcohol consumption and fibrinogen, first- and second-order multiple regression models describing the relation between fibrinogen and alcohol consumption were compared.

	Results

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The mean±SD age of the subjects was 47±10 years in women and men, and their mean fibrinogen level was 3.08±0.66 g/L and 2.92±0.64 g/L, respectively (Table 1). In both women and men, the fibrinogen concentration was highest in nondrinkers and lowest in those drinking 40 to 59 g of alcohol per day (Figure 1). The difference in fibrinogen between these categories was 10% in women and 8% in men. The relation between fibrinogen and alcohol consumption was U-shaped in men and curvilinear in women; including a second-order variable for alcohol into the model describing the association between fibrinogen and alcohol consumption added significantly to the variance explained (Table 2).

View this table: [in this window] [in a new window]   Table 1. General Characteristics of Men and Women as Means±SDs or Percentages: the DESIR Study

View larger version (42K): [in this window] [in a new window]   Figure 1. Mean fibrinogen concentrations (95% CIs) per category of alcohol consumption for men and women, adjusted for age and smoking status: the DESIR Study.

View this table: [in this window] [in a new window]   Table 2. Variances of Fibrinogen Explained (R2) by Alcohol Consumption, Type of Alcoholic Beverage, and Quadratic Terms, for Men and Women: the DESIR Study

When the associations between the type of alcoholic beverage (ie, wine, beer/cider, or spirits) and fibrinogen concentration were investigated, no association of fibrinogen with the consumption of beer/cider was observed, either in women or in men (Figure 2). The intake of wine and spirits remained strong determinants of fibrinogen in both sexes. In men, the association between fibrinogen and consumption of wine or spirits could be described by a U-shaped curve, whereas in women these associations were inverse and linear (Table 2).

View larger version (38K): [in this window] [in a new window]   Figure 2. Mean fibrinogen concentrations (95% CIs) per category of wine, beer/cider, and spirits intake of men and women, adjusted for age and smoking status: the DESIR Study.

In women, fibrinogen was higher in current smokers (mean±SE, 3.18±0.03 g/L) than in nonsmokers or ex-smokers (3.07±0.02 or 3.03±0.03 g/L, respectively, after adjustment for age). In nonsmokers and ex-smokers, alcohol consumption was inversely related to fibrinogen (Figure 3). In current smokers, the quadratic variable of alcohol consumption added significantly to the variance of fibrinogen explained, suggesting a U-shaped association. The difference in fibrinogen concentration between the category with the highest and that with the lowest level was 0.21 g/L in nonsmokers, 0.48 g/L in ex-smokers, and 0.30 g/L in current smokers. In men, fibrinogen was lower in nonsmokers than in ex-smokers and current smokers (mean±SE, 2.87±0.02, 3.09±0.02, and 3.84±0.02 g/L, respectively, after adjustment for age). Among nonsmokers, alcohol consumption was inversely related to fibrinogen, whereas the association was U-shaped among ex-smokers and current smokers (Figure 4). The difference in fibrinogen between nondrinkers and drinkers with the lowest fibrinogen concentration was higher in nonsmokers and ex-smokers than in current smokers (0.41 versus 0.27 g/L). Multiple adjustment for the classic cardiovascular risk factors (blood pressure, total cholesterol, and body mass index) did not change any of the results.

View larger version (28K): [in this window] [in a new window]   Figure 3. Mean fibrinogen concentrations (95% CIs) per category of alcohol consumption, by smoking, for women, adjusted for age: the DESIR Study.

View larger version (42K): [in this window] [in a new window]   Figure 4. Mean fibrinogen concentrations (95% CIs) per category of alcohol consumption, by smoking, for men, adjusted for age: the DESIR Study.

	Discussion

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In French men, fibrinogen concentration was strongly associated with alcohol intake in a U-shaped fashion, in particular for the intake of wine and spirits. The assessment of alcohol intake is, as for every nutritional factor, subject to flaws. Although study subjects, and especially heavy drinkers, tend to underestimate their alcohol intake, self-reported alcohol intake is the best method available.³⁰ If underreporting takes place and heavy drinkers are included in the category with moderate alcohol consumption, it would lower the strength of relations between fibrinogen and alcohol. The results may therefore be an underestimation of the true association between fibrinogen and alcohol intake.

Many studies have investigated the association between fibrinogen and alcohol consumption.^{6 7 8 10 12 13 14 16 17} Although categories of alcohol intake varied from nondrinkers versus drinkers in general, to nondrinkers versus 5 different categories of drinkers, the results of these studies all suggest a strong, inverse association between alcohol intake and fibrinogen concentrations in both men and women. Furthermore, results from a prospective study indicated a 0.78% decrease in fibrinogen concentration with each 10 g/d increase in alcohol intake.¹⁷ Krobot et al⁸ and Lee et al¹⁴ both investigated whether the association was truly linear or whether it could be better described by a U-shaped curve. The former study confirmed the curvilinear relation in a multiple polynomial regression model using a continuous variable for alcohol consumption.⁸ The latter study could not fit a quadratic curve to the data on alcohol intake and fibrinogen.¹⁴ It must, however, be noted that after multiple adjustment, these authors only observed an association between alcohol and fibrinogen in women but not in men.¹⁴ The lack of a U-shaped curve in the study of Lee et al¹⁴ may be explained by the categories of alcohol intake they had to use because of the low alcohol consumption in their population. The highest category comprised subjects who drank >21 g of alcohol per day in men and >9 g in women, whereas the highest category in the study of Krobot et al⁸ comprised subjects who consumed >80 g per day in men and >60 g in women. In our study we observed that the concentration of fibrinogen was still lower in people who drank 2 to 6 glasses of alcohol a day, thus no increase in fibrinogen in the highest category made by Lee et al¹⁴ can be expected. Because the alcohol consumption in France is high, we were able to study categories of >80 g/d. In men we indeed observed a U-shaped curve. The alcohol consumption among women was too low to show this type of curve as well. This finding suggests that nondrinkers and people who drink >6 glasses of alcohol per day are at risk of having a high fibrinogen concentration and thereby may have a higher risk for cardiovascular disease.

Two intervention studies investigated the effect of alcohol consumption on fibrinogen concentration. Pellegrini et al¹⁵ showed a decrease in fibrinogen concentration after consumption of 30 g of alcohol (from either red wine or alcohol diluted in fruit juice) during 4 weeks but no change after consumption of dealcoholized red wine. Gorinstein et al²⁰ studied the effect of 330 mL of beer per day (20 g of alcohol) during a 30-day period and did not observe a change in fibrinogen. Our observation that fibrinogen was related to the intake of wine and spirits only is in line with these results (it must be noted, however, that the mean intake of spirits in grams per day was low and that the observed U-shaped curve for this type of alcoholic beverage can be mainly explained by the fact that those men who drink spirits also drink wine). Because alcohol diluted in fruit juice had an effect similar to that of red wine, it seems that alcohol indeed is the effective substance in alcoholic drinks. In beer, however, there may be other substances that inhibit the beneficial effect of alcohol on fibrinogen. These observations seem to concur with our hypothesis that fibrinogen is an intermediate factor in the association between alcohol consumption and cardiovascular disease; both cardiovascular death rate²² and fibrinogen are associated with the consumption of wine and spirits but not with beer intake. Furthermore, the low incidence of cardiovascular disease in France compared with the amount of saturated fat consumed (ie, the French paradox) may be due to a protective effect of the high intake of wine.^{26 27} The lack of an association between fibrinogen or cardiovascular disease and beer intake also supports this hypothesis.

Two cross-sectional studies described the association of fibrinogen and alcohol intake separately for smokers and nonsmokers.^{7 13} Rogers et al¹³ showed similar results to ours: a higher difference between nondrinkers and drinkers, with the lowest fibrinogen level in nonsmokers than in smokers. Lee et al,⁷ however, reported a larger difference among smokers. One difference between these 2 studies is the use of different methods to measure fibrinogen. Nevertheless, this difference is unlikely to be the cause of the different conclusion by Lee et al,⁷ because in studies on fibrinogen and alcohol consumption, several methods have been used to determine fibrinogen, but the results were similar. Furthermore, the question arises as to whether the U-shaped curve in smokers that we observed can be explained by the number of cigarettes smoked, because fibrinogen increases with the number of cigarettes smoked and heavy drinkers are often also heavy smokers. However, when we adjusted our analyses for the number of cigarettes smoked per day, the results were comparable. Further studies are needed before any conclusion can be reached that the association between alcohol consumption and fibrinogen is different between nonsmokers, ex-smokers, and current smokers.

The results of our study showed that fibrinogen is lowest in those subjects who drank 20 to 59 g of alcohol per day. Subjects who drank more than this amount had higher concentrations of fibrinogen. Studies on alcohol consumption and cardiovascular disease also show a similar U-shaped curve, where the relative risk is highest in nondrinkers and again increases in subjects who drink >7 glasses of alcohol a day.^{23 24 25 31} Stampfer et al,³² Gaziano et al,³³ and Rimm et al³⁴ observed a steady decrease in relative risk for cardiovascular disease with higher intakes of alcohol. The reason why they did not observe a U-shaped curve probably lies in the low percentage of heavy drinkers in the United States. The highest categories used in these studies were >30 and >50 gams of alcohol per day, thus including subjects at lower risk.

Although many prospective studies have shown a positive association between fibrinogen concentration and cardiovascular disease,^{1 2 3 4 5} it is still debated whether this association is causal.³⁵ Fibrinogen is an acute-phase protein and is strongly associated with (preclinical) atherosclerosis.³⁶ Because the atherosclerotic process starts early in life, the fact that high levels of fibrinogen are associated with cardiovascular disease in prospective studies may be merely a reflection of ongoing atherosclerosis instead of being a true risk factor. The strong resemblance between the U-shaped curve describing the association between alcohol consumption and fibrinogen and the U-shaped curve describing the relation between alcohol consumption and cardiovascular disease is, however, in favor of fibrinogen's being a true risk factor. It is, though, still possible that the lower concentrations of fibrinogen with moderate alcohol intake only reflect the protective effect of alcohol on cardiovascular disease, because concentrations may decrease as a result of decreasing cardiovascular disease. In this case, other variables could explain the protective effect of alcohol. Gaziano et al³³ showed that the inverse association between alcohol consumption and cardiovascular disease was attenuated after adjustment for HDL concentrations. They suggested that HDL was a factor in the causal pathway between alcohol intake and cardiovascular disease, although HDL could not fully explain the observed association. HDL did not interfere with the association between fibrinogen and alcohol consumption in our study; in fact, adjustment for HDL showed similar results (data not shown). Further studies on alcohol consumption and cardiovascular disease should, therefore, also include the measurement of fibrinogen. If the association between alcohol consumption and cardiovascular disease weakens after adjustment for fibrinogen, as it does for HDL, it may indicate that fibrinogen is causally related to the protective effect of alcohol consumption.

In conclusion, the strong U-shaped association between fibrinogen and alcohol consumption may explain the protective effect of moderate alcohol intake on cardiovascular disease if fibrinogen is indeed a causal risk factor for cardiovascular disease.

	Appendix: the DESIR Study Group

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INSERM U21: B. Balkau, E. Eschwège, D. Simon.

INSERM U367: F. Alhenc-Gelas.

CHU d'Angers: A. Bechetoille, Y. Gallois, A. Girault, M. Marre.

Association de Cardiologie du Centre, Val de Loire: M. Brochier.

Centres d'Examens de Santé du Réseau 9: Alençon—B Royer, M.C. Chesnier; Angers—B. Mermod; Blois—J.M. Le Mauff; Caen—A. Buruil; Chartres—D. Arondel; Chateauroux—M. Novak; Cholet—A. Petrella; Le Mans—A. D'Hour; Orléans—P. Lépinay; Tours—C. Calvet, B. Royer.

Coordinateur Administratif du Réseau 9: D. Desclerc-Dulac.

Institut de Recherche en Médecine Générale: Basse–Normandie—Ph. Aubourg; Centre—J. Cogneau, C. Rougeron; Pays de Loire—V. Diquero; Medecins Géneralistes des Départements.

Institut Régional pour la Santé: E. Cacès, M. Cailleau, J.M. Jacquelin, J.G. Moreau, F. Rakotozafy, J. Tichet, S. Vol.

	Acknowledgments

 
This study was supported by a cooperative contract between the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Caisse Nationale de l'Assurance Maladies des Travailleurs Salariés (CNAMTS; contract No. 3AM004) and by INSERM Réseau en Santé Publique (contract No. 494003 and No. 4R001C). Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, the Fédération Française de Cardiologie, Lipha Pharmaceuticals, Novo Nordisk, Pierre Fabre, and Topcon all contributed to the funding of this study. We are grateful for the financial contribution from the Consel Régional d'Ile de France et INSERM to the postdoctoral position of Dr Mennen.

Received June 26, 1998; accepted August 25, 1998.

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