© 2000 American Heart Association, Inc.
Thrombosis |
Social Determinants of von Willebrand Factor
The Whitehall II Study
From the International Centre for Health and Society, Department of Epidemiology and Public Health, Royal Free and University College London Medical School, London, England.
Correspondence to Dr Meena Kumari, International Centre for Health and Society, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, UK. E-mail meena{at}public-health.ucl.ac.uk
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Abstract |
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Abstract—Data from the Whitehall II Study and others have demonstrated a role for the metabolic syndrome and fibrinogen underlying the association between social position and coronary heart disease. In this study, we examined the role of an additional hemostatic factor and marker of endothelial dysfunction, von Willebrand factor (vWF). Four thousand five hundred and forty-eight men and 1837 women were examined in the third phase of the study, which took place between 1991 and 1993. Employment grade was used as a measure of socioeconomic position. An inverse relation between employment grade and vWF was evident (P<0.0003). This employment grade gradient was apparent overall, and the relation persisted even when nonsmokers and participants with poor health were removed from the analyses (P=0.02). The difference between the highest (unified grades 1 to 6) and lowest (clerical/support) employment grades in vWF concentrations was 8.9 IU/dL (95% CI 6.0, 11.8; P<0.001) for men and 6.9 IU/dL (95% CI 4.0, 9.7; P=0.06) for women. vWF was associated with a number of biological factors that themselves showed an employment grade gradient, including fibrinogen (P<0.001), fasting and postload glucose (P<0.05) levels, and fasting and postload insulin (P<0.01) levels. Associations with smoking and alcohol intake were apparent. Smoking showed a threshold effect, such that only men who smoked >21 cigarettes per day produced a significantly increased vWF level (P<0.05) compared with lighter smokers. The health-related behaviors explained 25% of the grade gradient in men and 28% in women, while the biological factors accounted for 32% in men and 22% in women. We conclude that there is a grade gradient in vWF that was not fully explained by health-related behaviors and risk factors for coronary heart disease. These data are consistent with the hypothesis that endothelial dysfunction is part of the explanation for social inequalities in cardiovascular disease.
Key Words: von Willebrand factor • socioeconomic status • metabolic syndrome • smoking
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Introduction |
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There is a gradient in the incidence of coronary heart disease (CHD) such that members of lower socioeconomic groups experience higher rates of CHD morbidity and mortality.1 2 Classic risk factors for CHD such as smoking, overweight, and cholesterol provide an incomplete explanation of this phenomenon.3 4 Data from the Whitehall II Study have demonstrated the importance of plasma fibrinogen5 and the metabolic syndrome6 as possible links between social position, civil service employment grade, and cardiovascular disease. von Willebrand factor (vWF) is a glycoprotein synthesized in endothelial cells and megakaryocytes. It is released from endothelial cells and platelets after endothelial damage, and thus, a raised vWF concentration has been proposed as an indicator of current endothelial damage that occurs early in the disease process.7 The function of vWF is to promote thrombus formation by mediating adhesion of platelets to the injured vessel wall and to one another.8 9 vWF is a sensitive marker to many adaptive conditions, including the acute-phase response. Raised concentrations of vWF are strongly associated with diabetes10 11 and with an increased risk for CHD.12 13 The relationship between vWF and employment grade is examined in this report to assess whether endothelial dysfunction may be an additional biological factor linking social position with cardiovascular disease.
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Methods |
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Participants
Demographic and psychosocial characteristics as well as health and risk factor status of the 10 308 participants at baseline have been described previously.2 Subjects were recruited in 1985 to 1988 (phase 1) from 20 London-based Civil Service departments. The response rate was 73%, but detailed investigation in one department showed that 4% of those present on the list of employees had moved before our study, so the true response rate is likely to be higher. The data presented are from phase 3 (1991 to 1993) involving examination of 5616 men and 2488 women aged 39 to 63 years. South Asians and Afro-Caribbean subjects and those with unspecified ethnic origin have been excluded from the analyses, yielding vWF measurements from 4548 male and 1837 female European subjects.
Screening Examination
All measurements were carried out according to a standard
protocol, which has been described previously in
detail.6 14 Glucose level was determined in
fluoride plasma by an electrochemical glucose oxidase
method. Serum insulin level was measured by radioimmunoassay by using a
polyclonal guinea pig antiserum. Cholesterol and
triglycerides were measured in a centrifugal
analyzer by enzymatic colorimetic methods. HDL
cholesterol was determined after dextran
sulfate–MgCl2 precipitation of non-HDL
cholesterol. Fibrinogen was determined by an automated
modification of the Clauss method. Coefficients of variation were 2.0%
to 6.6% for glucose, cholesterol,
triglycerides, and HDL cholesterol; 23% for
insulin; and 7.7% for fibrinogen.
Analysis of vWF
vWF was measured by a double-antibody ELISA with reagents
provided by Dako Ltd and standards from the National Institute for
Biological Standards and Control. The reference preparation and the
first and second antibodies were plasma human 89/592, rabbit anti-human
vWF, and Dako peroxidase-conjugated rabbit anti-human vWF,
respectively. Technical error was estimated with a 5% sample of
duplicate plasma samples that were analyzed by the laboratory
in a blinded fashion. The coefficient of variation obtained was 16.1%.
The same standard pool of citrated, platelet-poor plasma from 120
donors was used throughout the study as the standard and calibrated
against the fourth British Standard for Blood Coagulation Factors,
Plasma Human 89/592 (established 1990) from the National Institutes for
Biological Standards and Control. vWF was expressed in international
units per deciliter.
Questionnaire and Employment Grade
Participants completed a machine-readable questionnaire,
which was checked for completeness and validity. An interviewer
elicited missing responses. Participants reported their Civil Service
grade title, which was assigned to 1 of 6 grades based on salary scale.
Grade 1 comprised subjects in unified grades 1 to 6 (annual salary
range as of August 1, 1992 was $49 137 to $148 923); grade 2
is equivalent to unified grade 7 ($43 061 to $61 232); grade 3 is
senior executive officer ($30 739 to $43 442); grade 4 is
higher executive officer ($24 575 to $35 445); grade 5 is
executive officer ($14 479 to $28 336); and grade 6 includes
clerical and office support staff ($11 021 to $20 259).
The metabolic syndrome has previously been defined as occupying 3 or more of the adverse sex-specific quintiles: 2-hour glucose, systolic blood pressure, fasting triglycerides, HDL cholesterol, and waist-hip ratio.6
Diabetic subjects were defined as "known" and "newly diagnosed
cases" identified from the questionnaire responses ("Do you suffer
from diabetes? Yes/no"); presence of diabetic eye disease or current
use of oral hypoglycemic drugs; or a postload glucose value 
11.1
mmol/L (or, if missing, a fasting glucose value 7.8
mmol/L).15 Poor health was defined a priori as
diagnosis of myocardial infarction, possible or probable angina (Rose
questionnaire); diabetes; hypertension (>160/90 mm Hg or taking
antihypertensive drugs); and
hypercholesterolemia (>8.5
mmol/L), resulting in 1174 men and 489 women.
Statistical Analysis
Statistical analysis was performed with SAS
computer software (SAS Inc). All models were sex-specific because of
the differences in anthropometric measures and body composition between
men and women. Biochemical variables were logarithmically
transformed. Linear regression models adjusted for age (and menopause
in women) were used to examine the association between vWF as a
continuous variable and each variable tested. Age was held to
its whole-sample mean of 50 years. Tests of trend were based on
regression analysis, with the relevant factor entered as a
continuous variable, with age (and menopausal status for women)
entered as a covariate. The association between vWF and employment
grade was also tested for nonlinearity by inclusion of a quadratic term
for employment grade, which was tested for significance
(P<0.05).
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Results |
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Table 1
shows that mean vWF levels
increased as employment grade decreased. This trend occurred in both
men and women and was largely unaffected by removal from the data set
of those in poor health (diagnosis of myocardial infarction, possible
or probable angina (by Rose questionnaire); with diabetes, hypertension
(>160/90 mm Hg or taking antihypertensive drugs), and
hypercholesterolemia (>8.5 mmol/L; n=1174
men and 489 women); or if repeated in never-smokers (resulting in
n=2123 men and 891 women) with the exception of men in the lowest
employment grade, in whom vWF concentrations were not different from
those in never-smokers in the highest grade. Poor health was associated
with raised levels of vWF in men (mean, 103.1 IU/dL; 95% CI, 99.6,
111.2 versus 99.6 IU/dL; 95% CI, 98.5, 100.7; P=0.06) and a
trend was also apparent in women (mean, 104.9 IU/dL; 95% CI, 99.5,
110.5 versus 100.5 IU/dL; 95% CI, 98.9, 102.2;
P=0.13).
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Tables 2 and 3 show analyses of vWF and risk
factors that were previously demonstrated to be associated with
employment grade4 14 in men and women. Age was associated
with increased concentrations of vWF in both men and women (data not
shown). Age-adjusted vWF was positively associated with fasting and
postload insulin, fibrinogen, and fasting and postload glucose values
in both men and women. In addition, age- and menopause-adjusted vWF
levels were associated with a worsening HDL cholesterol and
waist-hip ratio in women (Table 3), while a test for trend for
triglyceride levels approached significance
(P=0.2). No associations were observed with systolic
or diastolic blood pressure or serum total
cholesterol. Systolic blood pressure was not
related to vWF after the removal from the data set of those taking
antihypertensive medication. However, the moderately inverse
association between vWF and diastolic blood pressure
apparent in men reached statistical significance (P=0.02;
data not shown).
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A number of these variables are constituents of the
metabolic syndrome, which shows a striking employment grade
gradient. Individuals were considered to have the metabolic
syndrome when 3 or more of the following were in the worst sex-specific
quintile: 2-hour glucose, systolic blood pressure, fasting
triglycerides, HDL cholesterol, and waist-hip
ratio.6 Table 4 shows that
vWF was moderately raised in men positive for the metabolic
syndrome (n=505), an effect that was not apparent in women (n=218).
Concentrations of vWF were greatly increased in diabetic participants
compared with nondiabetics (n=58 male and 31 female diabetics).
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The associations between vWF and a number of health behaviors are shown
in Table 5. In men, vWF concentrations
were associated with smoking status, such that current smokers had
raised vWF levels compared with never-smokers. Only those men who
reported smoking >21 cigarettes per day had markedly raised serum vWF
concentrations compared with never-smokers (P=0.009). In
women, no significant differences in vWF were observed with smoking
status, although a similar pattern was observed with an increased level
of vWF in the group that reported smoking the greatest number of
cigarettes (P=0.16). In both men and women, adjustment for
employment grade failed to markedly alter the observed effects.
Reported exercise levels were not associated with vWF concentrations in
men, but a direct trend was observed in women (P=0.05),
which was largely unaffected by adjustment for employment grade
(P=0.04). Reported alcohol intake was strongly and inversely
associated with vWF in both men and women. This effect was still
apparent after adjustment for employment
grade.
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Figure 1 shows an employment grade gradient in vWF in men (ß
coefficient 1.01 [CI 1.00, 1.02]) and women (ß coefficient 1.02
[CI 1.01, 1.03]) in whom complete data were available for the
metabolic variables, fibrinogen, waist-hip ratio, and health related
behaviours (n=3942 men and n=1644 women). Data are expressed as
mean±standard error. The test for a nonlinear association between vWF
and employment grade in women was not significant (P=0.45
for quadratic term). Thirty-two percent of the employment grade
gradient in men was accounted for by adjustment with metabolic
covariates and fibrinogen (Figure 1B). Similarly, waist-hip ratio,
fibrinogen, and metabolic covariates accounted for 22% of the
employment grade gradient in women (Figure 1E). Health related
behaviours explained 25% of the gradient in men (Figure 1C) and 28%
of the gradient in women (Figure 1F).
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Discussion |
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Our findings demonstrate associations between plasma vWF and several risk factors for CHD. An association is also apparent between vWF and employment grade, which persisted after adjustment for health-related behaviors and metabolic variables. A trend for increasing vWF as employment grade decreased remained even when the analyses were repeated after removal from the data set of those in "poor health" or if repeated in never-smokers, suggesting that the effects are unlikely to be a consequence of prevalent ill health. Our findings suggest that vWF, a marker of endothelial dysfunction, can be added to the list of potential biological explanation for the increased risk of CHD observed in men and women of lower socioeconomic position.
vWF plays a pivotal role in the mechanisms of blood clotting and platelet thrombus formation; it binds and stabilizes factor VIII procoagulant protein. The structure of vWF supports the formation of stable platelet aggregates at the site of vascular injury under conditions of high shear stress.8 These changes are early steps in mediating endothelial dysfunction after vascular injury. Estimates of the endothelial source of serum vWF range from 85% to 90%17 18 and a suggestion that all of the circulating vWF is derived from the endothelium.9 19
As expected, vWF concentrations increased with age. Although the concentrations of vWF were the same in men and women, there is some controversy in the literature regarding sex differences in vWF, with reports of no difference10 or some considerable difference, such that women reportedly have higher values than men.11 This may reflect ethnic differences in the composition of the different studies. Our analyses were restricted to whites only. In the Atherosclerosis Risk in Communities Study, a sex difference in mean vWF was observed in black but not in white participants.9
The Whitehall II Study was established to examine the causes of the gradient in CHD associated with employment grade that was observed in the original Whitehall Study.18 Although employment grade gradients in traditional risk factors, eg, blood pressure and total cholesterol, were not observed, data from Whitehall II demonstrate that social gradients are apparent for a number of factors associated with CHD.2 Thus, we have already demonstrated differences across employment grade for two biological factors that may contribute to the increased CHD in the lower employment grades. Both plasma fibrinogen5 and the likelihood of having the metabolic syndrome6 are inversely associated with employment grade.
Our data in a limited number of diabetics agree with previous studies that have found strong associations between diabetes and plasma vWF concentrations, which are thought to reflect endothelial cell damage with subsequent release of vWF.10 We found a small association between vWF and the metabolic syndrome in men but not in women. However, in both sexes there were strong associations between components of the metabolic syndrome and vWF. Thus, an association with postload glucose was observed in both sexes. In accordance with previous reports, an association between waist-hip ratio11 21 and triglycerides11 was observed in women. No significant associations were observed with triglycerides and systolic blood pressure. These data were apparent in the whole cohort and also after removal from the data set of those on antihypertensive therapy. These data accord with a number of studies that have failed to find an association between blood pressure and vWF. The increased levels of vWF in diabetes may be a reflection of the association with insulin, which is not a component of the metabolic syndrome in our study. Alternately, the increased vWF may be a consequence of endothelial damage that occurs in response to diabetes. Our definition of metabolic syndrome required that women have approximately the same prevalence of the syndrome as men. If in fact the syndrome is less prevalent in women, our definition of abnormal may misclassify more women than men. It may be for this reason that the small association observed with vWF in men was not apparent in women.
Most epidemiological studies have not observed an association between smoking and vWF,11 22 whereas strong stimulatory effects are observed in short-term smoking studies23 and positive associations are found in case-control studies.24 25 There may be a difference in the acute versus chronic effects of smoking. Our data point to a threshold effect in smokers such that male heavy smokers only (defined as those who smoked >21 cigarettes per day) had increased vWF levels. Exsmokers did not have raised vWF levels compared with current smokers. These data suggest that the effect observed in our study may result from an acute effect of smoking on vWF release and/or current endothelial damage. The mechanisms by which smoking influences the release of vWF remain unclear but may include lipid peroxides, viscosity, and carbon monoxide, among others.23
Higher plasma vWF concentrations were associated with lower levels of self-reported alcohol intake. A monotonic inverse relationship was apparent between vWF and alcohol intake, such that the most heavy drinkers had decreased vWF levels, even after adjustment for employment grade. These data may provide some insight into the protective effects of alcohol intake.26 A weak, positive association between plasma vWF and self-reported exercise was observed in women.
An employment grade gradient was observed for vWF in men. Although the employment grade gradient in women appeared nonlinear with respect to vWF, the results of the analyses were not significant. This may be because there are fewer women in the higher employment grades, and thus, the study lacks the power to detect a nonlinear association. High concentrations in both top and bottom employment grades have been noted for a number of variables, such as insulin, HDL cholesterol, and triglycerides.6
Our data accord with a recent report that showed an association between vWF and social position, measured by educational attainment, in women.27 The employment grade gradient appeared to be independent of metabolic variables, which themselves show an employment grade gradient. Although it may be that vWF in part reflects prevalent poor health, the employment grade gradient was present after excluding from the analyses those in poor health, suggesting that this possibility is unlikely. Additionally, an employment grade gradient was observed in never-smokers, suggesting that factors additional to those that were measured in this study may help explain the increased levels of vWF in the lower employment grades.
In conclusion, vWF can be added to the list of biological variables that show an employment grade gradient in the Whitehall II Study. There is an inverse gradient for vWF and employment grade, which is present in the total cohort and is also apparent in never-smokers. This increased level of vWF represents poor endothelial function or altered hemostasis. The gradient is partially explained by health-related behaviors or biological variables, including the metabolic syndrome. Longitudinal data will allow us to determine the extent to which vWF explains the inverse social gradient in CHD incidence.
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Acknowledgments |
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The Whitehall II Study was supported by grants from the Medical Research Council; the British Heart Foundation; the Health and Safety Executive; the Department of Health; the National Heart, Lung, and Blood Institute (RO1-HL36310), and the National Institute on Aging (RO1-AG13196), (National Institutes of Health, Bethesda, MD); Agency for Health Care Policy Research (RO1-HS06516); and the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health. M.M. is supported by an MRC Research Professorship. E.B. is supported by the British Heart Foundation. We thank John O’Brien and Mike Etherington. We also thank all participating civil service departments and their welfare, personnel, and establishment officers; the Occupational Health and Safety Agency; the Council of Civil Service Unions; all participating civil servants in the Whitehall II Study; and all members of the Whitehall II Study team.
Received August 27, 1999; accepted April 5, 2000.
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