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Keywords:

  • cardiovascular diseases;
  • coagulation;
  • endothelium-derived factors;
  • epidemiology;
  • hemostasis;
  • inflammation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

Summary. Background: Circulating levels of C-reactive protein (CRP), fibrinogen, fibrin D-dimer, tissue plasminogen activator antigen (t-PA) and von Willebrand factor (VWF) are associated with incident coronary heart disease (CHD). However, their associations with metabolic syndrome and its components in large populations of men and women have not been well defined. Objectives: We compare the sex associations of these biomarkers with established CHD risk factors, metabolic syndrome and its components in a large cohort. Patients and Methods: 8302 men and women aged 45 years from the British 1958 birth cohort provided a blood sample. Analyses were restricted to 3457 men and 3464 women with complete data on all risk factors and no history of cardiovascular disease. Multiple regression analyses adjusted for smoking, social class, alcohol consumption and variables related to biomarker measurement error. Results: Adjusted sex differences in levels of all biomarkers (except VWF) varied according to presence/absence of metabolic syndrome, its components and obesity (BMI ≥30 kg m2). Associations in women were up to twice as strong for CRP, fibrinogen and t-PA with markers of obesity (body mass index, waist circumference), blood pressure, blood lipids and metabolic syndrome. D-dimer showed weaker associations and less heterogeneity by sex. There was no evidence of sex interaction in associations with VWF. Conclusions: Associations between CRP, fibrinogen and t-PA and metabolic syndrome and its components were stronger in women than in men. Understanding the reasons for these differences across sex will be important in understanding the pathophysiology of cardiovascular and metabolic disease in men and women.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

Circulating levels of hemostatic and inflammatory variables have been associated with risk of coronary heart disease (CHD) in prospective studies, including C-reactive protein (CRP) [1], fibrinogen [2], fibrin D-dimer [3], von Willebrand factor (VWF) [1,4] and tissue plasminogen activator antigen (t-PA) [5]. It has been debated whether these novel markers add to the discriminatory power of established risk scores in predicting future cardiovascular disease. (CVD) [1,6–9] Others have suggested that CRP be included in the clinical definition of metabolic syndrome (MS) [10–12]. There is a need to define associations between these biomarkers and MS, including its separate components, in large population-based studies of middle-aged subjects (at an age when risk scores are widely used). Comparisons of these associations in men and women will further our understanding of sex differences in inflammatory and hemostatic mechanisms. While some studies have suggested that chronic, subclinical inflammation, defined by raised CRP [10,13,14] and fibrinogen [15] levels, may have a greater impact on the development of MS or Type 2 diabetes [16] in women than in men, there is a need for further data on all of these potential risk markers.

The British 1958 birth cohort is a representative sample of men and women across the UK, in whom we have assayed these five biomarkers at 45 years of age. We have previously reported variations in these markers in relation to sex, seasonality, time of day and processing [17], as well as social position [18]. The aim of the present study was to compare the relationships of these five inflammatory/hemostatic markers to components of MS and obesity in men and women, after adjusting for such variables.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

Study design

The British 1958 birth cohort includes all persons born in England, Scotland and Wales during one week in March 1958. Cohort members have been followed-up periodically from birth into adulthood. From a target sample of 12 069 surviving members resident in Britain, 9377 (78%) participated in a clinical examination in their home undertaken by 122 specially trained nurses from the National Centre for Social Research during 2002–2004 [19].

Nurse examination

Standing height was measured to the nearest millimetre using a Leicester portable stadiometer placed on a hard floor. Waist circumference was measured to the nearest millimetre using a standard flexible tape measure. Weight was measured to the nearest 0.1 kg in light clothing with shoes removed. Body mass index (BMI) was calculated as kg m−2. Blood pressure was measured three times in the seated position after a period of 5 min rest, using the Omron 705CP automated sphygmomanometer (Omron, Tokyo, Japan), with a large cuff for subjects with a mid-upper arm circumference of 32 cm or greater. The mean blood pressure was determined for readings that the nurse considered to be reliable.

Adult socio-economic position was based on the participant’s current or most recent occupation at age 42 (or 33 if data were unavailable at 42) and categorized using the Registrar General’s Classification [18]. Smoking status was defined as lifelong never smoker, former smoker and current smoker (< 10 cigarettes per day, 10–19 cigarettes per day and ≥ 20 cigarettes per day). Alcohol consumption was defined as non-drinkers and three levels of alcohol consumption: light drinkers (< 21 units of alcohol per week for men; < 14 units of alcohol per week for women), moderate drinkers (21 to < 42 units per week for men; 14 to < 28 units per week for women) and heavy drinkers (≥ 42 units per week for men; ≥ 28 units per week for women).

Blood collection and measurement

Non-fasting venous blood samples were drawn, with the subjects sitting, into Sarstedt polypropylene tubes containing citrate anticoagulant. Samples were transported to the laboratory at ambient temperature, centrifuged, and aliquots of plasma were stored at −70 °C. Glycosylated hemoglobin (HbA1c) was assayed by ion exchange high performance liquid chromatography on whole blood. Triglycerides and total and high-density lipoprotein (HDL) cholesterol were measured by autoanalyser. Fibrinogen was determined by the automated Clauss method [20] in an MDA 180 coagulometer (Biomerieux, Basingstoke, UK). C-reactive protein (CRP) was measured by high-sensitivity nephelometric analysis of latex particles coated with CRP monoclonal antibodies (BN ProSpec protein analyzer; Dade Behring, Marburg, Germany). Tissue plasminogen activator antigen (t-PA) and von Willebrand factor antigen (VWF) were measured by ELISAs employing a double antibody sandwich (Biopool, Umea, Sweden, and DAKO, Copenhagen, Denmark, respectively). Fibrin D- dimer was measured by ELISA assay (Hyphen, Paris, France) and standardized for inter-batch variation [17]. All analytes were monitored for internal quality control using Levey-Jennings plots during the assay period, and coefficients of variation previously reported [17].

Metabolic syndrome in non-diabetics

MS was characterized using the International Diabetes Federation definition [21]: systolic blood pressure of at least 130 mmHg or diastolic blood pressure of at least 85 mmHg, serum HDL-cholesterol < 1.03 mmol L−1 in men and < 1.29 mmol L−1 in women, and serum triglyceride levels > 1.7 mmol L−1 in men or women; abdominal obesity was defined as a waist circumference of at least 94 cm in men and at least 80 cm in women. Fasting glucose measures were not made; therefore we were unable to include this component of the definition.

Statistical analysis

Statistical analyses were carried out using STATA/SE software (Stata/SE 10.1 for Windows; StataCorp LP, College Station, TX, USA). CRP, fibrinogen, D-dimer, t-PA and VWF were log transformed to normalize their distributions prior to performing analyses. Multiple regression analyses were adjusted throughout for social position (six categories), smoking status (five categories) and alcohol consumption (four categories). Variables contributing to the random error of biomarker measurements were also included [17,19] (month of examination, instrument, nurse, time of day blood sample was taken, delay in sample processing, month and laboratory batch, all as categorical variables).

Sex-specific adjusted geometric mean levels of CRP, fibrinogen, D-dimer, t-PA and VWF by MS status and adjusted sex differences by MS status, its components and obesity (defined as BMI≥ 30 kg m2) were determined. F-tests for sex interactions of associations between biomarkers and MS and its components were undertaken. In view of marked heterogeneity by sex in these associations, adjusted odds ratios of MS comparing top and bottom quartiles of biomarkers were calculated stratified by sex. Parallel analyses were undertaken to provide mutually adjusted odds ratios for each component of MS and obesity.

For comparison with other studies, adjusted geometric mean levels of biomarkers by quartiles of established cardiovascular risk factors (along with partial correlation coefficients with established cardiovascular risk factors in their original continuous form with log transformation for waist circumference, HDL-cholesterol and triglyceride) are given in an online supplement.

Those with missing data on categorical variables (smoking [n = 235], social position [n = 289] and alcohol consumption [n = 20]) were included in separate categories. The incidence of statin use was less than 1% in this cohort and therefore not included as a covariate in the analyses. Individuals with known diagnosis or treatment for diabetes, heart problems or hypertension were excluded from all analyses.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

Of the 9377 individuals who participated in the biomedical examination, 94% consented to blood sample collection, 8302 of whom provided a blood sample [22]. Five hundred and thirty-nine were excluded because of diagnosis or treatment for pre-existing CVD. A total of 6921 (78%, 3457 men and 3464 women) had a valid result for CRP, fibrinogen, D-dimer, t-PA and VWF [22], and had complete data on nine other cardiovascular variables. Reasons for invalid results included:(i) technical problems with venepuncture, (ii) delay in transportation of the blood sample to the laboratory, (iii) insufficient blood sample or (iv) invalid assay result.

Men had significantly higher levels of established CHD risk factors than women, and were more likely to be moderate/heavy drinkers (P < 0.001 in all instances), but patterns of smoking were broadly similar (Table 1). Overall, 1094 men (32%) and 536 women (15.5%) were classified as having MS. Women with MS had higher adjusted mean levels of CRP, fibrinogen and D-dimer and lower levels of t-PA than men with MS (P < 0.0001 in all instances) but no material differences in VWF (P = 0.51). Women without MS had significantly higher adjusted mean levels of fibrinogen, D-dimer and lower levels of t-PA and VWF (P < 0.0001 in all instances) than men, but CRP levels were similar (P = 0.84) (Table 2). Sex differences in biomarkers were greater in subjects with MS compared with those without; however, for t-PA the differences were less marked (P-value for interaction < 0.0001 in all instances expect for VWF; Table 2).

Table 1.   Cardiovascular and lifestyle characteristics of cohort
VariableMedian, interquartile range
Men, n = 3457Women, n = 3464
  1. *Alcohol consumption in men: light < 21 units per week; moderate 21 to < 42 units per week; heavy ≥ 42 units per week. In women: light < 14 units per week; moderate 14 to < 28 units per week; heavy ≥ 28 units per week.

BMI Kg m−²27.1, 4.825.5, 6.1
Waist circumference (cm)96.6, 12.882.6, 15.8
Systolic blood pressure (mmHg)130.7, 18.3117.7, 19.3
Diastolic blood pressure (mmHg)80.7, 13.374.0, 13.3
HbA1c (% total)5.20, 0.405.10, 0.40
Total cholesterol (mmol L−1)6.00, 1.505.60, 1.30
HDL-C (mmol L−1)1.40, 0.401.70, 0.50
Triglyceride (mmol L−1)2.00, 1.501.30, 1.00
Smoking statusIncidence % (N)
 Life-long non-smoker44% (1513)45% (1558)
 Ex-smoker26% (890)25% (854)
 Current smoker27% (920)27% (951)
Alcohol consumption*
 None4.3% (148)7.7% (266)
 Light77% (2656)77% (2679)
 Moderate/heavy19% (640)15% (512)
Social position
 Professional/managerial46% (1576)36% (1258)
 Skilled (manual + non-manual)39% (1336)39% (1360)
 Partly skilled and unskilled11.4% (394)20% (688)
 Other/unknown3.5% (121)4.6% (158)
Table 2.   Adjusted* geometric means (95% confidence intervals) of biomarkers in men and women according to metabolic syndrome status
BiomarkerMetabolic syndrome presentMetabolic syndrome absent
Men, n = 1094Women, n = 536Men, n = 2363Women, n = 2923Interaction P-value
  1. *Means adjusted for laboratory batch, month, time of day, delay in processing blood sample, smoking, social class and alcohol consumption. Interaction P-value is for sex differences in biomarkers according to metabolic syndrome status from adjusted analyses.

CRP mg L−11.34 (1.25,1.44)2.17 (1.97,2.39)0.85 (0.81,0.89)0.85 (0.81,0.89)< 0.0001
Fibrinogen g L−12.89 (2.86,2.92)3.15 (3.10,3.20)2.80 (2.78,2.82)2.90 (2.88,2.92)< 0.0001
D-dimer ng mL−1146 (141,150)214 (205,224)132.4 (130,135)182 (178,186)0.03
t-PA ng mL−16.5 (6.3,6.7)5.4 (5.2,5.7)4.7 (4.6,4.8)3.4 (3.4,3.5)< 0.0001
VWF IU dL−1120 (117, 122)117 (114,121)116 (115,118)112 (111,114)0.22

Table 3 gives the percentage differences in biomarkers between men and women according to presence or absence of MS, its components and obesity defined by BMI level. F-tests for sex interactions were highly statistically significant for associations with CRP, fibrinogen (except high blood pressure), D-dimer (except raised triglycerides) and t-PA. Sex differences in CRP, fibrinogen and to a lesser extent D-dimer, were more marked among individuals with MS or any of the components listed in Table 3. Women with metabolic syndrome, its components or obesity had higher levels of CRP, fibrinogen and D-dimer than men. In contrast, women without obesity had lower levels of CRP than men. Women also had lower levels of t-PA than men but differences were attenuated among those with factors listed in Table 3. There was no evidence of sex interaction in associations with VWF (Table 3).

Table 3.   Adjusted* percentage differences (95% confidence intervals) of biomarkers in women vs. men by metabolic syndrome, its components and obesity
FactorAdjusted percentage differences (95% CI) in women vs. menVWF
CRPFibrinogenD-Dimert-PA
  1. *Percentage differences adjusted for laboratory batch, month, time of day, delay in processing blood sample, smoking, social class and alcohol consumption. Interaction P-value is for sex differences in biomarkers according to metabolic syndrome status and its components from adjusted analyses.

Metabolic syndrome
 No0.1 (−6.4,7.1)3.5 (2.3,4.6)37.6 (33.4,42.0)−26.4 (−28.4,−24.4)−3.7 (−5.5,−1.9)
 Yes61.2 (42.7,82.2)8.9 (6.7,11.1)47.2 (39.1,55.8)−15.6 (−19.7,−11.3)−1.4 (−4.7,2.1)
 Interaction P-value< 0.0001< 0.00010.03< 0.00010.22
Abdominal obesity
 No−20.4 (−27.0,−13.1)0.1 (−1.4,1.6)29.1 (23.9,34.6)−29.9 (−32.4,−27.3)−3.4 (−5.8,−0.9)
 Yes19.6 (11.3,28.5)6.5 (5.3,7.9)43.2 (38.4,48.2)−26.7 (−28.8,−24.5)−3.7 (−5.7,−1.7)
 Interaction P-value< 0.0001< 0.00010.00010.0480.83
Obesity (BMI ≥ 30kg m−²)
 No−10.8 (−16.3, −4.8)2.1 (1.0,3.2)33.0 (28.9,37.2)−30.0 (−31.8,−28.0)−4.0 (−5.8,−2.2)
 Yes61.1 (43.8,80.5)10.8 (8.7,12.9)53.8 (45.6,62.5)−20.6 (−24.3,−16.7)−2.0 (−5.3,1.3)
 Interaction P-value†< 0.0001< 0.0001< 0.0001< 0.00010.29
High triglycerides
 No−5.4 (−13.0,2.8)3.1 (1.6,4.5)35.7 (30.5,41.1)−23.4 (−26.0,−20.8)−4.0 (−6.3,−1.7)
 Yes44.8 (32.8,58.0)6.6 (5.1,8.2)42.7 (37.0,48.5)−19.2 (−22.0,-16.3)−2.1 (−4.5,0.3)
 Interaction P-value< 0.00010.00040.070.020.23
Low HDL-cholesterol
 No−4.5 (−10.5,1.8)2.8 (1.8,3.9)35.0 (31.1,39.0)−30.3 (−32.2,-28.5)−3.5 (−5.2,−1.8)
 Yes34.4 (12.8,60.2)10.6 (7.5,13.9)51.4 (39.7,64.1)−14.6 (−20.6,−8.2)−5.8 (−10.3,−1.1)
 Interaction P-value0.0002< 0.00010.007< 0.00010.35
High blood pressure
 No2.6 (−5.1,10.9)4.6 (3.2,5.9)35.3 (30.6,40.2)−25.5 (−27.8,−23.0)−3.0 (−5.0,−0.8)
 Yes29.8 (17.7,43.1)5.4 (3.7,7.1)43.9 (37.5,50.5)−20.6 (−23.7,−17.3)−3.7 (−6.3,−1.1)
 Interaction P-value0.00010.410.030.010.64

Table 4 summarizes the association between the top and bottom quartile of each biomarker in relation to the odds of MS, its components and obesity. There were significant sex interactions for associations with CRP, t-PA and fibrinogen and to a lesser extent for D-dimer but not VWF. In general, independent associations were stronger in women than in men, particularly for MS, obesity (BMI≥ 30 kg m−²) and low HDL. Associations were strikingly (approximately up to 2-fold) stronger in women compared with men for CRP and t-PA. Associations for fibrinogen and D-dimer broadly followed a similar pattern but were less strong. VWF was weakly associated with MS and obesity (and with low HDL in men), with similar patterns in men and women. Fig 1 shows that although the absolute risks of MS and abdominal obesity were generally higher in men than in women for each biomarker quartile, the change in risk across quartiles is more marked in women than in men in all instances except VWF. Excluding the 7% of women using hormone therapy or restricting the analyses to lifelong non-smokers did not materially alter the sex differences reported (data available on request).

Table 4.   Adjusted* odds ratios (95% confidence intervals) of metabolic syndrome, its components and obesity comparing top and bottom quartiles of biomarker
BiomarkerMetabolic syndromeAbdominal obesityObesity (BMI ≥ 30 Kg m−²)High triglyceridesLow HDLHigh blood pressure
  1. *Odds ratios adjusted for laboratory batch, month, time of day, delay in processing blood sample, smoking, social class, alcohol consumption and each of the other components of metabolic syndrome. n = number of cases based on the International Diabetes Federation definitions [21].Interaction P-value is for sex differences in odds ratios from adjusted analysis.

CRP (men)3.7 (2.9, 4.7)3.9 (3.2, 4.9)7.3 (5.4, 10.0)1.3 (1.0, 1.6)2.1 (1.4, 3.1)1.6 (1.3, 2.0)
CRP (women)10.1 (7.0, 14.5)8.0 (6.2, 10.2)23.0 (15.1, 35.0)2.8 (2.2, 3.6)1.9 (1.0, 2.8)2.4 (1.9, 3.1)
Interaction P-value< 0.0001< 0.0001< 0.0001< 0.00010.260.002
Fibrinogen (men)1.6 (1.3, 2.0)2.0 (1.6, 2.4)2.4 (1.9, 3.2)1.0 (0.8, 1.3)1.4 (1.0, 2.0)1.5 (1.2, 1.8)
Fibrinogen (women)3.2 (2.4, 4.3)4.9 (3.9, 6.2)7.3 (5.4, 10.0)1.0 (0.8, 1.3)2.8 (1.9, 4.1)1.3 (1.0, 1.6)
Interaction P-value0.0001< 0.0001< 0.00010.070.010.67
D-dimer (men)1.6 (1.3, 2.0)1.8 (1.5,2.3)1.8 (1.4, 2.3)1.0 (0.8, 1.2)1.2 (0.9, 1.8)1.0 (0.8, 1.2)
D-dimer (women)2.2 (1.7,3.0)2.8 (2.2, 3.4)3.8 (2.9, 5.1)1.0 (0.8, 1.3)2.2 (1.5, 3.1)1.1 (0.9, 1.4)
Interaction P-value0.060.020.00010.180.010.17
t-PA (men)10.5 (8.0,13.8)6.5 (5.0, 8.4)9.1 (6.5, 12.6)5.3 (4.0, 7.0)2.0 (1.3, 3.2)2.7 (2.2, 3.5)
t-PA (women)19.7 (13.4,29.0)7.5 (5.7, 9.9)13.2 (9.2, 18.9)4.2 (3.2, 5.5)4.4 (2.9, 6.5)3.4 (2.6, 4.5)
Interaction P-value0.00010.0040.040.30.0010.58
VWF1.2 (1.0,1.5)1.5 (1.2,1.9)2.0 (1.5, 2.5)1.0 (0.8, 1.3)1.5 (1.0, 2.2)1.0 (0.8, 1.3)
VWF1.4 (1.1,1.9)1.4 (1.1,1.7)2.4 (1.8, 3.1)1.1 (0.8, 1.3)0.9 (0.6, 1.3)1.2 (0.9, 1.5)
Interaction P-value0.250.510.950.10.240.11
image

Figure 1.  Average probability with 95% confidence intervals for metabolic syndrome (upper panel) and abdominal obesity (lower panel) by quartiles of biomarkers. Probabilities adjusted for laboratory batch, month, time of day, delay in processing blood sample, smoking, social class and alcohol consumption, and in the case of abdominal obesity additionally for the other components of metabolic syndrome. Men are shown by solid squares, females by open circles.

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An online table gives adjusted mean levels of the five biomarkers by quartiles of classical CHD risk factors and shows that the linear associations were generally stronger in women than in men. CRP and t-PA were most strongly associated with markers of obesity (body mass index and waist circumference) and triglyceride levels, and to a lesser extent with blood pressure and total cholesterol. Fibrinogen, D-dimer and VWF showed similar but generally weaker associations with body mass index and waist circumference while associations with blood pressure and lipids were less consistent, particularly in men. All biomarkers showed positive associations with smoking (stronger in men than women). Inverse associations were observed between alcohol consumption, t-PA and fibrinogen in men and all biomarkers except CRP in women (data available on request from authors).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

In this large population-based healthy cohort, representative of 45-year-old men and women in the UK, we have shown that adjusted levels of CRP, fibrinogen and D-dimer were higher and levels of t-PA and VWF lower in women than in men. Sex differences were modified by the presence of MS and its components for all biomarkers except VWF. Among these five emerging risk markers, CRP, t-PA antigen and fibrinogen showed the strongest associations with MS, its components and obesity (defined as BMI ≥ 30 kg m−²) independent of smoking, alcohol intake and social class. In particular, risk factor associations between CRP and fibrinogen with MS, abdominal obesity and obesity (BMI ≥ 30 kg m−²) and between t-PA and MS and low HDL were twice as strong in women than in men. Fibrin D-dimer showed less strong associations with MS and obesity, but they were still stronger in women than in men. In contrast, VWF antigen showed weak associations. These findings have significant implications for understanding differences in inflammatory and hemostatic mechanisms in men and women in the pathogenesis and progression of CVD.

The strength of the associations between CRP and fibrinogen with classical CVD risk factors are consistent with previous reports [2,23,24,24–26]. VWF antigen (an endothelial cell product) and D-dimer (a measure of turnover of cross-linked fibrin, and hence thrombin and plasmin activity) were only weakly related to classical CVD risk factors.

The sex differences in levels of CRP [27,28], especially in those with MS [14,29], and the associations of CRP levels with MS, in particular with measures of obesity, agree with other reports of stronger associations in women between CRP and body size [13,16,30], MS [13,14,29,31,32], insulin levels [33] and Type 2 diabetes [16,34–37]. Our findings that the associations of fibrinogen with MS and measures of obesity were stronger in women, while in contrast the association of fibrinogen with smoking was stronger in men, are consistent with the findings of others [24,30,31,38].

While circulating levels of t-PA antigen, VWF and fibrin D-dimer increase during inflammatory reactions, as do fibrinogen and CRP [39], they are not simply acute-phase proteins synthesized by the liver. t-PA antigen levels reflect endothelial synthesis of t-PA, which rapidly complexes with its major inhibitor, plasminogen activator inhibitor type 1 (PAI-1), synthesized in both endothelial cells and the liver. t-PA antigen levels are therefore influenced by both endothelial cell and hepatocyte activity. In the present study, we confirmed that t-PA antigen levels were strongly associated with traditional CVD risk factors, and like CRP showed a striking sex difference in their associations with MS, abdominal obesity and HDL cholesterol. Sex differences in t-PA were diminished in the presence of MS and its components. Whether or not this is related to sex differences in hepatic synthesis of CRP and PAI-1 (and fibrinogen) is not known.

Reasons for the sex differences observed for associations of MS and its components with CRP, fibrinogen, D-dimer and t-PA are unclear; they are possibly attributed to different patterns of confounding or differences in the distribution of body fat. At a similar BMI, women tend to have more adipose tissue than men, leading to greater hepatic production of CRP, thereby leading to stronger associations of CRP (and possibly fibrinogen and t-PA) with more general markers of body size such as waist circumference and obesity. A recent study reported that women had higher CRP concentrations than men with similar visceral adiposity, but no sex difference was observed for men and women with similar accumulation of subcutaneous fat [40]. We found the association between CRP and BMI to be stronger in women (see Table S1) and this agrees with a recent study showing stronger associations in women between CRP and total fat mass index and truncal fat [41]. Women with raised CRP levels and MS appear to be at particularly high risk of CVD [10]. Collectively this suggests that sex differences in body fat distribution, that strongly relate to chronic inflammation, may partially offer an explanation for the sex difference in the risk of development of CVD or MS [13,14,28]. Sex differences in the expression of different inflammation-sensitive biomarkers in relation to MS and its components may relate to sex differences in hormone levels [28,40]. However, in agreement with others [14], excluding the 7% of women using hormone therapy did not influence the sex differences observed.

Strengths of this present study include: large population-based sample of men and women broadly representative of the initial UK birth cohort population [22]; uniform age (45 years) of all participants, hence no need for age-adjustment; direct comparison of five emerging potential cardiovascular risk markers; and evaluation at an age at which cardiovascular risk screening has been advocated in several countries. Limitations include: the sample consists of individuals almost exclusively of white ethnicity and therefore the findings are not directly transferable to other ethnic groups. There was some under-representation of individuals in the most deprived social groups; however, the 1958 cohort at 45 years is broadly representative of the total surviving cohort [22,42]. Social class and levels of established cardiovascular risk factors were similar in those with and without valid data on biomarkers.

In conclusion, among five biomarkers, CRP, fibrinogen and t-PA showed the strongest associations with MS and its components (especially measures of obesity), which differed markedly between men and women. Associations with traditional CHD risk factors were in line with previous reports. Although the absolute risks of MS and its individual components were generally higher in men than in women, associations were markedly stronger in women than in men for CRP, fibrinogen and t-PA and to a lesser extent for D-dimer. Heterogeneity in associations between men and women in an apparently ‘healthy’ cohort is worthy of further investigation, particularly for the biomarkers t-PA and D-dimer, which have not been as extensively studied in this context. Understanding the reasons for these differences across sex will be important in understanding the pathophysiology of cardiovascular and metabolic disease in men and women.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

We are especially grateful to the cohort members who participated in the 2002-2004 biomedical follow-up, and to the nurses and office and laboratory staff who contributed to the successful completion of the nationwide fieldwork. Ethical approval for the medical examination of the British 1958 Birth Cohort was obtained from South East MREC (ref: 01/1/44). The biomedical examination was funded by Medical Research Council grant G0000934, awarded under the Health of the Public initiative. The MRC played no role in study design, collection, analysis and interpretation of data, writing the report, or submitting the paper for publication.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

The authors state that they have no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of Conflict of Interests
  9. References
  10. Supporting Information

Table S1. Adjusted* geometric means in 3457 men by quartiles of established cardiovascular factors.

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JTH_4517_sm_TableS1.doc203KSupporting info item

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