Abdominal Obesity and the Risk of Venous Thromboembolism Among Women: A Potential Role of Interleukin-6

Abstract

Background:

Abdominal obesity increases the risk of venous thromboembolism (VTE). It remains unclear to what extent inflammation contributes to the risk of VTE from abdominal obesity. Our objectives were to investigate the association between abdominal obesity and VTE and the effect of inflammation on this association in a case–control study comprised of women.

Methods:

We included 84 patients with VTE (18–60 years of age) and 100 controls. Waist circumference (WC), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP) levels were determined at least 7 months after the thrombotic event.

Results:

A total of 51 patients (61%) and 43 (43%) controls had abdominal obesity (WC≥88 cm). The odds ratios (OR) adjusted for age were 2.40 [95% confidence interval (CI) 1.06–5.41; P=0.035] for a WC ≥88 cm compared to a WC <80 cm; the association was attenuated after adjusting for IL-6 (OR 1.86, 95% CI 0.80–4.33; P=0.149). For every 10-cm increment in WC, the risk of VTE adjusted for age increased by 1.38 (95% CI 1.08–1.77; P=0.010). The effect of an increased WC on the risk of VTE was again attenuated when IL-6 was entered in the regression model (OR 1.24, 95% CI 0.95–1.61; P=0.109). Risk estimates did not substantially change with adjustment for hsCRP.

Conclusion:

Our data indicate that the association between VTE and an increased WC was attenuated after adjustment for IL-6, suggesting a potential role of this interleukin in mediating the link between abdominal obesity and VTE.

Introduction

O besity, assessed by body mass index (BMI), is an established risk factor for venous thromboembolism (VTE), as demonstrated by a meta-analysis¹ and a recent large prospective study.² Likewise, prospective studies have also shown an association between abdominal obesity, evaluated by an increased waist circumference (WC) and VTE.^3

–6 Abdominal obesity is one of the criteria used to diagnose the metabolic syndrome, which is a cluster of risk factors for atherosclerosis that also includes hypertension, dyslipidemia, and insulin resistance.⁷ In the past few years, the metabolic syndrome has also been associated with VTE,^8

–12 and according to prospective data, among the components of the metabolic syndrome, abdominal obesity was the most important contributing risk factor for VTE.^13,14

WC correlates with abdominal visceral adipose tissue,¹⁵ and an increased WC might indicate the presence of a metabolically active tissue associated with a higher expression of tissue factor (TF), type 1 plasminogen activator inhibitor (PAI-1), and proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6).^16,17 Moreover, IL-6 is one of the chief stimulators of the hepatic production of acute-phase proteins such as C-reactive protein (CRP).¹⁸

The mechanisms by which abdominal obesity increases the risk of VTE are not fully elucidated. Inflammation could be one of the possible mechanisms, because abdominal obesity is related to an inflammatory state,¹⁷ and inflammation in turn might increase the risk of VTE, even though clinical data are somehow conflicting. For instance, while some studies, including those with prospective design, demonstrated a significant effect of inflammation, as reflected by increased CRP levels, on the risk of VTE,^19
–21 others found no link between CRP and a future event of VTE.^22

–25 Previously, we have shown in a case–control study that IL-6 levels were significantly associated with VTE,²⁶ which agreed with some,^27
–29 but not all, studies including a prospective cohort.^30,31

Taking into account the close relationship between abdominal obesity and inflammation and the potential role of these conditions in the development of VTE, we have sought to extend our investigation by exploring whether inflammation could contribute to the thrombosis risk from abdominal obesity. To the best of our knowledge, the potential influence of inflammatory markers on the relationship between abdominal obesity and VTE has not been evaluated thus far.

The purpose of the present study was to investigate in a case–control study the association of abdominal obesity and VTE in women and the effect of inflammatory markers IL-6 and CRP on this association.

Methods

Study population

Patients and controls of the present study are part of a case–control study on venous thrombotic disease that has been previously described.²⁶ Briefly, for this study, we included consecutive female outpatients aged between 18 and 60 years of age, who were admitted to the anticoagulation clinic of a university hospital in São Paulo with a first objectively confirmed episode of deep vein thrombosis (DVT) of the limbs or pulmonary embolism (PE), that occurred in the period between April, 2000, and August 2007. DVT was diagnosed by compression ultrasonography, and PE was diagnosed by helical computed tomography or combined ventilation/perfusion scan. Patients with overt malignancies, rheumatic and inflammatory bowel diseases, antiphospholipid syndrome, chronic renal or liver diseases, and cardiovascular and cerebrovascular diseases were excluded. VTE was defined as unprovoked if the event occurred in the absence of a known triggering condition such as surgery, trauma, fracture, immobilization, pregnancy, puerperium, and the use of oral contraceptive (OC). VTE was defined as provoked if it occurred in the presence of at least one of the previous conditions. Patients were treated with oral anticoagulant (OAC) for at least 6 months, and blood collection took place at least 1 month after the discontinuation of OAC and >7 months after the event of VTE. A total of 84 patients were included in the study, of whom 74 had DVT of the lower (n=71) and upper (n=3) limbs and 10 had symptomatic PE with or without clinical signs of DVT.

The control group was comprised of 100 healthy women recruited from acquaintances of patients and matched for age (±5 years). Controls had no biological relationship with the patients or with each other, no medical history of VTE, overt malignancies, rheumatic and inflammatory bowel diseases, chronic renal or liver diseases, and cardiovascular and cerebrovascular diseases. Exclusion criteria for both patients and controls also included pregnancy, delivery, surgery, or overt infection within 4 weeks prior to blood collection.

Patients and controls were from the same geographic region and had similar ethnic backgrounds. It is important to point out that the Brazilian population is constituted of different ethnic backgrounds, an admixture of Caucasians, Africans, and Native Americans,³² and patients and controls of the present study reflect Brazilian racial admixture. The study was approved by the local Ethics Committee on human research, and written informed consent was obtained from all study participants.

Blood collection and biochemical measurements

The date of blood collection (between October, 2006, and May, 2008) corresponded to the study inclusion for all patients and controls. After an overnight fasting of 12 h, venous blood was collected in ethylenediaminetetraacetic acid (EDTA) for IL-6 and in serum tubes for CRP measurements. Within 30 min, plasma was prepared by centrifugation for 15 min at 2000×g at room temperature and stored at −80°C until use.

A commercial highly sensitive enzyme-linked immunosorbent assay (ELISA) was used to measure plasma levels of IL-6 (Quantikine HS Human IL-6 Immunoassay, R&D Systems, Minneapolis, MN) in accordance with the manufacturer's protocol. The minimum detectable dose of the assay was 0.039 pg/mL.²⁶ Serum high-sensitivity (hs) CRP levels were measured on an Olympus AU 640 analyzer using an immunoturbidimetric method.²⁶

Data collection on anthropometric measures of obesity and other demographic factors

Anthropometric measures of obesity were determined at the time of blood collection. Height and weight were measured while the subjects were barefoot, wearing only light clothing. BMI was calculated as body weight in kilograms (kg) divided by the square of the height in meters (m). WC was measured in centimeters at the umbilical line. Current use of statins and smoking status were determined at the time of blood collection, along with information on self-reported diabetes mellitus and hypertension by the use of a standard questionnaire. Smoking status was defined by two categories—current smoker (regularly or occasionally) and nonsmoker.

Statistical analysis

Logistic regression model was used to calculate odds ratios (ORs) and 95% confidence interval (95% CI) as an estimate of the relative risk of VTE. Age, WC, and levels of IL-6 and hsCRP were entered in the logistic regression model as continuous covariates. WC was also categorized in quartiles based on control values, with the lowest quartile used as the reference level. In addition, women with abdominal obesity (WC ≥88 cm) and a marginally increased WC (80–88 cm)³³ were compared to those with a WC <80 cm.

Medians were presented with interquartile variation (25^th–75th percentile). Statistical differences between groups were tested by the Mann–Whitney test for continuous variables and by chi-squared or Fisher exact tests for categorical variables. Correlations between continuous parameters were calculated according to the Spearman rank correlation coefficient (r _s). A two-tailed P<0.05 was considered statistically significant. Statistical analyses were performed with the Statistical Package for the Social Sciences version 11.5 (SPSS Inc., Chicago, IL).

Results

A summary of the characteristics of thrombosis patients and controls is presented in Table 1. There was no significant difference between the two groups with regard to median age at study inclusion and the frequency of current smokers, use of statins, and self-reported hypertension and diabetes mellitus. Patients had a higher median WC and BMI than controls. Median levels of IL-6 and hsCPR were also significantly higher in patients than in controls. Seventy-one (84%) patients had provoked VTE, and most of the provoked events were related to exposure to exogenous (OC, n=35) or endogenous (pregnancy-related, n=12) sex hormones.

Table 1.

Characteristics of Study Participants

Variables	Patients n=84	Controls n=100	P
Age at study inclusion (years)	41 (32.2–49)	37 (29.2–45)	0.104
Age at the event of VTE (years)	37.5 (28.2–45.7)	—	—
Current smoker, n (%)	11 (13)	23 (23)	0.125
Current therapy with statins, n (%)	5 (6)	1 (1)	0.094
Self-reported hypertension, n (%)	20 (24)	14 (14)	0.129
Self reported diabetes mellitus, n (%)	1 (1.2)	1 (1)	1.000
WC (cm)	89 (84–98.7)	84 (78–94)	0.004
BMI (kg/m²)	27.7 (24.2–30.7)	25.3 (22.7–28.9)	0.016
hsCRP (mg/L)	2.64 (1.04–4.74)	1.72 (0.73–2.87)	0.015
IL-6 (pg/mL)	1.09 (0.54–2.11)	0.75 (0.37–1.26)	0.001

Metric variables are presented as medians and interquartile variation.

P values are calculated by Mann–Whitney, chi-squared, or Fisher exact tests.

VTE, venous thromboembolism; WC, waist circumference; BMI, body mass index; hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin-6.

As expected, in controls WC was positively correlated with BMI (r _s=0.916, P=0.0001), age (r _s=0.375, P=0.0001), and levels of hsCRP (r _s=0.360, P=0.0001) and IL-6 (r _s=0.416, P=0.0001). Likewise, in thrombosis patients, WC was correlated with BMI (r _s=0.896, P=0.0001), age (r _s=0.268, P=0.014), and levels of hsCRP (r _s=0.451, P=0.0001) and IL-6 (r _s=0.342, P=0.001).

Next, we investigated the association between VTE and an increased WC. In quartile-based analysis (Table 2), the ORs for VTE adjusted for age among subjects in the highest quartile of WC compared to the lowest quartile were 2.82 (95% CI 1.14–6.98; P=0.025). Risk estimates were, however, attenuated and became not significant when adjusted for IL-6 (OR 2.09, 95% CI 0.81–5.38; P=0.128). Table 3 shows that 51 patients (61%) and 43 (43%) controls had abdominal obesity. The thrombosis risk adjusted for age for a WC ≥88 cm compared to a WC <80 cm was 2.40 (95% CI 1.06–5.41; P=0.035). The association between VTE and abdominal obesity was attenuated after adjusting for IL-6 (OR 1.86, 95% CI 0.80–4.33; P=0.149). As shown in Tables 2 and 3, risk estimates did not substantially change with further adjustment for hsCRP.

Table 2.

Risk of Venous Thromboembolism in Women by Quartiles of Waist Circumference

WC (cm)	Cases n=84	Controls n=100	OR 1 (95% CI) ^a	OR 2 (95% CI) ^a	OR 3 (95%CI) ^a
<78	11	24	1^b	1^b	1^b
78–84	9	24	0.81 (0.28–2.30) P=0.687	0.82 (0.28–2.35) P=0.705	0.82 (0.28–2.38) P=0.717
84–94	27	25	2.22 (0.87–5.66) P=0.097	2.06 (0.79–5.32) P=0.138	2.05 (0.79–5.30) P=0.141
≥94	37	27	2.82 (1.14–6.98) P=0.025	2.09 (0.81–5.38) P=0.128	2.06 (0.80–5.32) P=0.136

OR 1, adjusted for age; OR 2, adjusted for age and IL-6 levels (continuous); OR 3, adjusted for age, IL-6 levels (continuous) and hsCRP levels (continuous).

Reference category.

WC, waist circumference; OR, odds ratio; CI, confidence interval; IL-6, interleukin-6; hsCRP, high-sensitivity C-reactive protein.

Table 3.

Risk of Venous Thromboembolism in Women by Definition of Abdominal Obesity

WC (cm)	Cases n=84	Controls n=100	OR 1 (95% CI) ^a	OR 2 (95% CI) ^a	OR 3 (95% CI) ^a
<80	13	29	1^b	1^b	1^b
80–88	20	28	1.52 (0.63–3.66) P=0.353	1.51 (0.62–3.70) P=0.363	1.51 (0.61–3.69) P=0.371
≥88	51	43	2.40 (1.06–5.41) P=0.035	1.86 (0.80–4.33) P=0.149	1.84 (0.79–4.27) P=0.159

OR 1, adjusted for age; OR 2, adjusted for age and IL-6 levels (continuous); OR, 3 Adjusted for age, IL-6 levels (continuous) and hsCRP levels (continuous).

Reference category.

WC, waist circumference; OR, odds ratio; CI, confidence interval; IL-6, interleukin-6; hsCRP, high-sensitivity C-reactive protein.

WC also was analyzed as a continuous variable. The risk of VTE adjusted for age increased by 1.38 (95% CI 1.08–1.77; P=0.010) for every 10-cm increment in WC. When IL-6 entered in the logistic regression model, the significant association between VTE and WC was no longer observed (OR 1.24, 95% CI 0.95–1.61; P=0.109), and additional adjustment for hsCRP had only a slight effect on risk estimates (OR=1.23, 95% CI 0.94–1.60; P=0.127). Of interest, IL-6 levels were positively associated with VTE. For every 1 pg/mL increment in IL-6 levels, the ORs adjusted for age and WC (continuous) increased by 1.56 (95% CI 1.08–2.25; P=0.019).

Among patients, the median time between the occurrence of VTE and blood collection was 34.5 months (range, 7–87 months). No correlation was found between time since the event of VTE and levels of inflammatory markers: IL-6 (r _s=0.076; P=0.491) and hsCRP (r _s=0.016; P=0.882).

Discussion

In this case–control study, we found that an increased WC was associated with a first event of VTE in a population comprised of relatively young women. However, the effect of an increased WC on the risk of VTE was attenuated and became no longer significant after adjustment for IL-6 levels, irrespective of whether WC was analyzed as a categorical or as a continuous variable.

Our findings are in agreement with previous studies in which an increased WC was associated with VTE. In a Swedish prospective cohort involving a random population sample of men born in 1913, a WC ≥100 cm was associated with an almost four-fold increased risk of VTE when compared with a waist size <100 cm.³ Recent large prospective Danish,⁴ American,⁵ and Norwegian⁶ studies found that WC, along with other anthropometric measures of obesity, such as BMI, hip circumference, and waist-to-hip ratio, were all predictors of the risk for VTE, even in multivariable models that included adjustment for age, smoking, and other variables, such as blood pressure, diabetes, and hormone therapy in women. Of interest, in the Norwegian cohort, among the anthropometric measures of obesity, WC exhibited the highest risk of a first event of VTE.⁶

In our results, however, the association between VTE and an increased WC was attenuated and it was no longer significant after adjustment for IL-6 levels. This finding might indicate that the association between VTE and abdominal obesity could, at least partially, be explained by an inflammatory response. This is biologically plausible, because visceral adipose tissue, as estimated by means of an increased WC in our study, is not only specialized in the storage and mobilization of lipids but it is also capable of expressing proinflammatory cytokines, such as IL-6 and TNF-α.¹⁷ For instance, among extremely obese subjects who underwent open gastric bypass surgery, IL-6 levels were significantly higher in the portal vein than in the peripheral arterial blood.³⁴ The portal circulation drains visceral fat, thus this finding suggests that visceral fat is an important site of IL-6 secretion.³⁴ Besides inducing a proinflammatory state, visceral adiposity is capable of expressing TF and PAI-1,¹⁶ therefore probably contributing to a procoagulant state.

In this case–control study, IL-6 levels were associated with VTE independently of an increased WC in women. Whether inflammation, as reflected by IL-6 and CRP levels, is only a consequence of the postthrombotic period or is also causally linked to VTE is so far an unsettled question. For instance, although in vitro studies show that CRP and IL-6 are capable of increasing the expression of TF,^35,36 the key inducer of blood coagulation, clinical data on the association of these inflammatory markers with venous thrombotic disease are conflicting and, particularly for IL-6, also limited. Whereas some studies demonstrated that IL-6 is associated with VTE,^27
–29 others, including a prospective cohort, found no relationship.^30,31 For CRP, there is strong evidence that this acute-phase protein is a predictor of arterial thrombotic events.³⁷ However, the role of CRP in VTE is uncertain, because the association of increased CRP levels and the future development of VTE is demonstrated by some,^19
–21 but not all, prospective studies.^22

–25

Interestingly, a randomized trial demonstrated that rosuvastatin significantly reduced the occurrence of symptomatic VTE in subjects with normal low-density lipoprotein cholesterol (LDL-C) but elevated hsCRP levels.³⁸ A recent metaanalysis of observational studies also showed lower rates of VTE associated with statin use.³⁹ These findings might favor the hypothesis of a potential role of inflammation in the development of VTE. Because LDL-C levels did not seem to influence the risk of VTE in prospective studies,^20,40 the protective effect of statins could be due to their nonlipid effects, which include not only antithrombotic but also antiinflammatory properties.⁴¹

Our study has limitations. First, the study design does not allow us to establish a causal effect of abdominal obesity or inflammation on the development of VTE. Because blood collection and measurement of WC took place after VTE, abdominal obesity and IL-6 levels could be consequences of the thrombotic event, without being causally related to each other or to VTE. Second, we studied a population characterized by racial admixture and composed of relatively young women, mostly with a provoked (hormone-related) event. It remains to be established whether our results, especially related to the influence of IL-6 on the relationship between abdominal obesity and VTE, could be generalized to other ethnicities, to older subjects, and to men. Finally, despite the limitations, the present study provides the notion for a potential role of inflammation in mediating the link between visceral fat and VTE, and supports the need for future studies with a prospective design to settle to what extent inflammation, and in particular IL-6, could contribute to the risk of VTE from abdominal obesity.

In conclusion, in this case–control study comprised of relatively young women, the association between VTE and an increased WC was attenuated after adjustment for IL-6 levels, therefore, suggesting a potential role of this cytokine in mediating the link between abdominal obesity and VTE.

Footnotes

Acknowledgments

The study was supported by a grant of the Fundação de Amparo à Pesquisa do Estado de São Paulo (no 2005/56799-0). The authors would like to thank all women who participated in the study.

Author Disclosure Statement

No competing financial interests exist.

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