OBJECTIVE: To elucidate the underlying mechanisms between C-reactive protein (CRP) and cardiovascular disease, we exa-mined the association of circulating CRP in healthy reference range (≤1.0 mg/dl) measured by high-sensitive CRP assay with the metabolic syndrome (MS).
DESIGN: Cross-sectional study of circulating CRP in adult men.
SUBJECTS: A total of 3692 Japanese men aged 34–69 y.
MEASUREMENTS: Serum CRP, total cholesterol, triglycerides, LDL-cholesterol, fasting glucose, fasting insulin, uric acid, systolic blood pressure, diastolic blood pressure, and body mass index (BMI).
RESULTS: There was a statistically significant positive correlation between CRP and BMI (r=0.25), total cholesterol (r=0.096), triglycerides (r=0.22), LDL-cholesterol (r=0.12), fasting glucose (r=0.088), fasting insulin (r=0.17), uric acid (r=0.13), systolic blood pressure (r=0.12), and diastolic blood pressure (r=0.11), and a significant negative correlation of CRP with HDL-cholesterol (r=0.24). After adjusting for age, smoking, and all other components of MS, obesity, hypertriglyceridemia, hyper-LDL-cholesterolemia, diabetes, hyperinsulinemia, and hyperuricemia were significantly associated with both mildly (≥0.06 mg/dl) and moderately (≥0.11 mg/dl) elevated CRP. Compared with men who had no such components of the MS, those who had one, two, three, four, and five or more components were, respectively, 1.48, 1.84, 1.92, 3.42, and 4.17 times more likely to have mildly elevated CRP levels (trend P<0.001). As for moderately elevated CRP, the same association was observed.
CONCLUSIONS: These results indicate that a variety of components of the MS are associated with elevated CRP levels in a systemic low-grade inflammatory state.
C-reactive protein (CRP), the major acute-phase protein, is an exquisitely sensitive and objective marker of bacterial infection, physical tissue damage, and other inflammatory conditions.1 CRP is regulated by the proinflammatory cytokines including interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and especially interleukin-6 (IL-6), and is exclusively produced by hepatocytes.2,3,4 As a general rule, 1.00 mg/dl has been used as the cutoff point to signify the clinically important levels. Recently, however, some studies5,6,7,8,9,10,11,12,13 have reported that elevated levels of CRP with a new high-sensitive CRP assay, although still for the most part in the healthy reference range, were associated with increased risk of future cardiovascular events. CRP is in the course of being identified as an independent, prospective risk factor of cardiovascular disease.16
The metabolic syndrome (MS) is characterized by the clustering of the following components based on insulin resistance: hypertension, impaired glucose tolerance, hyperinsulinemia, increased level of triglyceride, decreased level of HDL cholesterol, and obesity.15,16 It is well known that the MS is associated with a greatly increased risk of cardio-vascular disease.17
The link between CRP and cardiovascular disease is thought to be indirect. Circulating CRP only reflects the extent of nonspecific stimuli such as smoking, vascular injury, necrosis, infectious agents, and atherosclerosis. The association of CRP with MS also remains unknown. Therefore, we investigated the association of CRP with the components of the MS and their clustering in a large population-based sample to epidemiologically elucidate the underlying pathogenic mechanisms between CRP and cardiovascular disease.
Subjects and methods
We studied a population of 3739 Japanese men belonging to two workplaces in Nagoya, Japan, who responded to a self-reported questionnaire including medical history and lifestyle characteristics, underwent a physical examination including height and weight, and blood pressure measured sitting after 5 min rest, and provided a collection of fasting blood samples. A total of 47 subjects with CRP levels >1.00 mg/dl, indicating clinically relevant inflammatory conditions, were excluded from the study, but people with a history of chronic disease such as diabetes, cancer, or ischemic heart disease, were not excluded. Finally, the current analysis is restricted to 3692 men with complete data on all components of the MS and serum CRP concentration. All subjects in the study gave their informed consent to the use of personal information for analysis. This study protocol was approved by the Ethics Committee of Nagoya University Graduate School of Medicine, Nagoya, Japan.
Venous blood samples were drawn from each sample after 8-h or over fasting. The samples were stored at −80°C until assay. Total cholesterol (TC) and triglycerides (TG) were determined enzymatically. HDL-cholesterol (HDL-C) was measured by the phosphotungstate method. LDL cholesterol (LDL-C) was measured by the enzymatic method. Glucose was enzymatically determined by the hexokinase method. Insulin was measured by immunoradiometric assay. Uric acid (UA) was measured enzymatically. CRP was measured by using nephelometry, a sensitive immunoassay based on latex particle agglutination (N-assay LA CRP-S C-type, Nittobo). The assay is sensitive enough to detect 0.06–20.0 mg/dl of CRP. Undetectable CRP values were recorded as 0.05 mg/dl. Coefficients of variation for repeated measurements of CRP were 4.80% in the range of ≤1.0 mg/dl.
The characteristics of MS components were defined by the following cutoff limits: obesity; body mass index (BMI) calculated as weight (kilograms) divided by height (meters) squared, ≥26.4 kg/m2 according to the criteria recommended by the Japan Society for the Study of Obesity. Hypercholesterolemia: TC ≥5.7 mmol/l and/or medication for hyperlipidemia; hypertriglyceridemia: TG≥1.7 mmol/l and/or medication for hyperlipidemia; hypo-HDL-cholesterolemia: HDL-C <1.0 mmol/l; hyper-LDL-cholesterolemia: LDL-C ≥3.6 mmol/l; diabetes: fasting blood glucose≥7.0 mmol/l and/or medication for diabetes mellitus; hyperinsulinemia: serum insulin≥7 mU/l (upper quartile of the baseline distribution of serum insulin); hyperuricemia: UA≥416 μmol/l and/or medication for hyperuricemia; hypertension: systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure (DBP) ≥90 mmHg and/or medication for hypertension.
Spearman's correlation analysis was performed between CRP values and the values of each MS component.
The subjects were divided into two categories based on CRP concentration, undetectable (≤0.05 mg/dl) and mildly elevated (≥0.06 mg/dl). They were also divided into two categories based on the upper quartile value of the baseline distribution of CRP concentration, a moderately elevated CRP concentration of 0.11 mg/dl or more. Two outcome variables were defined: a mildly elevated CRP level (≥0.06 mg/dl) that was compared with an undetectable CRP, and a moderately elevated CRP level (≥0.11 mg/dl) that was compared with a CRP level of no more than 0.10 mg/dl. The association between each component of the MS and CRP was examined using age (years)- and smoking (never, former, or current)-adjusted unconditional logistic regression models (Model 1). Subsequent models included covariates for age, smoking status, and all other components of the MS (Model 2). We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for each MS component as an above-mentioned categorical variable. Subjects were grouped as follows to examine the association between the clustering of MS and CRP: no (reference category), two, three, four, five, or more components of MS. We also calculated ORs for the degree of the clustering components of MS. All tests were conducted using LOGISTIC procedures in SPSS software, version 10.0 for Windows.18
Mildly elevated (0.06–0.10 mg/dl) and moderately elevated (0.11–1.00 mg/dl) CRP levels were present in 27.4 and 25.2%, respectively. Other characteristics of the subjects and the distribution of the components of MS in the subjects are shown in Table 1.
Spearman's rank correlation coefficients between CRP and the components of MS are shown in Table 2. There was a statistically significant unadjusted positive correlation (P<0.0001) between CRP and each of age, BMI, TC, TG, LDL-C, fasting glucose, fasting insulin, UA, SBP, and DBP, and a significant negative correlation of CRP with HDL-C (P<0.0001). The strongest correlation (r=0.25) was observed between CRP and BMI.
The adjusted ORs for mildly and moderately elevated CRP by categorized components of MS are shown in Table 3. Each component of MS was significantly associated with both mildly and moderately elevated CRP, and obesity presented the strongest association with an OR of 2.70 (95% CI: 2.11–3.44) and 2.75 (95% CI: 2.19–3.46) for mildly and moderately elevated CRP, respectively, after adjusting for age and smoking (Model 1). This is in accordance with the strongest positive correlation of BMI and CRP seen in Spearman's rank correlation. After adjusting for age, smoking, and all other components of MS (Model 2), obesity, hypertriglyceridemia, hyper-LDL-cholesterolemia, diabetes, hyperinsulinemia, and hyperuricemia were still significantly associated with mildly elevated CRP, and obesity, hypertriglyceridemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia, diabetes, hyperinsulinemia, hyperuricemia, and hypertension were significantly associated with moderately elevated CRP. Obesity still showed the strongest association with mildly and moderately elevated CRP by an OR of 1.78 (95% CI: 1.38–2.32) and 1.91 (95% CI: 1.49–2.44), respectively. Hypercholesterolemia was not significantly associated with elevated CRP. Moreover, multiple linear regression analysis, performed with log-transformed CRP level as the dependent variable and with age, smoking status, BMI, LDL-C, HDL-C, TG, UA, systolic blood pressure, glucose, log-transformed insulin levels as the continuous independent variables, showed the significant and independent associations of CRP levels with age, smoking, BMI, LDL-C, HDL-C, TG, UA, and glucose (data not shown). To resolve the question of whether CRP in the presence of MS components is higher because of obesity or insulin resistance, we also compared levels of CRP and insulin in tertiles of BMI. There was the significant and positive association between elevated CRP and hyperinsulinemia in both lowest and highest tertiles of BMI but not in middle tertile (data not shown).
Table 4 shows the ORs for mildly and moderately elevated CRP by clustering components of MS after age and smoking adjustment. Compared with men who had no such component, those who had 1, 2, 3, 4, and 5 or more components were 1.48 (95% CI: 1.21–1.81), 1.84 (95% CI: 1.51–2.24), 1.91 (95% CI: 1.54–2.39), 3.42 (95% CI: 2.66–4.41), 4.17 (95% CI: 3.21–5.41) times more likely, respectively, to have mildly elevated CRP levels. The test for trend by a comparison of adjacent categories was significant (P<0.001). As for moderately elevated CRP, the same association was observed.
These above-mentioned associations between CRP and MS were unchanged in the analysis including the subjects with the CRP levels >1.0 mg/dl.
We reported a positive association between serum CRP levels and MS in a large-scale population-based study of the Japanese. Adjusting only for age and smoking, a statistically significant association of elevated CRP was found with each component of MS. Furthermore, after adjustment for age, smoking, and all other components of MS, obesity, hypertriglyceridemia, hyper-LDL-cholesterolemia, diabetes, hyperinsulinemia, and hyperuricemia were still significantly associated with both mildly and moderately elevated CRP, and both hypo-HDL-cholesterolemia and hypertension were significantly associated only with moderately elevated CRP. The strongest association of elevated CRP was with obesity.
Some previous studies12,13,19,20,21,22,23 have shown a positive association between CRP and obesity. The mechanisms for the apparent association between CRP and BMI or obesity are unclear, but several explanations are possible.24,25,26 The main modulators of CRP are IL-1, IL-6, and TNF-α. TNF-α messenger RNA has been reported to be overproduced by adipocytes from obese humans,24 and a circulating concentration of TNF-α increases in such people.27,28 Since TNF-α is a potent inducer of IL-6 in various cells, serum levels of IL-6, which promotes the production of CRP,29 is raised in obese individuals.30 This fact may explain the positive association between CRP and obesity. CRP may indirectly reflect the association between other factors such as TNF-α, IL-6, and obesity.
Some studies have reported the association between CRP and other MS components besides obesity. The Cardiovascular Health Study12 showed a significant positive association between CRP and BMI, TG, and UA, and a significant negative association with HDL-C. Mendall et al22 reported that CRP was associated with TC, TG, and glucose, and was negatively associated with HDL-C. In the population-based monitoring trends and determinants in cardiovascular disease study (MONICA study)13 composed of men aged 45–65 y, CRP increased significantly in parallel with BMI and blood pressure, and decreased with increase of HDL-C. Subjects with diabetes had significantly higher CRP concentrations than those without it. These findings also emerged in our study.
Several mechanisms may link CRP with MS. First, CRP levels have been considered to reflect the extent of the inflammatory reactions in atherosclerotic vessels which were promoted by MS.31 Thus, by virtue of its acute-phase behavior, CRP is a marker for the severity and progression of atherosclerotic processes in the vessels.32,33,34 Second, local or circulating proinflammatory cytokines, such as IL-1, TNF-α, and IL-6, are detectable in atherosclerosis.35 Accordingly, these cytokines may be the real risk factor, whereas serum CRP merely reflects the release of these mediators. Most of the explanations for the association between CRP and MS discussed above maintain that CRP levels are indirectly linked to the extent and severity of the atherosclerotic process. In this study, hypertriglyceridemia, hypo-HDL-cholestelolemia, hyper-LDL-cholesteloremia, hyperglycemia, hyperuricemia, and hypertension were related to elevated CRP independently of obesity. The mechanisms through which each component of MS increases CRP levels directly are not yet biochemically established. They are well known to play important roles in the atherosclerotic process independently of obesity and may increase CRP levels indirectly through atherosclerosis. However, it may not be appropriate to pay attention only to isolated variables because MS represents a cluster of simultaneously occurring components. Indeed, this study found a strong association of elevated CRP with a number of MS manifestations.
The strong point of this study is that the association between insulin and CRP levels was examined in a large-scale population-based study. In the report from the ECAT Angina Pectoris Study36 involving 1484 patients, serum insulin concentration was significantly correlated with CRP (r=0.12, P<0.001). This agrees with our findings that serum insulin was significantly correlated with CRP (r=0.17, P<0.001), and that hyperinsulinemia was significantly associated with elevated CRP. As for the issues of whether CRP in the presence of MS components is higher because of obesity or insulin resistance, or whether insulin resistance is a primary driver in the observed relations between elevated CRP and MS components, we performed the additional analyses. There was the significant and positive association between elevated CRP and hyperinsulinemia in both lowest and highest tertiles of BMI but not in middle tertile. Moreover, multiple linear regression analysis, which contains CRP levels as the dependent variable and all components of MS as the independent variable, showed the significant associations of CRP with BMI, LDL-C, HDL-C, TG, UA, and glucose, but showed no association between CRP and insulin levels. We could not elucidate whether elevated CRP levels in MS components are induced by obesity or insulin resistance. However, these results suggested the positive associations between CRP and MS components independently of obesity and insulin resistance. They also suggested that CRP in hyperinsulinemia may increase through the MS components based on insulin resistance or through atherosclerosis which is resulted from the MS.
In summary, we found an association between elevated CRP and each MS, especially obesity, hypertriglyceridemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia, diabetes, hyperinsulinemia, hyperuricemia, and hypertension. Furthermore, we also found that the strong association of elevated CRP is presented with a number of manifestations of MS. This finding indicates that MS, especially the clustering of its components, is associated with a systemic low-grade inflammation which may cause the progression of atherosclerosis. Recently, some studies37,38,39 have reported the possibility that CRP might directly interact with atherosclerotic vessels or ischemic myocardium by activation of the complement system. Unraveling the molecular, clinical, and epidemiological background of the association among CRP, MS, and cardiovascular disease may provide new directions for the prevention of atherosclerosis and cardiovascular events.
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We are grateful to Dr Noboru Okamoto (Aichi San-no-maru Hospital), Dr Tsutomu Yoshida (Department of Public Health, Fujita Health University School of Medicine), Dr Takashi Kawamura (Kyoto University Center for Student Health), and Dr Junji Toyama (Aichi Prefectural Owari Hospital) for their cooperation in conducting the survey and collecting information for this study.
This work is supported in part by a grant to Hideaki Toyoshima (09470112), Koji Tamakoshi (12670352), and Hiroshi Yatsuya (13770192) from the Ministry of Education, Culture, Sports, and Science and Technology.
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