Published online before print October 19, 2007, doi: 10.1161/ATVBAHA.107.155465
© 2008 American Heart Association, Inc.
Clinical and Population Studies |
Are Serum Carcinoembryonic Antigen Levels Associated With Carotid Atherosclerosis in Japanese Men?
From the Departments of Cardiovascular Medicine (N.I., R.N.), and Infectious Diseases (K.K), University of Tokyo Graduate School of Medicine, and Center for Multiphasic Health Testing and Services, Mitsui Memorial Hospital (Y.I., E-I.T., M.Y.), Tokyo, Japan.
Correspondence to Dr Nobukazu Ishizaka, Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan. E-mail nobuishizka-tky{at}umin.ac.jp
Abstract
Objective— Carcinoembryonic antigen (CEA), a serological marker of malignant tumors, may show a modest increase under some nonmalignant conditions, such as ageing and cigarette smoking. We have investigated whether serum CEA levels are associated with early carotid atherosclerosis.
Methods and Results— Cross-sectional data from 4181 male individuals who underwent general health screening were analyzed. The interquartile of cutoff values of serum CEA levels were 1.0, 1.6, and 2.5 ng/mL. Cigarette smoking was associated with increased serum CEA levels in a dose- and duration-dependent manner, and this association was more prominent in current than former smokers. Logistic regression analysis adjusted for age, body mass index, serum lipid and glucose profiles, white blood cell count, C-reactive protein, and smoking habits showed that the first, second, third, and fourth CEA quartiles were associated with carotid plaque with an odds ratio of 1 (reference), 1.25 (95% CI 1.03 to 1.52, P=0.023), 1.49 (95% CI 1.23 to 1.82 P<0.001), and 1.34 (95% CI 1.08 to 1.65, P=0.007), respectively. Although serum CEA levels were associated with metabolic syndrome, association between serum CEA and carotid plaque was significant in individuals without metabolic syndrome.
Conclusions— Serum CEA was associated with carotid atherosclerosis independently of atherogenic risk factors and markers of inflammation. Our data suggest that a slight elevation of CEA in current smokers, as well as in never smokers, may not be an innocuous observation from the viewpoint of atherosclerosis.
Association between serum levels of carcinoembryonic antigen (CEA) and carotid atherosclerosis was investigated by analyzing the cross-sectional data of 4181 Japanese men undergoing general health screening. Multivariate analysis showed that serum CEA levels were associated with carotid atherosclerosis that was independent of white blood cell count and hsCRP.
Key Words: tumor marker • carotid atherosclerosis • health screening • cigarette smoking
Carcinoembryonic antigen (CEA) is a glycoprotein with a molecular weight of 180 to 200 kDa.1 CEA is overexpressed in adenocarcinomas in the colon and other organs including pancreas, lung, prostate, urinary bladder, ovary, and breast; therefore, it is used as a serological marker of malignant tumors worldwide. On the other hand, serum CEA levels may increase under some nonmalignant conditions, for example, ageing, chronic renal failure, hypothyroidism, cigarette smoking, and some chronic inflammatory diseases,2–5 although the extent of CEA elevation in such nonmalignant conditions, when present, is usually only modest. Stimulation of monocytes and macrophages with CEA may result in an increase in the production of proinflammatory cytokines,6,7 which may subsequently upregulate adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, on the surface of vascular endothelial cells.7 These processes are thought to play a role in facilitating the metastasis of cancer cells. Interestingly, the early stage of atherosclerosis involves recruitment of inflammatory cells and their transendothelial migration, which is mediated by such cellular adhesion molecules on the surface of vascular endothelial cells.8 Of note, some epidemiological studies have demonstrated a possible association between neoplastic diseases that would potently increase serum CEA and coronary artery disease.9–11 Although modest elevation of serum CEA can be observed in apparently healthy individuals, especially in cigarette smokers,3,12 little information is available on the possible association between serum CEA and atherosclerosis in the general population. In the current study, by analyzing the data of Japanese men who underwent general health screening, we have investigated whether there is an association between serum CEA levels and early carotid atherosclerosis.
Methods
Study Subjects
The study was approved by The Ethical Committee of Mitsui Memorial Hospital and that of University of Tokyo, Graduate School of Medicine. In Japan, regular health check-ups for employees are legally mandated. Therefore, the majority of the subjects enrolled did not have serious health problems. Between January 2003 and April 2007, 7292 subjects (2471 women, 4821 men) underwent general health screening for whom data on carotid ultrasonography and fasting insulin were available. Data on cigarette smoking habit data were collected in a self reported questionnaire, and among 4821 male subjects, 4181 answered the questionnaire in full concerning the amount and the duration of smoking, and concerning the duration since they had stopped smoking at the time of the general health check if when they were former smokers. In the current study, subjects who had quit smoking for 1 month or less and those who had quit for more than 1 month before the time of the health screening were considered to be, respectively, current and former smokers, and those without a smoking history were considered to be never smokers. We were unable to identify any specific reasons for why the remaining 640 subjects failed to complete the questionnaire about their smoking status. We found that these the 640 individuals excluded were slightly but significantly older than those enrolled in the study (60±10 and 57±11 years old, respectively, P<0.001).
Laboratory Analysis
Blood samples were obtained from the subjects in the morning after an overnight fast, and the assays for variables analyzed in the current study were performed on the same day of blood draw without freezing the samples. Serum levels of total cholesterol (TC), HDL-cholesterol (HDL-C), and triglycerides (TG) were determined enzymatically. Serum uric acid was measured by the uricase-peroxidase method, and hemoglobin A1C was determined using the latex agglutination immunoassay. Plasma glucose was measured by the hexokinase method and serum insulin was measured by enzyme immunoassay. Serum CEA was measured using a commercially available immunometric chemiluminescent assay kit (Bayer Medical Co) with an interassay coefficient of variation ranging between 2.0 and 3.5%. High sensitivity C-reactive protein (hsCRP) concentration was measured by a turbidimetric immunoassay. Metabolic syndrome was diagnosed by National Cholesterol Education Program Adult Treatment Panel III13 with a modification and it was said to be present when 3 or more of following conditions were present: (1) fasting plasma glucose (FPG) 
110 mg/dL; (2) systolic blood pressure (SBP)/diastolic blood pressure 130/85 mm Hg; (3) TG 150 mg/dL; (4) HDL-C <40 mg/dL; and (5) BMI 25 kg/m2.
Carotid Ultrasonography
Carotid artery status was assessed by high resolution B-mode ultrasonography, using a machine (Sonolayer SSA270A, Toshiba, Japan) equipped with a 7.5-MHz transducer (PLF-703ST, Toshiba). The carotid arteries were examined bilaterally at the levels of the common carotid, the bifurcation, and the internal carotid arteries from transverse and longitudinal orientations by trained sonographers. The intima-media thickness (IMT) was measured using a computer-assisted method by experienced sonographers who were unaware of the subjects’ clinical and laboratory findings. Carotid intima-media wall thickening was said to occur when the IMT which was measured at the far wall of the distal 10 mm of the common carotid artery was 1.0 mm. Max IMT was defined as the thickest IMT in the scanned regions, and carotid plaque was defined when there was one or more focally thickened region(s) with the IMT of 1.1 mm.14 The difference in the prevalence of carotid plaque in the individuals undergoing general health screening in the current study and that reported in some previous studies15 would be explained by the difference in diagnostic criteria for carotid plaque.
Statistical Analysis
The data in this study were analyzed by the 
2 test, ANOVA with Bonferroni post-hoc analysis, and univariate and multivariate logistic regression analysis using computer software, StatView ver. 5.0 (SAS Institute). A value of P<0.05 was taken to be statistically significant. Results are expressed as the mean±SD unless stated otherwise.
Results
Baseline Characteristics
The age of the subjects enrolled ranged from 21 to 89 years with a median of 57 years. Former smokers were significantly older (P<0.001) whereas current smokers were significantly younger (P<0.001) than never smokers (Table 1). Carotid plaque was found in 632/1556 (41%) of never smokers, 678/1427 (48%) of former smokers, and 539/1198 (45%) of current smokers. Carotid intima-media thickening was found in 125/1556 (8%) of never smokers, 161/1427 (11%) of former smokers, and 114/1198 (10%) of current smokers. Pearson’s correlation coefficients between CEA and various variables are described in Table 2. Age, WBC count, FPG, hemoglobin A1c showed only a weak correlation with CEA with the correlation coefficients ranging between 0.1 and 0.2; however, the correlation between serum CEA and hsCRP was not statistically significant (Table 2). The median (range) of the first to fourth quartiles of CEA values was 0.5 (0.5 to 0.7), 1.0 (0.8 to 1.2), 1.6 (1.3 to 1.9), and 2.5 (2.0 to 37.2) ng/mL, respectively. Of the 4181 subjects enrolled, 489 (12%) and 36 (0.9%) had CEA levels greater than 2.5 ng/mL (upper normal limit) and 5.0 ng/mL, respectively.
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Smoking Habits and Serum CEA Levels
In current smokers, CEA levels increased according to the amount and duration of smoking, whereas this tendency was less apparent in former smokers (Figure). In smokers, the prevalence of the highest CEA quartile was found to increase with the daily number of cigarettes smoked as well as with smoking duration (Table 3). This trend was more prominent in current smokers than in former smokers. The odds ratio for the highest CEA quartile tended to get smaller with the length of smoking cessation in former smokers; however, after adjusting for age, former smokers who had last smoked 5 years ago at the time of assessment were found to still have a greater prevalence of the highest serum CEA quartile as compared with never smokers (Table 3), in agreement with a previous observation.16
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Association Between CEA and Carotid Atherosclerosis
Of the individuals in the first to fourth CEA quartiles, carotid plaque was found in 343/1051 (33%), 613/1071 (43%), 532/1074 (50%), and 516/985 (52%), respectively, and carotid intima-media thickening was found in 73/1051 (7%), 92/1071 (9%), 101/1074 (9%), and 134/985 (14%), respectively. When the lowest serum CEA quartile was used as a reference, logistic regression analysis showed that the higher serum CEA quartiles were positively associated with carotid plaque even after adjusting for age, SBP, lipid and glucose data, smoking status, and the inflammatory markers, WBC and hsCRP (Model 4 in Table 4). In this model, hsCRP was also significantly associated with carotid plaque with an odds ratio of 1.26 (95% CI 1.04 to 1.54, per 1 mg/dL increase, P=0.019). In contrast, after adjusting for the same variables, the association between the second, third, and fourth serum CEA quartiles with carotid intima-media thickening was not significant with an odds ratio of 0.92 (95% CI 0.66 to 1.29), 0.84 (95% CI 0.60 to 1.18), and 1.10 (0.79 to 1.55), respectively. Of 4173 study subjects, 3890 (93%) had a fasting glucose level of less than 140 mg/dL and were not taking antidiabetic medication. In these subjects, the second, third, and fourth serum CEA quartiles were associated with carotid plaque with an odds ratio of 1.28 (95% CI 1.05 to 1.57, P=0.013), 1.49 (95% CI 1.22 to 1.82, P=0.0001), and 1.32 (1.06 to 1.64, P=0.013), respectively, after adjusting for HOMA-IR and the covariates used in Model 4 of Table 4. The odds ratio of each serum CEA quartile for the carotid plaque in never, former, and current smokers is described in Table 5. The association between the highest serum CEA quartile and carotid plaque did not reach statistical significance after this subdivision.
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Metabolic syndrome was found in 783 (19%) individuals. After adjusting for age, logistic regression analysis showed that the first to fourth CEA quartiles were associated with metabolic syndrome with an odds ratio of 1 (reference), 1.04 (95% CI 0.83 to 1.31, P=0.72), 1.15 (95%CI 0.92 to 1.44, P=0.21), and 1.40 (95% CI 1.12 to 1.75, P=0.004), respectively. Among the 3383 individuals who did not have metabolic syndrome, the first to fourth serum CEA quartiles were associated with carotid plaque with an odds ratio of 1 (reference), 1.04 (95% CI 0.83 to 1.31, P=0.72), 1.48 (95% CI 1.20 to 1.84, P<0.001), and 1.30 (95% CI 1.02 to 1.64, P=0.031), respectively. We then investigated the association between serum CEA and increased insulin resistance, defined here as the highest HOMA-IR quartile (HOMA-IR >2.15), in 3890 individuals who had a fasting glucose level of less than 140 mg/dL and were not taking antidiabetic medication. We found that the first to fourth CEA quartiles were associated with the highest HOMA-IR quartile with an odds ratio of 1 (reference), 1.26 (95% CI 1.02 to 1.56, P=0.032), 1.30 (95% CI 1.05 to 1.64, P=0.015), and 1.32 (95% CI 1.05 to 1.65, P=0.015), respectively.
Discussion
In the current study, we have investigated the possible association between serum CEA levels and carotid atherosclerosis by analyzing the data of 4181 male individuals who underwent general health screening. As compared with the lowest serum CEA quartile, individuals in the 3 higher serum CEA quartiles had significantly increased prevalence of carotid plaque (Table 3). This association remained statistically significant even after adjusting for age, SBP, FPG, BMI, LDL-C, HDL-C, TG, smoking status, WBC, and hsCRP. In the smokers, especially the current smokers, serum CEA levels were increased according to the daily number of cigarettes smoked and duration of smoking (Figure, Table 3). We found previously that circulating WBC count, a marker for systemic inflammation, was also increased according to the amount and duration of smoking,17,18 and increased WBC count was a risk factor for carotid atherosclerosis independent of other conventional risk factors.19 Therefore, the association between serum CEA levels and carotid atherosclerosis might be confounded by that between circulating WBC count and atherosclerosis. However, the association between CEA and carotid plaque remained statistically significant after adjustment for WBC count and hsCRP (Model 4, Table 4).
What is the possible underlying mechanism, if present, which would explain the observed link between serum CEA and carotid plaque? First, serum CEA was associated with metabolic syndrome and increased insulin resistance. Because both of these conditions can increase the risk for carotid atherosclerosis, increased insulin resistance or metabolic syndrome may explain the observed link between serum CEA and carotid plaque. On the other hand, the association between serum CEA and carotid plaque remained statistically significant after adjustment for HOMA-IR, and this association was found to be statistically significant among individuals who did not have metabolic syndrome, suggesting that the association was, at least in part, independent of increased insulin resistance or metabolic syndrome. Second, several previous studies have suggested that CEA may stimulate the monocytes/macrophages to release proinflammatory cytokines, which eventually lead to the induction of adhesion molecules on the surface of vascular endothelial cells, which may facilitate the metastasis of malignant cells.6,7,20 Interestingly, it has been found that ICAM-1 and VCAM-1 levels correlate with serum CEA levels in colorectal cancer patients.21 Recruitment of inflammatory cells from the circulation after the induction of adhesion molecules on the surface of vascular endothelial cells is postulated to be an early phase of atherosclerosis8; therefore, enhanced expression of certain adhesion molecules on vascular cells may explain the observed link between CEA and carotid plaque. Third, serum CEA may be increased in patients with chronic inflammatory disorders22 such as inflammatory bowel disease,23,24 collagen disease, and chronic viral hepatitis,25 although this idea remains controversial.26 Patients with such chronic inflammatory diseases may have an increased risk of carotid atherosclerosis.27–29 It is possible that a similar immune-inflammatory reaction, such as activation of the CD40/CD40 ligand system, might play a crucial role in both atherosclerosis and inflammatory diseases.30,31 Whether serum CEA levels are associated with blood levels or membrane-bound levels of adhesion molecules and CD40 ligand should be investigated in future studies. Although cigarette smoking increases serum CEA levels without evidence of malignant diseases,2 elevated serum CEA levels may be associated with a more accelerated decline in the percent forced expiratory volume in one second (FEV1%) value among smokers.32 Thus, our data may provide additional evidence that an increase in serum CEA levels among cigarette smokers may not be an innocuous observation also from the viewpoint of atherosclerosis.
This study has several potential limitations. First, we analyzed only men in the current study, because the number of female subjects who had a smoking history was much smaller during the study period. Second, because of the cross-sectional nature of the study, we cannot determine whether there is a causal or resultant relationship between the elevation of serum CEA and carotid plaque. Third, in addition to cigarette smoking, serum CEA is known to be elevated in other nonmalignant conditions, such as hypothyroidism,4 and end-stage lung diseases.33 We did not include these disorders as confounding variables, because their prevalence is considered to be very low among the study population.
In conclusion, we have shown that cigarette smoking increases serum levels of CEA in a dose- and duration-dependent manner in Japanese men who underwent general health screening. The increase in serum CEA was found to be associated with an increased prevalence of carotid plaque independent of blood pressure, fasting glucose, serum lipids, and inflammatory markers. Our data suggested that an elevation of CEA in smokers may not be an innocuous observation from the viewpoint of atherosclerosis.
Acknowledgments
The work was supported in part by a Grant from the Smoking Research Foundation.
Disclosures
None.
Footnotes
Original received July 17, 2007; final version accepted October 2, 2007.
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