In subcohort A (from CEA to MetS), 1,370 participants developed incident MetS from January 2010 to December 2015. The average follow-up time was 26.39 months (SD=12.24). Participants with Hyper-CEA were older and had significant higher SBP, DBP, FPG and WBC measures, lower BMI, triglyceride, HDL-C, ALT and blood uric acid values and greater percentage of smoking (Table 1). The incidence density of MetS was 84.56 per 1000 person-years among individuals with Hyper-CEA at baseline and 99.28 per 1000 person-years among those without (Table 2).
In subcohort B, 596 participants developed incident Hyper-CEA from January 2010 to December 2015 and the average follow-up time was 28.03 months (SD=12.84). At baseline, participants with MetS were older, and had significantly higher SBP, DBP, BMI, FPG, triglyceride, ALT, AST, gamma-glutamyl transpeptidase, blood uric acid, hemoglobin, WBC, smoking and alcohol intake, lower HDL-C and serum creatinine level (Table 1). The incidence densities of Hyper-CEA among individuals with or without MetS were 33.42 per 1000 person-years and 29.13 per 1000 person-years, respectively (Table 2).
Table 2. The follow-up information of subcohort A and subcohort B
|
Characteristics
|
Subcohort A (from CEA to MetS)
|
|
Subcohort B (from MetS to CEA)
|
High-CEA (N=551)
|
Norm-CEA (N=5888)
|
|
MetS (N=2451)
|
Non-metS (N=6082)
|
follow-up time (months)
|
22.94 ± 9.40
|
26.72 ± 12.42
|
|
28.24 ± 12.95
|
27.52 ±12.56
|
incident frequency (%)
|
88 (15.97)
|
1282 (21.77)
|
|
185 (7.55)
|
411 (6.76)
|
incidence density (per 1000 person-years)
|
84.56
|
99.28
|
|
33.42
|
29.13
|
Subcohort A showed the MetS incident in High-CEA group and Norm-CEA group; subcohort B showed the Hyper-CEA incident in MetS group and Non-metS group. CEA: carcinoembryonic antigen; Hyper-CEA: elevated serum CEA level above the reference range; Norm-CEA: within the normal reference ranges; MetS: metabolic syndrome; Non-MetS: without metabolic syndrome.
In subcohort A, participants with Hyper-CEA had 0.89 (95% CI, 0.71 to 1.12)-fold hazard ratio for developing MetS (P =0.326) than without Hyper-CEA at baseline, adjusted for age, smoking, alcohol intake, the components of MetS, blood uric acid, ALT, AST, gamma-glutamyl transpeptidase, hemoglobin and white blood cell count (Table 3, supplemental Table S3). In different age and smoking strata, Hyper-CEA did not have an effect on MetS, either (Table 4).
In subcohort B, the associations were similar when adjusting for different sets of confounders (Table 3). After adjusting for age, smoking, AST, gamma-glutamyl transpeptidase, serum creatinine and WBC, the hazard ratio of MetS for incident Hyper-CEA was 1.02 (95% CI, 0.84 to 1.22, P=0.864) comparing without MetS at baseline (Table 3, supplemental Table S4). In the stratified analysis (Table 5), participants aged > 65 years and nonsmoking, the adjusted hazard ratio of MetS for Hyper-CEA was 1.87 (95% CI, 1.09 to 3.20; P=0.022).
Table 3. Crude and adjusted hazard ratios (95% CI) of Hyper-CEA in MetS and MetS in Hyper-CEA
Characteristics
|
Hazard ratio (95% CI)
|
Model 1 a
|
Model 2 b
|
Model 3 c
|
Model 4
|
Subcohort A
|
|
|
|
|
Hyper-CEA
|
0.94 (0.76, 1.18)
|
0.86 (0.69, 1.07)
|
0.83 (0.66, 1.04)
|
0.89 (0.71, 1.12)d1
|
Norm-CEA
|
1.00
|
1.00
|
1.00
|
1.00
|
Subcohort B
|
|
|
|
|
MetS
|
1.17 (0.99, 1.40)
|
1.05 (0.88, 1.25)
|
1.04 (0.87, 1.24)
|
1.02 (0.84, 1.22)d2
|
Non-MetS
|
1.00
|
1.00
|
1.00
|
1.00
|
a: Model 1, crude model without adjusting for any confounders;
b: Model 2, adjusted for age;
c: Model 3, adjusted for age and smoking;
d1: Model 4 in subcohort A, adjusted for age, smoking, alcohol intake, the components of MetS, blood uric acid, Alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, hemoglobin and white blood cell count;
d2: Model 4 in subcohort B, adjusted for age, smoking, alanine aminotransferase, serum creatinine and white blood cell count.
CEA: carcinoembryonic antigen; Hyper-CEA: elevated serum CEA level above the reference range; Norm-CEA: within the normal reference ranges; MetS: metabolic syndrome; Non-MetS: without metabolic syndrome.
Table 4. The hazard ratio (95%CI) of Hyper-CEA for MetS in subcohort A by stratified analysis
Characteristics
|
Model 1a
|
|
Model 2b
|
Hazard ratio (95%CI)
|
P value
|
Hazard ratio (95%CI)
|
P value
|
Age ≤ 45 y, nonsmoking (n=2498)
|
|
|
|
|
Hyper-CEA
|
1.14 (0.69, 1.91)
|
0.607
|
|
0.99 (0.58, 1.7)
|
0.981
|
Norm-CEA
|
1.00
|
|
|
1.00
|
|
Age > 45 y and ≤65 y, nonsmoking(n=1107)
|
|
|
|
|
Hyper-CEA
|
0.70 (0.41, 1.18)
|
0.18
|
|
0.69 (0.4, 1.2)
|
0.189
|
Norm-CEA
|
1.00
|
|
|
1.00
|
|
Age > 65 y, nonsmoking (n=335)
|
Hyper-CEA
|
0.90 (0.46, 1.79)
|
0.768
|
|
1.01 (0.48, 2.15)
|
0.971
|
Norm-CEA
|
1.00
|
|
|
1.00
|
|
Age ≤ 45 y, smoking (n=1527)
|
Hyper-CEA
|
0.84 (0.49, 1.46)
|
0.543
|
|
0.80 (0.45, 1.42)
|
0.439
|
Norm-CEA
|
1.00
|
|
|
1.00
|
|
Age > 45 y and ≤65 y, smoking (n=855)
|
|
|
|
|
Hyper-CEA
|
0.83 (0.56, 1.23)
|
0.35
|
|
0.98 (0.64, 1.51)
|
0.927
|
Norm-CEA
|
1.00
|
|
|
1.00
|
|
Age > 65 y, smoking (n=86)
|
|
|
|
|
|
Hyper-CEA
|
0.56 (0.12, 2.54)
|
0.452
|
|
1.37 (0.15, 12.45)
|
0.779
|
Norm-CEA
|
1.00
|
|
|
1.00
|
|
a Model 1 was the unadjusted hazard ratio; b Model 2 was adjusted for age, alcohol intake, the components of MetS, blood uric acid, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, hemoglobin and white blood cell count. CEA: carcinoembryonic antigen; Hyper-CEA: elevated serum CEA level above the reference range; Norm-CEA: within the normal reference ranges; MetS: metabolic syndrome.
Table 5. The hazard ratio (95%CI) of MetS for Hyper-CEA in subcohort B by stratified analysis
Characteristics
|
Model 1a
|
|
Model 2b
|
Hazard ratio (95%CI)
|
P value
|
|
Hazard ratio (95%CI)
|
P value
|
Age ≤ 45 y, nonsmoking (n=3052)
|
|
|
|
|
MetS
|
0.92 (0.59, 1.44)
|
0.720
|
|
0.85 (0.53, 1.35)
|
0.489
|
Non-MetS
|
1.00
|
|
|
1.00
|
|
Age > 45 y and ≤65 y, nonsmoking (n=1660)
|
MetS
|
1.31 (0.92, 1.89)
|
0.137
|
|
1.40 (0.96, 2.05)
|
0.083
|
Non-MetS
|
1.00
|
|
|
1.00
|
|
Age > 65 y, nonsmoking (n=523)
|
MetS
|
1.78 (1.08, 2.92)
|
0.023
|
|
1.87 (1.09, 3.20)
|
0.022
|
Non-MetS
|
1.00
|
|
|
1.00
|
|
Age ≤ 45 y, smoking (n=2000)
|
MetS
|
0.98 (0.66, 1.45)
|
0.929
|
|
0.90 (0.59, 1.36)
|
0.616
|
Non-MetS
|
1.00
|
|
|
1.00
|
|
Age > 45 y and ≤65 y, smoking (n=1147)
|
MetS
|
0.72 (0.49, 1.06)
|
0.095
|
|
0.73 (0.49, 1.09)
|
0.119
|
Non-MetS
|
1.00
|
|
|
1.00
|
|
Age > 65 y, smoking (n=104)
|
MetS
|
0.84 (0.3, 2.33)
|
0.733
|
|
0.55 (0.14, 2.11)
|
0.380
|
Non-MetS
|
1.00
|
|
|
1.00
|
|
a Model 1 was the unadjusted hazard ratio; b Model 2 was adjusted for adjusted for alanine aminotransferase, serum creatinine and white blood cell count. CEA: carcinoembryonic antigen; Hyper-CEA: elevated serum CEA level above the reference range; MetS: metabolic syndrome; Non-MetS: without metabolic syndrome.
Besides, in our study, smoking was an important risk factor for incident Hyper-CEA (adjusted hazard ratio, 1.55; 95% CI, 1.31 to 1.84; P<0.001; supplemental Table S4). However, the association between smoking and incident MetS was disappear after adjusting for other confounders (Supplemental Table S4). In subcohort A, stratification of the adjusted models according to Hyper-CEA (yes or no), smoking showed no significant with incident MetS (Table 6). In subcohort B, stratification according to MetS (yes or no), smoking without MetS was associated with incident Hyper-CEA (hazard ratio, 1.76; 95% CI, 1.43 to 2.15; P<0.001) (Table 7).
Table 6. The hazard ratio (95%CI) of smoking among different CEA status in subcohort A
Characteristics
|
No. of patients with MetS
|
Event rate %
|
Hazard ratio for MetSa
|
P value
|
Hyper-CEA (n=547)
|
|
|
|
|
Smoking
|
47
|
16.49
|
0.94 (0.55, 1.59)
|
0.814
|
Nonsmoking
|
41
|
15.65
|
1.00
|
|
Norm-CEA (n=5861)
|
|
|
|
|
Smoking
|
533
|
24.42
|
1.02 (0.9, 1.16)
|
0.742
|
Nonsmoking
|
742
|
20.17
|
1.00
|
|
a the hazard ratio was adjusted for age, alcohol intake, the components of MetS, blood uric acid, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, hemoglobin and white blood cell count. CEA: carcinoembryonic antigen; Hyper-CEA: elevated serum CEA level above the reference range; Norm-CEA: within the normal reference ranges; MetS: metabolic syndrome.
Table 7. The hazard ratio (95%CI) of smoking among different MetS status in subcohort B
Characteristics
|
No. of patients with Hyper-CEA
|
Event rate %
|
Hazard ratio for Hyper-CEAa
|
P value
|
MetS (n=2434)
|
|
|
|
|
Smoking
|
75
|
7.56
|
1.18 (0.86, 1.62)
|
0.31
|
Nonsmoking
|
110
|
7.63
|
1.00
|
|
Non-MetS (n=6052)
|
|
|
|
|
Smoking
|
205
|
9.07
|
1.76 (1.43, 2.15)
|
<0.001
|
Nonsmoking
|
204
|
5.38
|
1.00
|
|
a the hazard ratio was adjusted for age, alanine aminotransferase, serum creatinine and white blood cell count. CEA: carcinoembryonic antigen; Hyper-CEA: elevated serum CEA level above the reference range; MetS: metabolic syndrome; Non-MetS: without metabolic syndrome.