710 901
IL-1ra
IL-1ra
IL-1ra 70
( healthy controls ) 95 ( CAD ) 165
IL-1ra IL-1ra
( 1 ) CAD BMI HDL-
( 2 ) CAD IL-1ra
( p 0.01 ) Bilirubin CAD
hs-CRP IL-6 ( 3 )
IL-1ra HDL- Bilirubin BMI TG
hs-CRP IL-6 WBC ( 4 ) IL-1ra
CAD ( Odds ratio, 2.57
95% CI, 1.119 to 5.914 p = 0.026 ) IL-1ra
IL-1ra
IL-1 receptor antagonist ( IL-1ra ) Coronary artery disease ( CAD ) Interleukin-6 ( IL-6 )
High sensitive C-reactive protein ( hs-CRP )
( Cardiovascular disease )
1 , 2
1990
( coronary artery disease;
C A D )
( atherosclerosis )
3-5( 1 ) ( Lipid modified ) ( aggregation )
6-9( 2 ) ( Endothelial Dysfunction )
4
( 3 )
10
( 4 )
11( 5 ) ( herpesvirus ) ( Chamydia pneumoniae )
12-145 3-5
( LDL )
( reactive oxygen species ) sphin- gomyelinase secretory phospholipase 2
myeloperoxidase LDL
15( scavenger receptor )
LDL ( foam
cells )
3-5
( fibrous plaques ) ( p l a q u e s )
( thrombosis ) ( Acute
Myocardial Infraction ) ( stroke )
( pro-inflammatory cytokine ) IL-1 T-
NF- IL-6
ICAM-1 VCAM-1
16-20
IL-1
21-23
IL-
1 IL-1 IL-1 IL-1ra IL-1
24
IL-
1ra IL-1 IL-1
IL-1
19, 25-27
28-31
IL-1ra
( rheumatoid arthritis ) ApoE ( ApoE gene knockout mice )
IL- 1ra ( IL-1ra gene knockout )
IL-1 IL-1ra
28, 33
IL-1ra Bilirubin
70 51 19
CAD ( Treadmill Exercise Test Thallium Scan.
CAD ) ( CAD )
95 65 30
50%
Aspirin Statin
( )
IL-1ra IL-6 IL-1ra IL-6
ELISA ( R D system ) w e l l Wash Buffer
I L - 1 r a I L - 6 2 0 0 l
( Conjugated with Horseradish peroxidase ) Wash Buffer
200 l Substrate Solution [ H2O2 tetramethylbenzidine mixture ( 1 1 ) ] well
20 50 l Stop
solution ( 2N sulfuric acid )
30 ( OD 450nm )
10%
hs-CRP
High sensitivity C-reactive protein ( hs-CRP ) C R P
polystrene particle CRP
( Behring BN II nephelometer )
Cholesterol LDL TG HDL-
C Total Bilirubin ( Wako
Pure Chemical Industries Ltd ) HITACHI 7070
SPSS 12.0
Chi-Squire test
Independent t test
Manny-Whitney U test Spearman's test multiple Logistic re- gression
I L - 1 r a
( Levels 1~4 ) IL-1ra
CAD ( relative
risk ) mean standard deviation
( SD ) p 0.05
CAD
70 51 19 59
( 41-83 ) CAD 95 65
30 62 ( 40-79 )
LDL- (
) B M I
T G C A D
HDL- CAD
( )
IL-1ra ( )
C A D I L - 1 r a
( 492.2 337.9 V.S. 355.4 146.6 pg/mL, p 0.01 )
Controls (n=70) CAD (n=95)
p valueAge, mean (range) 59.1 (41-83) 62.0 (40-79) NS
Gender, M/ F (M%) 51/19 (72.9) 65/30 (68.4) NS
BMI, kg/m
224.0 ± 3.2
a25.8 ± 3.8 0.01
Diastolic Blood pressure, mmHg 79.2 ± 9.5 79.4 ± 11.6 NS
Systolic Blood pressure, mmHg 124.7 ± 18.3 134.9
± 18.40.001
Risk factors of CAD(%)
Family history of CAD 10.7 12.3 NS
Smoker 21.6 42.6 0.01
Hypertension 33.3 57.4 0.01
Diabetes 20.0 31.5 NS
Glucose, mg/dl 105.9 ± 32.4 152.2 ± 80.0 0.001
Cholesterol, mg/dl
Total 219.9 ± 39.8 214.5
± 49.5NS
LDL 133.3 ± 40.3 133.6 ± 39.6 NS
HDL 59.4 ± 26.3 43.9
± 11.30.001
Triglycerides, mg/dL 118.36 ± 80.0 196.1 ± 120.8 0.001
NS not significant. P>0.05
a
mean SD
IL-1ra
Levels of IL-1ra are presented as median 25th 75thpercentile, triangle represent outlier values.
IL-1ra hs-CRP IL-6
Data are mean SEM, p< 0.05 and p< 0.01, comparing differences between controls and CAD patients.
( )
Bilirubin CAD
( 0.48 0.2 V.S. 0.95 0.4 mg/dl, p < 0.001 ) CAD hs-CRP ( 11.5 21.7 V.S. 2.5 4.6 mg/L, p < 0.001 ) IL-6 ( 13.6 45.5 V.S. 0.99 2.9 ng/L, p< 0.001 ) WBC ( 7,700 2,100 V.S. 6,400 1,800 p < 0.001 ) Neutrophil ( 61.2 10.7 V.S.
56.6 8.8% p< 0.001 )
( ) IL-1ra
IL-6 CRP IL-1ra, IL-6,
hs-CRP ( )
IL-1ra
IL-1ra
( ) ( 1 ) IL-1ra TG hs-CRP W-
BC
IL-1ra hs-CRP ( p < 0.01 )
( 2 ) IL-1ra CAD
HDL- ( r = -0.234, p < 0.01 ) Bilirubin ( r = -0.219, p < 0.01 ) ( 3 ) IL-
Controls n=70 CAD n=95
p valueIL-1ra, pg/mL 355.4 ± 146.6 492.2 ± 337.9 0.05
Bilirubin, mg/dl 0.95 ± 0.4 0.48 ± 0.2 0.001
IL-6, ng/L 0.99 ± 2.9 13.6 ± 45.5 0.001
hs-CRP, mg/L 2.5 ± 4.6 11.5
± 21.70.001
WBC, 10
3/ L 6.4 ± 1.8 7.7 ± 2.1 0.001
Neutrophil, % 56.6 ± 8.8 61.2 ± 10.7 0.001
Monocyte, % 7.4 ± 2.2 7.5 ± 2.5 NS
Data are shown as mean SD
IL-1ra ( vari-
ables ) ( Correlation Coefficient )
Controls CAD All Glucose, mg/dl 0.155 0.177 0.250
**BMI, kg/m
20.241 0.199 0.264
**TG, mg/dL 0.352
**0.110 0.275
**HDL-choesterol, mg/dL -0.229 -0.121 -0.234
**LDL-choesterol, mg/dL 0.104 -0.108 -0.013 Total Cholesterol, mg/dl 0.031 -0.144 -0.069 Hs-CRP, mg/L 0.393
**0.284
**0.360
**IL-6, ng/L 0.019 0.185 0.172
*Total Bilirubin, mg/dl -0.181 -0.06 -0.219
**Neutrophil % 0.115 0.017 0.114
Monocyte % -0.151 -0.053 -0.084
WBC, 10
3/UL 0.637
**0.194 0.414
**Values are Spearman rank correlation coefficient.
*p
0.05 ,
**p0.01
1ra CAD ( r = 0.250, p <
0.01 ) BMI ( r = 0.264, p < 0.01 ) TG ( r = 0.275,
p < 0.01 ) ( 4 ) hs-
CRP IL-6 WBC ( p < 0.05 )
IL-1ra
IL-1ra
Logistical Regression IL-1ra
( Levels 1~4 ) Levels 2 ( 265~361 pg/mL ) Levels 3 ( 361~498 pg/mL ) Levels 4 ( 498~1955 pg/mL )
Levels 1 ( 135~265 pg/mL )
( relative risk ) IL-1ra Levels 2 Levels 3 Levels 4 Levels 1 Odds ratio ( 95%
CI ) 1.85 ( 0.827~4.117 ) 1.17 ( 0.537~2.552 ) 2.57 ( 1.119~5.914 ) Levels 4 Levels 1
( p < 0.05 ) ( ) IL-1ra ( Levels 4 )
( Levels 1 ) 2.57 CAD
IL-1ra
50th 75th 90th 95th (
) IL-1ra 50th 75th
( p > 0.05 ) IL-1ra 90th 95th ( p < 0.01 p 0.01 )
IL-1ra
( 1 ) CAD IL-1ra
Bilirubin ( 2 ) CAD
hs-CRP IL-6
( 3 ) IL-1ra HDL- IL-1ra Total Bilirubin
BMI TG
hs-CRP IL-6 WBC
( 4 ) IL-1ra
2.57 CAD
IL-1ra
IL-1ra CAD
3 - 5
27
( )
IL-1 TNF- IL-6
6 - 2 5
CRP
17,18( )
HMG-CoA -Statin
LDL-C
IL-1ra logistic
CAD ( variables )
IL-1ra Levels 1~4 Controls, CAD, Odds ratio p value ( range, pg/mL ) % ( n ) % ( n ) 95% CI
1 (135~265) 28.8 (23) 16.7 (18)
2 (265~361) 18.8 (15) 24.1 (26) 1.85 0.135 0.827~4.117 3 (361~498) 25 (20) 20.4 (22) 1.17 0.691
0.537~2.552 4 (498~1955) 15 (12) 26.9 (29) 2.57 0.026
1.119~5.914
p values were calculated by logistic regression analyses.CI denotes confidence interval.
IL-1ra IL-1ra
Cutpoints,percentile IL-1ra, pg/mL Controls, ( n ) CAD, ( n ) 95 CI
p value50
th361.33 40 ( 32 ) 47.2 ( 51 ) -0.2168~0.724 0.324
75
th498.49 15 ( 12 ) 26.9 ( 29 ) -0.2344~-0.026 0.052
90
th757.52 1.3 ( 1 ) 13.9 ( 15 ) -0.1970~0.558 0.002
95
th995.69 0 ( 0 ) 7.5 ( 8 ) -0.125~-0.241 0.012
CI denotes confidence interval.
( )
IL-1ra IL-1 IL-1
28,29,32-34
IL-1
29,34
CAD
IL-1ra ( p < 0.05 )
( ) IL-1ra IL-6 hs-CRP
3 5 , 3 6
( )
hs-CRP
37-39IL-1ra hs-
CRP IL-6
( ) CRP IL-1ra
40
IL-1ra CAD
HDL- IL-1ra
IL-1ra Total Bilirubin
( ) IL-1ra
CAD IL-1ra Total Bilirubin
CAD
41IL-1ra CAD
IL-1ra 4
( Odds ratio )
CAD ( level 4 )
( ) ( )
CAD IL-1ra
IL-1ra CAD
IL-1ra ( IL-
1ra gene polymorphism; IL-1RN )
IL-1RN*2 ( IL-1ra Allel 2 )
42-47
IL-1RN*2
IL-1ra
48-50IL-1ra
IL-1RN*2 IL-1ra
CAD IL-1ra total bilirubin
CAD
IL-1ra IL-1ra CAD
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Assessment of Serum IL-1 Receptor Antagonist Level in Patient with Coronary Artery Disease
Hui-Yi Yap, Yun-Chen Kung
1, Tung-Nan Liao
2, Chih-Chiang Huang
3, Yi-Chueh Yang
4, Yung-Liang Liao
4, and Ching-Nan Lin
4Previous studies show that coronary artery disease (CAD) is a multi-factors and chronic inflammatory dis- ease. IL-1ra is a naturally occurring anti-inflammatory molecules that block the action of IL-1. However, little is known about the dysbalance among IL-1ra, bilirubin, and inflammatory mediators in CAD. We attempted to in- vestigate the relationships between inflammatory mediators and serum IL-1ra levels in patients with CAD. In 95 patients with angiographically defined CAD, and 70 healthy controls were studied in a case-control manner. Serum levels of IL-1ra, IL-6, bilirubin, hs-CRP and the risk factor of CAD were examined. Our major finding include: (1) The risk factors such as elevated BMI, systolic BP, smoking, hypertension, blood glucose, and TG was more fre- quently found in the CAD group than the control group ( p < 0.001). The HDL-C was significantly higher in con- trol group than the CAD group; (2) Five different inflammatory markers were significantly elevated including IL- 1ra, hs-CRP, IL-6, leukocyte count, and neutrophil percentage between healthy controls and CAD patients. In contrast, control group with elevated bilirubin than CAD group ( p < 0.001); (3) By contrast, levels of IL-1ra and other variables such as blood glucose, BMI, TG, IL-6, hs-CRP, and leukocyte count were significantly correlated ( p < 0.01) in all study subjects. In contrast, the levels of IL-1ra were inversed correlation in bilirubin, and HDL- C; (4) In the multiple logistic regression analysis, adjustment was made for variables. The relative risk of CAD for the highest quartile of IL-1ra, as compared with the lowest quartile, had an odds ratio 2.57 (95% confidence in- tervals, 1.119-5.914, p=0.026) increase in risk for CAD. In conclusion, we find a significant association of ele- vated IL-1ra in the patients with CAD. Thus, in part, may be explained by the anti-inflammatory effects of IL-1ra and bilirubin on CAD. ( J Intern Med Taiwan 2007; 18: 262- 269 )
Department of Internal Medicine, Chi-Mei Foundation Hospital Liou Ying Campus
1
Institute of Biomedical Science, National Sunyat-Sen University
2
Department of Medical Technology, Chung-Hwa College of Medical Technology
3
Department of Internal Medicine, Chi-Mei Foundation Hospital
4
