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Effects of Interleukin-1 Gene Polymorphisms and Chlamydia Pneumoniae Infection on the Development of Coronary Artery Disease

November 15, 2001

Abstraction Template
     
Key variables & Description Article

Reference
Complete the bibliographic reference for the article according to AJE format.

 

Momiyama Y, Hirano R, Taniguchi H, Nakamura H, Ohsuzu F. Effects of interleukin-1 gene polymorphisms on the development of coronary artery disease associated with Chlamydia pneumoniae infection. Journal of the American College of Cardiology 2001; 38(3):712-7.

 

Category of HuGE information
Specify the types of information (from the list below) available in the article:

  1. Prevalence of gene variant
  2. Gene-disease association
  3. Gene-environment interaction
  4. Gene-gene interaction
  5. Genetic test evaluation/monitoring

 

  1. Prevalence of gene variant
  2. Gene-disease association
  3. Gene-environment interaction

Study hypotheses or purpose
The authors study hypotheses or main purpose for conducting the study

 

To elucidate the effects of interleukin (IL)-1 gene polymorphisms on coronary artery disease (CAD) associated with Chlamydia pneumoniae infection.

 

Gene(s)
Identification of the following:

  1. Gene name
  2. Chromosome location
  3. Gene product/function
  4. Alleles
  5. OMIM #
  1. Gene: Interleukin-1 beta
  2. Chromosome location:  2q14
  3. Gene product/function: IL-B is a cytokine which mediates inflammatory response.
  4. Alleles:  C/T substitution at position -511
  5. OMIM #: 147720

  1. Gene: Interleukin-1 receptor antagonist
  2. Chromosome location:  2q14.2
  3. Gene product/function: IL-1Ra is a cytokine which mediates inflammatory response.
  4. Alleles:  VNTR (5 alleles, 2-6 repeats) in intron 2
  5. OMIM #: 147679

Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral)

 

Chlamydia pneumoniae (CP) immunoglobulin G (IgG) seropositivity.

 

Health outcome(s)
Identification of the major health outcome(s) studied

 

  1. Coronary artery disease (CAD)
  2. Myocardial infarction (MI)
Study design
Specification of the type of study design(s)
  1. Case-control
  2. Cohort 
  3. Cross-sectional
  4. Descriptive or case-series
  5. Clinical trial
  6. Population screening

 

Case-control

Case definition 
For study designs 1, 4, and 5, the following are defined, if available.

  1. Disease case definition
  2. Exclusion criteria
  3. Gender
  4. Race/ethnicity
  5. Age
  6. Time period
  7. Geographic location
  8. Number of participants

 

  1. Disease case definition: Coronary artery disease (CAD) defined as at least one coronary artery having >50% luminal diameter stenosis, diagnosed by coronary angiography.
    Cases were patients were those with the above diagnosis from a population of 292 consecutive patients having coronary angiography for suspected CAD at the Japanese National Defense Medical College Hospital.
    Secondary diagnosis, myocardial infarction (MI), confirmed by documentation of coronary artery stenosis plus elevated leveles of cardiac enzymes or diagnostic changes on electrocardiogram.
  2. Exclusion criteria:Not mentioned Patients who had coronary artery bypass grafting were excluded.
  3. Gender: Males only
  4. Race/ethnicity: Japanese
  5. Age: No age restrictions, average age 64 +/- 9 years
  6. Time period: July 1999 to December 2000
  7. Geographic location: Saitama, Japan
  8. Number of participants: 104

 

Control definition 
For study design 1, the following are defined, if available.  

  1. Control selection criteria
  2. Matching variables
  3. Exclusion criteria 
  4. Gender
  5. Race/ethnicity
  6. Age
  7. Time period
  8. Geographic location
  9. Number of participants

 

  1. Control selection criteria: Controls were patients without a diagnosis of CAD from a population of 292 consecutive patients having coronary angiography at National Defense Medical College Hospital.
  2. Matching variables: None
  3. Exclusion criteria: Patients who had coronary artery bypass grafting were excluded.
  4. Gender: Males
  5. Race/ethnicity: Japanese
  6. Age: No age restrictions, average age 60 +/- 10 years
  7. Time period: July 1999 to December 2000
  8. Geographic location: Saitama, Japan
  9. Number of participants: 104
Assessment of environment factors
For studies that include gene-environment interaction, the following are defined, if available.
  1. Environmental factor
  2. Exposure assessment
  3. Exposure definition
  4. Number of participants with exposure data (% of total eligible)

 

  1. Environmental factor: Serum Chlamydia pneumoniae- specific immunoglobulin G (IgG) titer
  2. Exposure assessment: CP-specific IgG titer was measured, in blood samples taken in fasting state, by an ELISA suing commercially available kit (HITAZYME).  The ELISA used the CP outer membrane complex as a CP-specific antigen.
  3. Exposure definition: A CP IgG titer at least 1.10 was considered to be seropositivity.
  4. Number of participants with exposure data: N00% of total eligible (n=292) had exposure data.

 

Genotyping
Specification of the following:
  1. Gene
  2. DNA source
  3. Methodology
  4. Number of participants genotyped (% of total eligible)

 

  1. Gene: Interleukin-1 beta (IL-1B); Interleukin-1 receptor antagonist (IL-1Ra)
  2. DNA source: Fasting blood samples obtained from all study participants.
  3. Methodology: Genomic DNA was extracted from blood and genotyping was performed using polymerase chain reaction (PCR). – based methods.  For  IL-1B, the polymorphic site was amplified by PCR, followed by AvaI digestion and restriction fragment length polymorphism (RFLP) analysis.  The region containing the IL-1Ra polymorphic site was amplified by PCR and analyzed by electrophoresis on 2% agarose gel stained with ethidium bromide.
  4. Number of participants genotyped: 292 (100%)

 

Results
Specification of the major results under each of the following HuGE categories, including tables when data is provided.
  1. Prevalence of gene variant
  2. Gene-disease association
  3. Gene-environment interaction
  4. Gene-gene interaction
  5. Genetic test evaluation

Table 1. Prevalence of gene variant - control subjects

Note:  Table displays genotype prevalences among study subjects referred for coronary angiography without diagnosis of CAD, as presented in the paper.

Genotype
Number
%
II-1B
T/T or C/T
90
87
C/C
14
13
II-1Ra
4.5 or 6 repeat
101
97
2 or 3 repeat
3
3

Investigators were unable to distinguish independent effects of the two polymorphisms; thus, all analyses were conducted using only the HPA-2 genotyping data.*

Table 2. Gene-disease association
Genotype
Cases 
CAD+
(n=188)
Control
CAD-
(n=104)
P Value
OR (95% CI)
Calculated by reviewers
II-1B
T/T or C/T
146(78%)
90 (87%)
Ref.
C/C
42(22%)
14 (13%)
NS
1.8 (0.9,3.6)
II-1Ra
4,5 or 6 repeat
174(93%)
101(97%)
Ref.
2 or 3 repeat
14(7%)
3(3%)
NS
2.7(0.8,9.6)
II-1B and / or II-1Ra
No mutation
133 (71%)
87 (84%)
Ref.
C/C and/or 2 or 3 repeat
55(29%)
17(16%)
<0.025
2.1(1.1,3.9)

Gene-MI association not presented.

Table 3. Gene-environment interactions  

Note:  Results for gene-environment interactions were not presented for individual polymorphisms.  Tables represent effects of both gene variants, defined as Il-1B C/C and/or Il-1Ra 2 or 3 repeat.  

3a.       CAD analysis  

CAD
Genotype
CP Seropositivity
% with CAD
II-1B and / or II-1Ra
No mutation
No (n=93)
56%
Yes (n=127)
64%
C/C and / or 2 or 3 repeat
No (n=31)
68%
Yes (n=41)
83%

p-value for 83% vs. 64% <0.05
p-value for 83% vs. 56% <0.005  

CAD

OR (95% CI)

Main effect of CP*
1.5 (0.9, 2.5)
Main effect of variants
2.1 (1.2, 3.9)
Effect of CP+ and variants+ vs. CP- and variants-
3.8 (1.5, 9.5)

In multivariate analysis (controlling for age, gender, smoking, and other CAD risk factors), gene variants were associated with CAD both among patients with and among those without CP seropositivity.  

CAD

adj. OR (95% CI) for II-1 gene variants

CP+
2.8 (1.3, 5.8)
CP-
2.9 (1.0, 8.5)


3b.       MI analysis

MI
Genotype
CP seropositivity
% with MI
II-1B and / or II-1Ra No mutation No (n=93) 29%
    Yes (n=127) 28%
  C/C and / or 2 or 3 repeat No (n=31) 26%
    Yes (n=41) 54%

p-value for 54% vs. 29% <0.025

In multivariate analysis (controlling for age, gender, smoking, and other CAD risk factors), gene variants were associated with MI only among patients with CP seropositivity.  

adj. OR (95% CI) for II-1 gene variants

CP+
2.8 (1.3, 5.8)
CP-
NS

 

Conclusion
The author’s overall conclusions from the study

 

The authors conclude that IL-1 gene polymorphisms are associated with an increased prevalence of CAD and MI among patients with CP infection.  For CAD, the observed stepwise progression in CAD prevalence depended on CP seropositivity and/or IL-1 variants.  The authors conclude that IL-1 variants and CP seropositivity have additive interactive effects on CAD prevalence.  In multivariate analysis, the presence of IL-1b and/or Il-1Ra variants was associated with an increased prevalence of CAD, both among subjects with and among those without CP seropositivity.  For MI, IL-1b and/or Il-1Ra variants were associated with increased prevalence of disease only among subjects with CP seropositivity.

 

Comments  
Additional insight, including methodologic issues and/or concerns about the study.

While the authors demonstrate an increased prevalence of CAD among patients with both CP seropositivity and the IL-1 gene variants, they do not present statistical evidence of interaction.  The results may not be highly generalizable as the entire study population is a select group of Japanese men undergoing coronary angiography.  Further study should address the functional role of these gene variants and investigate gene products and their relationships with coronary artery disease.  Additional evaluation within a larger study population is warranted to determine the association of the gene variants and CP infection with myocardial infarction.

 

Last Updated August 24, 2004