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HuGENet e-Journal
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“The findings and conclusions in this e-journal abstract are those of the author(s) and do not necessarily represent the views of the funding agency.”
Effects of Interleukin-1 Gene Polymorphisms and
Chlamydia Pneumoniae Infection on the
Development of Coronary Artery Disease
June 5, 2003
Abstraction Template
 
Key variables & Description Article

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

 

Awomoyi AA, Marchant A, Howson JM, et al. Interleukin-10, polymorphism in SLC11A1 (formerly NRAMP1), and susceptibility to tuberculosis. J Infect Dis. 2002 186:1808-14

 

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 confirm the genetic association between polymorphism in SLC11A1 and susceptibility to tuberculosis (TB). Furthermore, the study explores the role of this polymorphism in the regulation of innate macrophage responses required for control of early mycobacterial infection.

 

Gene(s)
Identification of the following:

  1. Gene name
  2. Chromosome location
  3. Gene product/function
  4. Alleles
  5. OMIM #
  1. Gene: Solute carrier family 11, member 1 (SLC11A1)
  2. Chromosome location:  2q35
  3. Gene product/function: Integral membrane protein in macrophages; peripheral blood leukocytes; and cells of the lungs, spleen, and liver.  The protein functions to respond to bacterial products by activation of microbicidal responses such as production of tumor necrosis factor (TNF)-alpha and interleukin (IL)-alpha, and to increase macrophage activation by interferon (IFN)-alpha for immunity.
  4. Alleles:  Alleles1-4:  1 and 4 are rare, with a frequency of <0.01.  Alleles 2 and 3 occur with a frequency of 0.25 and 0.75, respectively
  5. OMIM #: 600266

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

 

Mycobacterium tuberculosis

 

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

 

Tuberculosis
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

 

1. Case-control genetic study (in two parts)

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: Subjects with pulmonary tuberculosis with microscopically proven smear-positive tuberculosis in the context of clinical and radiologic findings consistent with tuberculosis.
  2. Exclusion Criteria: Human Immunodeficiency Virus infection, other chronic illnesses, or previous treatment with corticosteroids
  3. Gender: Male
  4. Race/ethnicity: Not specified
  5. Age: 19-58 years (mean=36 years)
  6. Time period: Unspecified
  7. Geographic location: Serrekunda Health Centre, The Gambia
  8. Number of participants: 340
  1. Disease case definition: Participants recruited from tuberculosis records and previously treated for the disease.
  2. Exclusion criteria: Signs of disease at enrollment
  3. Gender: Male
  4. Race/ethnicity: Not specified
  5. Age: 18-56 years (mean=35 years)
  6. Time period: Not specified
  7. Geographic location: Serrekunda Health Centre
  8. Number of participants: 40

 

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: Healthy, HIV-negative blood donors without tuberculosis
  2. Matching variables: Ethnicity, age
  3. Exclusion criteria: None
  4. Gender: Male
  5. Race/ethnicity: Not specified
  6. Age: 18-50 years (mean=32 years)
  7. Time period: Not specified
  8. Geographic location: Royal Victoria Hospital , Banjul
  9. Number of participants: 340
  1. Control selection criteria:  Healthy, HIV-seronegative unrelated matched control within the same household
  2. Matching variables: Ethnicity, age
  3. Exclusion criteria: None
  4. Gender: Male
  5. Race/ethnicity: Not specified
  6. Age: 18-59 years (mean=33 years)
  7. Time period: Not specified
  8. Geographic location: Serrekunda Health Centre
  9. Number of participants: 40

 

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: Mycobacterium tuberculosis
  2. Exposure assessment:  
      a. Smear-positive tuberculosis assessment at time of enrollment
      b. Ex-cases of tuberculosis treated with a 6-month course of chemotherapy
  3. Exposure definition: Prior tuberculosis infection
  4. Number of participants with exposure data: N=40 (100% of total eligible)

 

Genotyping
Specification of the following:
  1. Gene
  2. DNA source
  3. Methodology
  4. Number of participants genotyped (% of total eligible)
  1. Gene: SLC11A1
  2. DNA source: Blood
  3. Methodology: DNA extracted by use of a standard proteinase K, phenolchloroform protocol. Polymorphism region was amplified by PCR, and fragments were sized by electrophoresis.
  4. Number of participants genotyped: N=653 (96% of total eligible)
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. Gene-disease association:

Parameter

Cases (N=329)

Controls (N=324)

Odds Ratio

95% CI

SLC11A1 polymorphism

 

Allele 1

20

15

1.31

0.67-2.56

Allele 2

121

89

1.40

1.04-1.88

Allele 3

514

544

0.68

0.51-0.90

Allele 4

3

0

-

-

Genotype

 

2/2 or 2/other

109

81

1.49

1.06-2.09

Other/other

220

243

1.00

Reference


Gene-environment interaction:
Statistically significant up-regulation of IL-1ß and TNF-alpha and down-regulation of IL-10 were observed when blood was primed with IFN-alpha, highlighting importance of IFN-Y in mycobacterial immunity (not influenced by allele genotype). 

Statistically significant difference in IL-10 production was observed by genotype (increased in those with allele 2).  

No significant difference between TNF-alpha and IFN-Y production was observed between ex-cases of tuberculosis and matched controls. 

Significant difference in IL-10 production was observed between ex-cases and controls with higher production in ex-cases.

 

Conclusion
The author’s overall conclusions from the study

 

1. Production of TNF/IL1ß and production of IL-10 must balance for optimal response to mycobacterial infection. 

2. TNF/IL-1ß production is enhanced by IFN, which in turn is affected by genotype (Allele 2 = decreased IFN activity, therefore decreased TNF/IL-1ß activity). 

IL-10 production is not affected by decreased TNF/IL-1ß activity. As a result, too much IL-10 further increases susceptibility to mycobacterial infection 

Further studies need to be performed to explore role of other genes associated with IL-10 production, and associated with the role of the SLC11A1 gene 

3. Manipulation of IL-10 pathway may be a novel alternative to treatment of mycobacterial infection. Reduction of IL-10 (and other down-regulatory responses to infection) may be effective in balancing effects of pro-inflammatory cytokines 

4. Interferon has been used as therapy but in doses that can be toxic

 

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

The authors do not indicate whether cases and controls were matched on a 1:1 basis or were frequency matched. The former would require a matched analysis of data, which is not indicated. 

Although this study replicated the results of one other study (performed in the same area), further studies are needed to strengthen consistency by replication of results and to explore the interaction among genes that produce the various cytokines associated with mycobacterial infection immunity and as they interact with the various genotypes of the SLC11A1 gene.

 

 

Page last reviewed: June 8, 2007 (archived document)
Page last updated: November 2, 2007
Content Source: National Office of Public Health Genomics