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NOD2 Variants and Crohn’s Disease

June 5, 2001
Abstraction Template
     
Key variables & Description Article

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

 

Hugot J-P, Chamaillard M, Zouali H, et al.  Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease.  Nature 2001;411:599-603.

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

 

 

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

 

 Hypothesis:  Mutations in the NOD2 gene are associated with Crohn’s disease.

Gene(s)
Identification of the following:

  1. Gene name
  2. Chromosome location
  3. Gene product/function
  4. Alleles
  5. OMIM #

 
  1. Gene: NOD2
  2. Chromosome location: 16q12
  3. Gene product/function:  protein involved in cell signaling pathways that have a role in innate immune response  
  4. Alleles: 1-BP ins 980 (SNP13), G881R (SNP8), R675W (SNP12)
  5. OMIM #: 605956, also 266600 (IBD1)

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

 

N/A

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

 

1. Crohn’s disease
2. ulcerative colitis

 

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
Case definition
For study designs 1, 4, and 5, define the following 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:  Crohn’s disease diagnosed by criteria in ref 30.
  2. Exclusion criteria: not specified case per family
  3. Gender: not specified
  4. Race/ethnicity: not specified
  5. Age: not specified
  6. Time period: not specified
  7. Geographic location: not specified
  8. Number of participants: 468 (Methods section says 457)
Control definition
For study design 1, define the following 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:   “unaffected, unrelated”
  2. Matching variables: not specified
  3. Exclusion criteria:  not specified
  4. Gender: not specified
  5. Race/ethnicity: not specified
  6. Age: not specified
  7. Time period: not specified
  8. Geographic location: not specified
  9. Number of participants: 103

Cohort definition
For study designs 2, 3, and 6, define the following if available:

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

 

 N/A
Assessment of environment factors
For studies that include gene-environment interactions, define the following, if available:
  1. Environmental factor
  2. Exposure assessment
  3. Exposure definition
  4. Number of participants with exposure data (% of total eligible)

 

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

 
  1. Gene: NOD2
  2. DNA source:  not specified 
  3. Methodology: not specified, but confirmed by sequencing
  4. Participants genotyped:  468 CD patients, 159 ulcerative colitis patients, 103 controls
Results
Describe the major results under each of the following HuGE categories. Include tables when data are provided:
  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

Authors provided allele frequencies (but not genotype frequencies) for the 3 variants.  Genotypes were summarized as shown:

Genotype

Cases
#  (%)

Controls
 #       %

No variant

   267 (57)

 
88   (85)
Simple heterozygous

  133  (28)

  
15   (15)
Homozygous
  
28  (6)
   
0   (0)
Compound heterozygous
  
40  (9)
   
0   (0)
Total
468
103

2. Gene-disease association

Genotype
OR (95% CI)
No variant
Ref
Simple heterozygous
  
3
Homozygous
38
Compound heterozygous
44
Total 

 
Conclusion
State the author's overall conclusions from the study

The 3 NOD2 variants were independently associated with Crohn’s disease (they were never found on the same chromosome), and there was a gene dose effect.  This finding suggests a role for defects in innate immunity in the etiology of Crohn’s disease.

 
Comments
Provide additional insight, including methodologic issues and/or concerns about the study

The main focus of this report was a positional cloning study conducted in 235 families.  Selected SNPs were typed in 1272 members of these families; thus, the study involved much more sequencing than was done for the case-control study, which evaluated association of CD only with 3 of the SNPs suggested by the family study. 

Little information was provided about the selection of cases/families and controls.  Alleles were assumed to be in Hardy-Weinberg equilibrium among controls to estimate an expected value for the zero cells; these were used to arrive at the OR s for homozygosity and compound heterozygosity.  ORs calculated from the data differed slightly from those reported (43 instead of 38; 46 instead of 44).  In part, this may be due to rounding error in those reported, but conclusions are the same. 

The AF for homozygosity and compound heterozygosity combined was about 15%, and for homozgosity/any heterozygosity combined was 33%. AF s associated with individual variants or combinations of variants could not be calculated from the reported data. 

The 3 variants were not associated with ulcerative colitis, whose allele frequencies were similar to controls.

 
Last Updated August 25, 2004