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The ACE D/D Genotype is Protective Against the Development of
Idiopathic Deep Vein Thrombosis and Pulmonary Embolism

April 8, 2004
Abstraction Template
     
Key variables & Description Article

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

 

Wells PS, et al. The ACE D/D genotype is protective against the development of idiopathic deep vein thrombosis and pulmonary embolism. Thromb Haemost 2003; 90: 829-34.

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 associatio
  3. Gene-gene interaction

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

The primary purpose was to see if the ACE D/D genotype is associated with idiopathic thrombophilia. The authors also wished to examine interactions between the ACE gene and other known genetic and environmental factors affecting the risk of DVT and PE.

 

Gene(s)
Identification of the following:

  1. Gene name
  2. Chromosome location
  3. Gene product/function
  4. Alleles
  5. OMIM #
  1. Gene name: ACE
  2. Chromosome location: 17q23
  3. Gene product/function: codes for angiotensin-converting enzyme
  4. Alleles: intron 16: D/D (deletion), I/I (insertion), I/D (heterozygous)
  5. OMIM#: 106180
  1. Gene name: F5
  2. Chromosome location:  1q21-q25
  3. Gene product/function: Produces factor V, which convert prothrombin to thrombin.
  4. Alleles:   R506Q (factor V Leiden)
  5. OMIM#: 227400
  1. Gene name: F2
  2. Chromosome location: 11p11-q12
  3. Gene product/function: Thrombin
  4. Alleles: F2, 20210G-A
  5. OMIM#: 176930
  1. Gene name: F8
  2. Chromosome location: 28q
  3. Gene product/function: Produces FVIII-C, involved in coagulation
  4. Alleles: A, B
  5. OMIM#: 306700

 
Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral) 		Information was obtained on smoking, BMI, surgery, immobilization, pregnancy, hospitalization, postpartum, trauma, varicose veins, cancer, use of oral contraceptives or ACE inhibitors, HRT or antiplatelet agents, presence of hyperlipidemia, diabetes, hypertension, CAD, peripheral vascular disease, stroke, personal history of thrombosis, and family history of thrombosis. A history of malignant disease was used to exclude cases and controls from the study, as was use of anticoagulating drugs. However, of the factors which were investigated, only BMI and smoking were controlled for in the final logistic regression, along with factor V Leiden, prothrombin G20210A, and factor VIII.

 

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

Idiopathic deep vein thrombosis (DVT)
Idiopathic pulmonary embolism (PE)


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 (% of total eligible)

 
  1. Disease case definition: Anyone with at least one idiopathic DVT or PE, with at least 3 months of follow-up.
  2. Exclusion criteria: Any malignant disorder
  3. Gender: Both (distribution not specified)
  4. Race/ethnicity: 97% Caucasian, 3% unspecified
  5. Age: Mean age 56.15
  6. Time period: not specified
  7. Geographic location: Ottawa Hospital
  8. Number of participants: 300

 
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 (% of total eligible)

 
  1. Control selection criteria: Friends of cases
  2. Matching variables: Age, race and gender
  3. Exclusion criteria: Any malignant disorder or use of oral anticoagulants
  4. Gender: Both (distribution not specified)
  5. Race/ethnicity: 97% Caucasian, 3% unspecified
  6. Age: Mean age 56.15
  7. Time period: not specified
  8. Geographic location: Ottawa Hospital
  9. Number of participants: 300

 

 
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)

 

Clinical information was obtained by 'trained staff' although the exact method was not disclosed. The definition and classification of the environmental factors was also not given.

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

 
  1. Gene: ACE, factor V Leiden, factor VIII and prothrombin 20210A
  2. DNA source: Whole blood sample
  3. Methodology: Agarose gel separation of PCR amplified DNA
  4. Number of participants genotyped: 580 (96.7% of eligible)

 
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. The D/D genotype was present in 25.3% of cases and 32.4% of controls.
  2. When adjusted for FVL, prothrombin G20210A, factor VIII, BMI and smoking, the D/D genotype was more common among controls than cases, with an OR of .66 (95% CI [.433, .997])
  3. Factor V Leiden and Prothrombin G20210A were associated with risk of thrombophilia (OR's and CI's 8.33 [4.37, 15.88] and 3.6 [1.37, 9.46] respectively) when adjusted for FVL, prothrombin G20210A, ACE genotype, factor VIII, BMI and smoking.
Conclusion
State the author's overall conclusions from the study

The public health utility of this study is not clear. First, the reported effect was not large; the protective effect was .66, and findings in other studies are inconsistent. Furthermore, the findings contradict the a priori hypothesis that ACE D/D would lead to elevated plasma ACE and increased risk of VTE. However, research on genetic susceptibility to thrombophilia is important and should be continued because this condition presents a significant burden in terms of prevalence and costs-of hospitalization, treatment, and prophylaxis.

 

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

The public health utility of this study is not clear. First, the reported effect was not large; the protective effect was .66, and findings in other studies are inconsistent. Furthermore, the findings contradict the a priori hypothesis that ACE D/D would lead to elevated plasma ACE and increased risk of VTE. However, research on genetic susceptibility to thrombophilia is important and should be continued because this condition presents a significant burden in terms of prevalence and costs-of hospitalization, treatment, and prophylaxis.

 
Last Updated August 25, 2004