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Angiotensinogen Gene Polymorphisms: Relationship to Blood
Pressure Response to Antihypertensive Treatment

June 8, 2004

Abstraction Template
     
Key variables & Description Article

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

 

Kurland L, Liljedahl U, Karlsson J, et al. Angiotensinogen gene polymorphisms: relationship to blood pressure response to antihypertensive treatment. Results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial. Am J Hypertens. 2004 Jan;17(1):8-13.

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 -disease association
  2. Gene-disease association: angiotensinogen gene (AGT) single nucleotide polymorphisms and hypertension
  3. Gene-environment interaction: specific SNPs in AGT with the antihypertensive treatments irbesartan and atenolol
  4. Gene-gene interaction: linkage disequilibrium between AGT 1198C and AGT -6A alleles
  5. Genetic test evaluation/monitoring: DNA polymerase-assisted minisequencing single nucleotide primer extension reaction in microarray format

 

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

 

The purpose of the study was to investigate the association of specific SNPs in AGT with blood pressure reduction due to specific antihypertensive treatments (irbesartan vs. atenolol).

 

Gene(s)
Identification of the following:

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

 

  1. Gene name: Angiotensinogen (AGT)
  2. Chromosome location: 1q42-q43
  3. Gene product/function: vasoconstriction, fluid retention
  4. Alleles: A-6G, T1198C (M235T)
  5. OMIM#:106150

 

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

 

1. Irbesartan
2. Atenolol

 

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

 

1. Hypertension
2. Left Ventricular Hypertrophy


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

 

5. Clinical trial
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)

 

Disease case definition: White men and women greater than 18 years of age with primary mild to moderate hypertension and confirmed LVH.
Exclusion criteria:

a. inclusion criteria

  1. left ventricular mass index of greater than 131 g/m2 for men and greater than 100 g/m2 for women
  2. hypertension was defined as diastolic bp of 90-115 mmHg at two examinations within a week, differing by no more than 8 mmHg

b. exclusion criteria

    1. persons with secondary hypertension by physical exam and laboratory analyses

Gender: male and female
Race/ethnicity: white
Age: >18
Time period: 4-6 weeks placebo lead-in period followed by 12 weeks of monotherapy
Geographic location: Sweden
Number of participants (% of total eligible): 101(101/115=87.83%)

 

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)

 

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)

 

  1. Environmental factor: Irbesartan
  2. Exposure assessment: prescription of antihypertensive monotherapy
  3. Exposure definition: 150 mg once daily for 12 weeks; dose doubled after six weeks if diastolic bp>90 mmHg
  4. Number of participants with exposure data: N=48 (48/97=49.48%)
  1. Exposure factor: Atenolol
  2. Exposure assessment:prescription of antihypertensive monotherapy
  3. Exposure definition: 50 mg once daily for 12 weeks; dose doubled after six weeks if diastolic bp ≥90 mmHg
  4. Number of participants with exposure data: N=49 (49/97=50.52%)
Genotyping
Specify the following:
  1. Gene
  2. DNA source
  3. Methodology
  4. Number of participants genotyped (% of total eligible) 

 

  1. Gene: Angiotensinogen (AGT)
  2. DNA source: not specified
  3. Methodology: DNA polymerase-assisted minisequencing single nucleotide primer extension reaction in a microarray format
  4. Number of participants genotyped (% of total eligible): 97 (97/101=96.04%)

 

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

 

Table 1: Mean single nucleotide polymorphism-specific changes in blood pressure following 12 weeks of antihypertensive pharmacotherapy

Gene-disease/gene-environment association: two SNPs of the AGT gene were significantly associated with the reduction of blood pressure following treatment with atenolol but not irbesartan.
Gene-gene interaction: the AGT 1198C and -6A alleles are in linkage disequilibrium.
Genetic test evaluation/monitoring: fluorescence signals and signal ratios.
Statistical analysis: chi-square tests, factorial one-way ANOVA.

Conclusion
State the author's overall conclusions from the study

Two linked SNPs of the AGT gene were associated with the reduction in systolic bp in hypertensive patients following treatment with atenolol, but not with irbesartan. This is a good hypothesis-generating study whose methods may be used to identify a large number of candidate SNPs with high predictive power in order to develop a strong clinical test that would allow individualized treatment of hypertension with antihypertensive pharmacotherapy.

 

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

The major limitation of this study was small sample size, which did not allow stratification based on factors such as gender that could influence the significance of the associations.

Both a strength and a weakness of the study was the homogeneity of the study population, which limits its generalizability; however, as the prevalence of alleles depends heavily on race, this was an essential characteristic of the cohort.

As noted by the authors, the microarray approach is a good preliminary method because it allows for the testing of large number of SNPs simultaneously, but may lead to multiple comparisons, necessitating validation of the results by further studies.

Although the results of this study demonstrate the potential benefit of genotyping in the treatment of hypertension, especially if it could be used to identify and target treatment for high risk individuals early in order to avoid more serious complications, one must be wary of the benefit in relation to the cost.

 

Last Updated August 25, 2004