Ten renin-angiotensin system-related gene polymorphisms in maximally treated Canadian Caucasian patients with heart failure

Br J Clin Pharmacol. 2008 May;65(5):742-51. doi: 10.1111/j.1365-2125.2007.03091.x. Epub 2008 Feb 12.


What is already known about this subject: The progression and pharmacological response of heart failure-affected patients are subject to interindividual variability. It is also acknowledged that the genotype frequency of certain gene polymorphisms varies across different ethnic groups and that a difference in gene polymorphism frequencies between healthy and heart failure patients seems to exist.

What this study adds: This study investigated associations between 10 gene polymorphisms of RAAS-related genes with an individual's susceptibility to heart failure. Our data suggest that the angiotensinogen (AGT) 235 single nucleotide polymorphism (SNP) may be associated with heart failure in our population and that the AGT(M174)-AGT(T235) haplotype, as well as the AGT/angiotensin-converting enzyme (ACE) gene combination, may play an important role in disease predisposition.

Aims: Racial differences in survival outcomes point towards a genetic role in the pathophysiology of heart failure. Furthermore, contemporary evidence links genetics to heart failure (HF) predisposition. We tested for a difference in prevalence of 10 renin-angiotensin-aldosterone system (RAAS)-related gene polymorphisms between a homogenous population of HF patients and healthy controls.

Methods: One hundred and eleven healthy volunteers and 58 HF patients were included in this study. The healthy control group consisted of males aged between 18 and 35 years old. The HF group consisted of patients (89.7% male) who were 63.8 +/- 7.9 years old, were in New York Heart Association (NYHA) class II-III and had a documented left ventricular ejection fraction (LVEF) <or= 40% within the previous 6 months. Despite being treated maximally for their condition with angiotensin-converting-enzyme (ACE)-inhibitors and beta-adrenoceptor blockers, they continued to be symptomatic and, as such, were a highly specialized and homogeneous patient population. Both groups were composed of Canadian Caucasians. The analyzed polymorphisms were: ACE (I/D), angiotensin-II-receptor-type-1 (AGTR1)(A1166C), angiotensinogen (AGT)(M235T and T174M), endothelial-nitric-oxide-synthase (eNOS)(T-786C and Glu298Asp), adrenergic-receptor-â2 (ADRB2)(Gln27Glu), bradykinin-receptor-beta2 (BDKRB2)(+9/-9), aldosterone-synthase (CYP11B2)(T-344C) and adducin-1 (ADD1)(Gly460Trp). RESULTS The AGT (T235) allele (P = 0.0025, OR 2.02, 95% CI 1.24, 3.30) was found to be more prevalent in our HF group. The AGT (174M)-AGT (235T) haplotype was also associated with the HF phenotype (P = 0.0069). Exploratory evaluation of gene-gene combinations revealed an indicative association of the AGT (T235)/ACE(D) combined polymorphisms in the HF group (P = 0.02, OR 2.12, 95% CI 1.11, 4.06).

Conclusions: This study demonstrates that the SNPs of AGT may be associated with HF in our population and that the AGT/ACE gene combination may play an important role in disease predisposition.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Canada / epidemiology
  • Double-Blind Method
  • Female
  • Gene Frequency / genetics
  • Genetic Predisposition to Disease / genetics
  • Heart Failure / blood
  • Heart Failure / genetics*
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Genetic*
  • Renin-Angiotensin System / genetics*
  • Whites / genetics*