Renin-angiotensin system inhibitors, angiotensin I-converting enzyme gene insertion/deletion polymorphism, and cancer: the Rotterdam Study

Cancer. 2008 Feb 15;112(4):748-57. doi: 10.1002/cncr.23215.


Background: Angiotensin I-converting enzyme (ACE) inhibitors, angiotensin II antagonists, and the ACE insertion/deletion (I/D) gene polymorphism all influence serum angiotensin II action. Because angiotensin II levels have been associated with cancer, the objective of the current epidemiologic study was to investigate whether renin-angiotensin system inhibitors and/or ACE genotypes were associated with an altered risk of colorectal, lung, breast, and prostate cancer.

Methods: Data were obtained from the Rotterdam Study, a population-based, prospective cohort study with 7983 participants. Participants who had a history of 1 of the cancers of interest (n = 216) or who had a medication history <6 months (n = 88) were excluded, leaving 7679 participants, of whom the ACE genotypes could be assessed in 6670 individuals. The mean follow-up was 9.6 years, during which 730 incident cancers occurred. The effect of medication, ACE I/D genotypes, and their interaction on cancer risk and progression was studied by using Cox proportional hazard models.

Results: Carriers of the high-activity genotype DD had an increased risk of breast cancer compared with low-activity II/ID genotype carriers (hazard ratio [HR], 1.47; 95% confidence interval [95% CI], 1.05-2.04), but no association was demonstrated for other cancers. DD carriers who were exposed to long-term and high-dose medication were at lower risk for cancer (HR, 0.28; 95% CI, 0.10-0.79). Short-term, high-dose users were at risk for colorectal cancer progression in the II/ID stratum (HR, 3.83; 95% CI, 1.67-8.79).

Conclusions: Renin-angiotensin system-inhibiting drugs seemed to protect against cancer in individuals with the DD genotype, which was associated with high levels of ACE.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Angiotensin II Type 1 Receptor Blockers / therapeutic use*
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / epidemiology
  • Breast Neoplasms / genetics
  • Cohort Studies
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / epidemiology
  • Colorectal Neoplasms / genetics
  • Female
  • Follow-Up Studies
  • Genotype
  • Humans
  • Incidence
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / epidemiology
  • Lung Neoplasms / genetics
  • Male
  • Middle Aged
  • Mutagenesis, Insertional
  • Neoplasms / drug therapy*
  • Neoplasms / epidemiology
  • Neoplasms / genetics
  • Netherlands / epidemiology
  • Peptidyl-Dipeptidase A / genetics*
  • Polymorphism, Genetic
  • Proportional Hazards Models
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / epidemiology
  • Prostatic Neoplasms / genetics
  • Renin-Angiotensin System / drug effects
  • Risk Assessment / statistics & numerical data
  • Sequence Deletion


  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin-Converting Enzyme Inhibitors
  • Peptidyl-Dipeptidase A