The ACE Insertion/Deletion Polymorphism and Risk of Cancer, a Review and Meta-Analysis of the Literature

R.      Ruiter; L.      E. Visser; C.      M. Van Duijn; B.      H.Ch. Stricker

doi:10.2174/156800911795538147

Abstract

The renin-angiotensin system (RAS) plays an important role in the regulation of the cardiovascular system. In addition to RAS enzymes in plasma, the RAS is present in various local organ systems. Moreover, local expression of the RAS has been shown in various malignant cells. In 1990, an insertion/deletion (I/D) polymorphism in the ACE gene was discovered, accounting for half of the variance of the serum ACE enzyme levels. Serum ACE concentrations were significantly higher in homozygotes with the shorter deletion allele (DD) than in heterozygotes (ID) or in homozygotes with the longer insertion allele (II). Since 2000, twentyfour studies have been published hypothesizing an association between the ACE I/D polymorphism and cancer risk. This review focuses on the insertion/deletion polymorphism in the ACE gene in association with the risk of cancer and consequently on its potential role as therapeutic drug target in cancer. Furthermore a meta-analysis of the published studies was performed. Fourteen statistically non-significant studies were found, as well as ten studies with a statistically significant finding. The results of the meta-analyses performed were not consistent. However, both methods (one based on the Fisher p-value, and one on inverse variance weighted meta-analysis), indicated a (nearly) statistically significantly decreased risk in carriers of the II genotype in comparison to the DD genotype with regard to risk of prostate cancer and risk of (postmenopausal) breast cancer. Nevertheless, results show a large variation and are often contradictory. As this may be partly explained by a lack of power, genotyping techniques, and choice of study population, it is expected that future studies will shed more light on these associations.

Keywords: ACE, renin-angiotensin system, polymorphism, cancer, Angiotensin 1 Receptor, Colorectal cancer, Chymase gene, decapeptide angiotensin I, bradykinin