ACE Polymorphisms

Abstract

Abstract-Angiotensin converting enzyme (ACE) plays an essential role in two physiological systems, one leading to the production of angiotensin II and the other to the degradation of bradykinin. The wide distribution and multifunctional properties of these peptides suggest that ACE could be involved in various pathophysiological conditions. The discovery that ACE levels are under genetic control ushered in a new era of investigation; most studies focused on an insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene as a marker for a functional polymorphism. Recently, many single nucleotide polymorphisms were detected in the gene and the search for the locations of functional polymorphisms became a topic of extensive investigation. Nevertheless, association studies on the I/D polymorphism and clinical outcomes continued, mostly with conflicting results. This article reviews the current state of knowledge regarding ACE polymorphisms and suggests that a functional polymorphism is most likely located between intron 18 and the 3Ј UTR. The potential existence of another functional polymorphism in the 5Ј UTR, however, cannot be excluded. This review also presents an overview of ACE function in different pathophysiological systems, and summarizes previous reports on ACE and clinical outcomes. Although findings on the I/D polymorphism and disorders like diabetic nephropathy and Alzheimer disease can be considered conclusive, reports on most of the cardiovascular phenotypes are still controversial. Genotypic and phenotypic misclassifications, insufficient power in some studies, and the presence of interaction with other genes or environmental factors are possible explanations for the contradictory findings.

Polymorphisms of angiotensinogen and angiotensin-converting enzyme associated with lower extremity arterial disease in the Health, Aging and Body Composition study

“…In fact, this racial difference in the effects of ACE inhibitor for hypertensive treatment was observed in the Antihypertensive and Lipid-Lowering Treatment 41 The ACE gene is located in intron 16, a non-coding site. 42 Thus, the ACE activity may be influenced by other polymorphisms within or nearby the ACE gene through the linkage disequilibrium with ACE_I/D. Future studies are needed to investigate other polymorphisms of the ACE gene and their interaction with A-T haplotype for the risk of LEAD in these participants.…”

Genetics of arterial hypertension and hypotension

“…12 Topology and localization of mutations in Barttin, that cause Bartter's syndrome type 4 and in the NaCl-Cotransporter, that cause Gitelman's syndrome, both monogenic forms of hypotension somatic ACE form using exons 1 to 26 except 13 which is widely expressed, and by alternative splicing to ii) a testicular form using exons 13 to 26, which is required for male fertility. Another ACE homologue, ACE2, encoded on the X-chromosome and expressed in heart, kidney and testes, is involved in the inactivation of AngII (for review of the ACE system, see Sayed-Tabatabaei et al 2006). Numerous reports have linked a common insertion-deletion (I/D) polymorphism in the ACE gene with a wide variety of diseases including hypertension, atherosclerosis, cardiac hypertrophy, stent stenosis, progression of kidney diseases and more.…”

A genome-wide association study identifies new loci for ACE activity: potential implications for response to ACE inhibitor

“…Angiotensin II also contributes to other biological processes either through direct pathological effects on tissues, including vascular remodeling and inflammation or through indirect action on nitric oxide bioavailability and its consequences. 9 Furthermore, the ACE genetic variation, in particular Alu insertion/deletion polymorphism in intron 16, has been associated with the risk of a wide range of clinical outcomes including cardiovascular diseases, response to ACE inhibitor (ACEI) therapy, diabetic nephropathy, muscle performance, longevity and Alzheimer's disease, 10,11 although the results are conflicting.…”