doi: 10.1161/01.RES.0000223145.74217.e7
© 2006 American Heart Association, Inc.
Review |
ACE Polymorphisms
From the Departments of Epidemiology & Biostatistics (F.A.S.-T., A.I., C.M.v.D., J.C.M.W.) and Clinical Genetics (B.A.O.), Erasmus Medical Centre, Rotterdam, The Netherlands.
Correspondence to F.A. Sayed-Tabatabaei, MD, PhD, Department of Epidemiology & Biostatistics, Erasmus Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail fakhredin{at}gmail.com
This Review is part of a thematic series on Angiotensin-Converting Enzyme, which includes the following articles:
Six Truisms Concerning ACE and the Renin-Angiotensin System Educed from the Genetic Analysis of Mice
ACE II in the Heart and the Kidney
Signaling by the Angiotensin-Converting Enzyme
ACE Polymorphisms
ACE and Vascular Remodeling
Kathy K. Griendling and Rudi Busse Editors
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 3' UTR. The potential existence of another functional polymorphism in the 5' 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.
Key Words: angiotensin • polymorphism • genetics
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