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Angiotensin Converting Enzyme Gene Insertion/Deletion Polymorphism and Cardiovascular Disease

Therapeutic Implications

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Abstract

Cardiovascular disease is the major cause of morbidity and mortality in Westernised societies. It is well known that the aetiology of this devastating disorder involves both genetic and environmental factors. Sequence variants of the components of the renin-angiotensin-aldosterone system and the kallikrein-kinin system are suggested to have significant influences on cardiovascular homeostasis.

Both gene targeting and transgenic studies in mice have clearly suggested a critical role of the angiotensin converting enzyme (ACE) gene in blood pressure regulation. Furthermore, an up-regulation of myocardial ACE gene expression has been observed in patients with heart failure. Thus, the ACE gene has been recognised as a top candidate gene for cardiovascular research.

Over the past decade, the insertion/deletion (I/D) polymorphism of a 287-bp Alu element in intron 16 of the ACE gene has attracted significant attention and has been extensively investigated in a spectrum of cardiovascular phenotypes, because of its correlation with serum ACE activity. A large majority of previous studies have shown a positive association between the DD genotype and an increased risk of myocardial infarction, but results in hypertension, left ventricular hypertrophy, cardiomyopathy and restenosis after percutaneous transluminal coronary angioplasty remain quite controversial.

Since ACE inhibitors are widely used in hypertension and congestive heart failure, we also review the literature on the relationship of ACEI/D polymorphism with ACE inhibitor response. It appears that this polymorphism has some moderate impact on the cardiovascular response to ACE inhibitors but there is no consensus as to which allele confers a more pronounced effect. In addition, previous data are suggestive of an association between the ACE I allele and a greater risk of increased occurrence of ACE inhibitor-induced cough, but such a relationship needs further confirmation. Overall, since ACE I/D is only an intronic marker, the true locus that controls the ACE enzyme activity remains to be identified, and could be located within either the ACE gene or another nearby gene such as the human growth hormone gene. We note that since associations tend to vary across different gender or ethnic groups, or across different socio-ecological settings, consideration of potential gene-gene and gene-environment interactions should be made. Furthermore, the dissection of the genetic underpinning of cardiovascular disease needs delineation of all molecular variants of the key physiological pathways that influence cardiovascular function.

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Acknowledgements

This work is supported in part by NIEHS Kresge Center Grant ES-00002 and IR01 HL64109-01 from NHLBI. GeneVISTA version 1.0 is developed by Dr Niu in collaboration with Dr. Zhenjun Hu, and is available upon request from Dr Niu. We are also grateful to Dr. Scott Venners and Ms. Marcia Rich for their comments and careful reading.

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Authors and Affiliations

  1. Program for Population Genetics, Harvard School of Public Health, 665 Huntington Ave., Boston, FXB-101, Massachusetts, 02115-6195, USA

    Tianhua Niu & Xiping Xu

  2. Department of Pharmacology, Hunan Medical University, Changsha, Hunan, China

    Xiu Chen

  3. Center for Ecogenetics and Reproductive Health, Beijing Medical University, Beijing, China

    Xiping Xu

  4. The Channing Laboratory, Department of Medicine, Harvard Medical School, Brigham, USA

    Xiping Xu

  5. Women’s Hospital, Boston, Massachusetts, USA

    Xiping Xu

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  1. Tianhua Niu
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  2. Xiu Chen
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Correspondence to Tianhua Niu.

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Niu, T., Chen, X. & Xu, X. Angiotensin Converting Enzyme Gene Insertion/Deletion Polymorphism and Cardiovascular Disease. Drugs 62, 977–993 (2002). https://doi.org/10.2165/00003495-200262070-00001

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