Renin–angiotensin system gene polymorphisms: potential mechanisms for their association with cardiovascular diseases

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Abstract

Since the first description of the angiotensin-converting enzyme insertion/deletion polymorphism more than a decade ago, many hundreds of investigations have reported associations between this polymorphism and cardiovascular diseases. Subsequently, similar studies were performed in relationship with several other renin–angiotensin system gene polymorphisms, most notably the angiotensinogen M235T polymorphism and the angiotensin AT1 receptor A1166C polymorphism. Surprisingly however, especially in view of the many contradictory results that have been obtained, very little attention has been paid to the mechanism(s) that may link these genetic variants and respective diseases. Here, we review the limited evidence that is currently available on the functional consequences (including compensatory mechanisms) of the above three renin–angiotensin system gene polymorphisms, in order to provide an explanation for the reported associations (or lack thereof) between these polymorphisms and cardiovascular diseases.

Introduction

In the past decade, associations between several cardiovascular diseases and polymorphisms of renin–angiotensin system genes have been reported, in particular for the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme gene, the M235T polymorphism of the angiotensinogen gene and the A1166C polymorphism of the angiotensin AT1 receptor gene. Although many of these associations were supported or disputed in hundreds of subsequent investigations, little attention has been paid to the mechanisms that may link these genetic variants and respective diseases. Specifically, the intermediate phenotypes that may result from these polymorphisms should be identified in much more detail in order to understand why contradictory results have been obtained. In this respect, the only observations that have been made consistently are elevated angiotensin-converting enzyme levels in carriers of the angiotensin-converting enzyme D allele and elevated angiotensinogen levels in carriers of the angiotensinogen T235 variant (Fig. 1). Convincing evidence for a relationship between angiotensin AT1 receptor density and/or function and the angiotensin AT1 receptor C allele has not yet been obtained.

In the present study, we review the limited evidence that is currently available on the functional consequences (including compensatory mechanisms) of the above three renin–angiotensin system gene polymorphisms, in order to provide an explanation for the reported associations (or lack thereof) between these polymorphisms and cardiovascular diseases.

Section snippets

Angiotensin-converting enzyme gene I/D polymorphism

Angiotensin-converting enzyme is an ectoenzyme found in most mammalian tissues on the external surface of the plasma membrane of endothelial and epithelial cells. In addition, an active, soluble form of angiotensin-converting enzyme, derived from endothelial cells, is present in circulating blood plasma. Angiotensin-converting enzyme cleaves a number of substrates, most notably, angiotensin I and bradykinin. Angiotensin I is activated to the vasoconstrictor angiotensin II, while bradykinin, a

Angiotensin-converting enzyme gene I/D polymorphism

Functional angiotensin-converting enzyme genotype-related differences in angiotensin I–II conversion have been studied in vivo either by quantifying regional angiotensin I–II conversion during infusion of angiotensin I or by measuring potential differences in pressor responses to angiotensin I Lachurié et al., 1995, Ueda et al., 1995, Chadwick et al., 1997, Danser et al., 1999, Van Dijk et al., 2000. Only one of these studies (Ueda et al., 1995) provided evidence for enhanced angiotensin I–II

Renin–angiotensin system gene polymorphisms and the effect of renin–angiotensin system blockade

Studying the effects of renin–angiotensin system blockade in relationship with renin–angiotensin system gene polymorphisms provides an alternative approach of unraveling the importance of these polymorphisms. However, the interpretation of such studies is complex. At first sight, one would predict that subjects with elevated levels of a certain renin–angiotensin system component need higher doses of renin–angiotensin system blockers to obtain equally sufficient blockade. For instance, patients

Renin–angiotensin system gene polymorphisms and complex cardiovascular diseases

Given the uncertainty as to whether the angiotensin-converting enzyme I/D polymorphism has any implications for the rates of angiotensin I–II conversion or bradykinin degradation, it may be of surprise how intensively the association with this genetic variant and complex disorders has been studied (for review see Samani et al., 1996 and Schunkert et al., 1997). Indeed, one of the most extensively studied associations between any genetic polymorphism and a cardiovascular disease is that of the

Conclusions and directions for future investigations

This review summarises initial data from a young discipline: genetics of complex diseases. In fact, the angiotensin-converting enzyme I/D polymorphism was the first to be associated with myocardial infarction. While data on this topic are fashionable and provocative, we must realise that answers from associations with complex diseases will not come easily. Right now, we learn more on how we should perform studies properly rather than about specific questions on the genes that cause

Acknowledgements

We wish to acknowledge the statistical advice from Dr. M. Fischer.

References (83)

  • S Mizuiri et al.

    Renal ACE immunohistochemical localization in NIDDM patients with nephropathy

    Am. J. Kidney Dis.

    (1998)
  • U.F Mondorf et al.

    Contribution of angiotensin I-converting enzyme gene polymorphism and angiotensinogen polymorphism to blood pressure regulation in essential hypertension

    Am. J. Hypertens.

    (1998)
  • Y Nakano et al.

    Angiotensin I-converting enzyme gene polymorphism and acute response to captopril in essential hypertension

    Am. J. Hypertens.

    (1997)
  • N Ohmichi et al.

    Relationship between the response to the angiotensin converting enzyme inhibitor imidapril and the angiotensin converting enzyme genotype

    Am. J. Hypertens.

    (1997)
  • A Pende et al.

    Characterization of the binding of the RNA-binding protein AUF1 to the human AT(1) receptor mRNA

    Biochem. Biophys. Res. Commun.

    (1999)
  • Y.M Pinto et al.

    Deletion-type allele of the angiotensin-converting enzyme gene is associated with progressive ventricular dilatation after anterior myocardial infarction

    J. Am. Coll. Cardiol.

    (1995)
  • P.J.J Admiraal et al.

    Metabolism and production of angiotensin I in different vascular beds in subjects with hypertension

    Hypertension

    (1990)
  • P.J.J Admiraal et al.

    Regional angiotensin II production in essential hypertension and renal artery stenosis

    Hypertension

    (1993)
  • A Bonnardeaux et al.

    Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension

    Hypertension

    (1994)
  • N.J Brown et al.

    ACE insertion/deletion polymorphism affects bradykinin metabolism

    J. Cardiovasc. Pharmacol.

    (1998)
  • H Buikema et al.

    The deletion polymorphism of the angiotensin-converting enzyme gene is related to phenotypic differences in human arteries

    Eur. Heart J.

    (1996)
  • I.G Chadwick et al.

    Pressor and hormonal responses to angiotensin I infusion in healthy subjects of different angiotensin-converting enzyme genotypes

    J. Cardiovasc. Pharmacol.

    (1997)
  • M Challah et al.

    Angiotensin I-converting enzyme genotype influences arterial response to injury in normotensive rats

    Arterioscler. Thromb. Vasc. Biol.

    (1998)
  • A.H.J Danser et al.

    Metabolism of angiotensin I by different tissues in the intact animal

    Am. J. Physiol.

    (1992)
  • A.H.J Danser et al.

    Cardiac renin and angiotensins: uptake from plasma versus in situ synthesis

    Hypertension

    (1994)
  • A.H.J Danser et al.

    Angiotensin-converting enzyme in the human heart. Effect of the deletion/insertion polymorphism

    Circulation

    (1995)
  • A.H.J Danser et al.

    Prorenin, renin, angiotensinogen and ACE in normal and failing human hearts: evidence for renin-binding

    Circulation

    (1997)
  • A.H.J Danser et al.

    Angiotensinogen (M235T) and angiotensin—converting enzyme (I/D) polymorphisms in association with plasma renin and prorenin levels

    J. Hypertens.

    (1998)
  • A.H.J Danser et al.

    Determinants of interindividual renin and prorenin variation. Evidence for a sexual dimorphism of (pro)renin in humans

    J. Hypertens.

    (1998)
  • A.H.J Danser et al.

    Angiotensin I-to-II conversion in the human forearm and leg. Effect of the ACE gene I/D polymorphism

    J. Hypertens.

    (1999)
  • L.M De Lannoy et al.

    Renin–angiotensin system components in the interstitial fluid of the isolated perfused rat heart. Local production of angiotensin I

    Hypertension

    (1997)
  • C Dudley et al.

    Prediction of patient response to antihypertensive drugs using gene polymorphisms: investigation of renin–angiotensin system genes

    J. Hypertens.

    (1996)
  • Editorial, 1999. Freely associating. Nat. Genet., 22 (1999)...
  • L Faure-Delanef et al.

    Plasma concentration, kinetic constants, and gene polymorphism of angiotensin I-converting enzyme in centenarians

    Clin. Chem.

    (1998)
  • M Fornage et al.

    Variation in the region of the angiotensin-converting enzyme gene influences interindividual differences in blood pressure levels in young white males

    Circulation

    (1998)
  • S.A Griffin et al.

    Angiotensin II causes vascular hypertrophy in part by a non-pressor mechanism

    Hypertension

    (1991)
  • M Haas et al.

    Angiotensin-converting enzyme gene polymorphism determines the antiproteinuric and systemic hemodynamic effect of enalapril in patients with proteinuric renal disease. Austrian study group of the effects of enalapril treatment in proteinuric renal disease

    Kidney Blood Pressure Res.

    (1998)
  • L.J Heller et al.

    Myocardial and plasma renin–angiotensinogen dynamics during pressure-induced cardiac hypertrophy

    Am. J. Physiol.

    (1998)
  • D Henrion et al.

    Angiotensin II type 1 receptor gene polymorphism is associated with an increased vascular reactivity in the human mammary artery in vitro

    J. Vasc. Res.

    (1998)
  • J Higaki et al.

    Deletion allele of angiotensin-converting enzyme gene increases risk of essential hypertension in Japanese men: the Suita Study

    Circulation

    (2000)
  • K.F Hilgers et al.

    1166 A/C polymorphism of the angiotensin II type 1 receptor gene and the response to short-term infusion of angiotensin II

    Circulation

    (1999)

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