© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
The ACE gene polymorphism: the good, the bad and the ugly
Department of Clinical Pharmacology, University of Groningen, Groningen, The Netherlands
* Corresponding author. Tel.: +31-50-363-2810; fax: +31-50-363-2812.
See article by Perticone et al. ([3], pages 192–199) in this issue.
After its first entry into the scientific stage [1] the deletion polymorphism of the Angiotensin Converting Enzyme presented cardiovascular researchers with a grateful opportunity to explore genetic mechanisms in cardiovascular disease. However, after a Good start, conflicting results gave the genotype a Bad reputation, and the stage now looks rather Ugly. After having discovered how promiscuously ACE behaves as an enzyme, it became apparent that the genotype was not much more faithful, being associated with an enormous variety of cardiovascular disorders, ranging from an association with myocardial infarction, vascular changes, even to issues like the ability to increase one’s physical performance [2].
In this issue of Cardiovascular Research Perticone et al. [3] report in a carefully executed study an association between the Angiotensin Converting Enzyme (ACE) deletion type gene and the prevalence of left ventricular hypertrophy in a population of untreated italian hypertensives. One of the most striking findings was that the deletion type allele of ACE was related to a more eccentric type of hypertrophy. This data further extends earlier observations suggesting a relation between the ACE genotype and left ventricular hypertrophy [4] and the relation between the ACE genotype and the propensity for left ventricular dilatation after myocardial infarction [5].
Since the first description by Cambien et al. [1] the number of papers on the ACE genotype have steeply increased (Fig. 1). The most important lesson to date is that despite an impressive volume of data on the subject, we can still not answer exactly what the role is of the ACE genotype in cardiovascular disease. The associations between the ACE genotype and cardiovascular abnormalities are diffuse so that it is hard to define a common cardiovascular mechanism behind the associations. Therefore, the ACE genotype seems to be the victim of its own success, decreasing the clinical applicability with each novel association published, and making it more unlikely that a unifying explanation will become available to explain the wide variety of associations.
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So we still are left with many more questions than when Cambien first published his landmark paper. One of the main questions is whether a consistent pattern emerges from the available data so far. Firstly, it has been previously noted that the larger the sample size, the smaller the increase in relative risk associated with the genotype [6]. Secondly, large samples obtained in the United States failed to demonstrate an association [7] whereas studies in Europe and Japan more often yield an association. In general, associations are found both with altered myocardial architecture, and with vascular changes in the broadest sense. Secondly, the absence of any relation with higher blood pressure is also fairly consistent. The current study in this issue of Cardiovascular Research also is a relatively small European study in patients whose families had been living in Calabria (South Italy) for at least two generations. The study demonstrates an association with left ventricular hypertrophy but not with higher blood pressure. In that sense it extends the observations of myocardial changes associated with the ACE genotype.
The high amount of D-alleles in the sample investigated by Peticone et al. suggests that there are regional differences in the prevalence of the D-allele, particularly within small communities with a low migration rate. This further underlines that the role of the ACE genotype may depend importantly on the sample population, and possibly on genetic background.
Some aspects are quite obvious but have not yet been addressed: the first descriptions of the ACE deletion type gene in Europeans demonstrated an increase in circulating ACE activity in this population, which has been a most consistent finding in Europe. However, data on ACE activity in relation to the deletion allele is lacking for samples of the US populations in which associations with clinical end-points were absent. This suggests that the ACE genotype may have lost its linkage to a functional mutation in part of the ACE gene or another gene in subjects from a US lineage. The present study typically examines subjects with a low migration rate, so that it is conceivable that in the US population – which may be of a more heterogenous background – the deletion type allele identifies a smaller number of subjects that carry the ancestral gene variation that actually increases risk.
We are still also left without an explanation why the deletion type gene for ACE would be related to an altered cardiac architecture. The most obvious hypothesis postulates that the increase in ACE activity exerts its effects via increased angiotensin II levels. However, it is still unclear whether ACE is rate-limiting in the renin-angiotensin system, so that it is quite questionable whether the modest increase in ACE activity translates into elevated angiotensin II levels, and whether the effects of an increase in ACE activity may depend on renin-status.
Alternatively, the diffuse associations of the ACE genotype may also be related to the diffuse functions of the enzyme as it degrades a wide variety of substrates, including bradykinin, substance P, the hemopoietic stemcell regulator AcSDKP, and probably many more. Additionally, one could also postulate that an increase in ACE activity may decrease levels of Ang (1–7) which seems to be an intrinsic modulator of the activity of the renin-angiotensin system.
Finally, it is important to postulate that the associations found with the ACE genotype may have nothing to do with the enzyme at all, but that the deletion type allele is in linkage disequilibrium with a mutation in a completely different gene. As also indicated by Perticone et al., the proximity of the human growth hormone gene led to speculate about possible alterations in the growth hormone gene, but this has not yet been confirmed.
In conclusion, as evidenced by the paper of Perticone et al. in the current issue of Cardiovascular Research, the deletion type allele for ACE seems to confer a moderately increased risk for various cardiovascular disorders, including hypertension related eccentric hypertrophy. However, despite an impressive amount of data on the subject we do not seem to approach a better understanding of the exact magnitude of the risk, and of the mechanism underlying it.
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 Top References |
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- Cambien F., Poirier O., Lecerf L., et al. Deletion polymorphism in the gene for angiotensin converting enzyme is a potent risk factor for myocardial infarction. Nature (1992) 359:641–644.[CrossRef][Medline]
- Montgomery H.E., Marshall R., Hemingway H., et al. Human gene for physical performance. Nature (1998) 393:221–222.[CrossRef][Medline]
- Perticone F., Maio R., Cosco C., et al. Hypertensive left ventricular remodeling and ACE-gene polymorphism. Cardiovasc Res (1999) 43:192–199.
[Abstract/Free Full Text] - Schunkert H., Hense H.V., Holmer S.R., et al. Association between a deletion polymorphism of the angiotensin-converting enzyme gene and left ventricular hypertrophy. New Eng J Med (1994) 330:1634–1638.
[Abstract/Free Full Text] - Pinto Y.M., van Gilst W.H., Kingma J.H., Schunkert H. Deletion-type allele of the angiotensin-converting enzyme gene is associated with progressive ventricular dilation after anterior myocardial infarction. Captopril and Thrombolysis Study Investigators. J Am Coll Cardiol (1995) 25:1622–1626.[Abstract]
- Samani N.J., Thompson J.R., O’Toole L., Channer K., Woods K.L. A meta-analysis of the association of the deletion allele of the angiotensin-converting enzyme gene with myocardial infarction. Circulation (1996) 94:708–712.
[Abstract/Free Full Text] - Lindpainter K., Lee M., Larson M.G., et al. Absence of association or genetic linkage between the angiotensin-converting enzyme gene and left ventricular mass. New Eng J Med (1996) 334:1023–1028.
[Abstract/Free Full Text]
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