Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction

Abstract

Factors involved in the pathogenesis of atherosclerosis, thrombosis and vasoconstriction contribute to the development of coronary heart disease. In a study comparing patients after myocardial infarction with controls, we have explored a possible association between coronary heart disease and a variation found in the gene encoding angiotensin-converting enzyme (ACE). The polymorphism ACE/ID is strongly associated with the level of circulating enzyme. This enzyme plays a key role in the production of angiotensin II and in the catabolism of bradykinin, two peptides involved in the modulation of vascular tone and in the proliferation of smooth muscle cells. Here we report that the DD genotype, which is associated with higher levels of circulating ACE than the ID and II genotypes, is significantly more frequent in patients with myocardial infarction (n = 610) than in controls (n = 733) (P = 0.007), especially among subjects with low body-mass index and low plasma levels of ApoB (P < 0.0001). The ACE/ID polymorphism seems to be a potent risk factor of coronary heart disease in subjects formerly considered to be at low risk according to common criteria.

Association of the angiotensin-converting enzyme (ACE) gene G2350A dimorphism with essential hypertension

“…Several studies have suggested that the D allele of ACE I/D dimorphism confers increased risk of developing CVDs. 7,22,25 At the same time, considerable negative evidence exists on this question. An analysis of 11 000 cases and controls showed no relationship between MI and the I/D dimorphism.…”

“…3,4 An insertion/deletion (I/D) dimorphism, due to the presence or absence of a 287 base pair (bp) alu-type sequence in intron 16 of the ACE gene, has been shown to cosegregate with serum and tissue ACE activities, and that the D allele is associated with elevated ACE levels. [3][4][5] Thus, the ACE gene is viewed as a quantitative trait locus (QTL) that modulates circulating ACE levels, and the ACE I/D dimorphism is a marker that is thought to be in linkage disequilibrium (LD) with functional variants located in the ACE gene [6][7][8] that are implicated in CVDs.…”

Aspects of gene polymorphisms in cardiovascular disease: the renin‐angiotensin system

“…The mechanism underlying the association between the D allele and coronary risk could be related to an effect of the ACE genotype on ACE circulating and local levels. The distribution of plasma ACE levels in families is compatible with a Mendelian segregation of a major gene, possibly related to the presence, within or nearby the ACE gene, of a functional locus (a postulated ACE Ss polymorphism) that controls the levels of expression of the enzyme [37,43,45]. In the earliest study by Cambien et al, a genotype-dependent induction of ACE by ACE-inhibitors was also demonstrated.…”

“…It has been hypothesised that this trait is in strong linkage disequilibrium with a major gene locus controlling the ACE levels [43].…”

Protection against ischemia/reperfusion injury and myocardial dysfunction by antisense-oligodeoxynucleotide directed at angiotensin-converting enzyme mRNA

“…[1][2][3][4] ACE gene deletion polymorphism, which relates to a high plasma level of ACE, has been reported to be associated with a high risk of myocardial infarction and sudden death. [5][6][7][8] Many studies show that ACE activity and angiotensin-II (Ang-II) levels increase in plasma after acute myocardial ischemia, which may lead to exacerbation of myocardial ischemia, cardiac dysfunction and expansion of infarct size. 4,[9][10][11] A large body of data indicates that ACE inhibitors protect myocardium against ischemia/reperfusion in in vitro and in vivo animal models.…”