ClinVar

Cambien et al. (1992) stated that the ACE enzyme plays a key role in the production of angiotensin I/I and in the catabolism of bradykinin, 2 peptides involved in the modulation of vascular tone and in the proliferation of smooth muscle cells. Cambien et al. (1988) showed that about 50% of the interindividual variability of plasma ACE concentration is determined by a major gene effect. Soubrier et al. (1988) cloned the ACE gene, and Tiret et al. (1992) demonstrated that this major gene effect is associated with an insertion (I)/deletion (D) polymorphism involving about 250 bp situated in intron 16 of the ACE gene, the so-called ACE/ID polymorphism. Rigat et al. (1990) found that the ACE/ID polymorphism was strongly associated with the level of circulating enzyme. The mean plasma ACE level of DD subjects was about twice that of II subjects, with ID subjects having intermediate levels. Rigat et al. (1992) determined that the ACE insertion corresponds to an Alu repetitive sequence and is 287 bp long.

Jeffery et al. (1999) studied 97 Ghanaian individuals and found significantly lower ACE levels in those with the II genotype than in those with the ID or DD genotype, but no difference between the ID or DD groups. Jeffery et al. (1999) concluded that the D allele shows dominance rather than codominance relative to the I allele.

Pharmacologic ACE inhibition enhances survival of human endothelial cells (ECs) by upregulating genes involved in cell growth, survival, and immortalization. Hamdi and Castellon (2004) found that human ECs with the II genotype showed enhanced growth, increased cell survival in culture after slow starvation, and reduced angiotensin II levels compared with ECs with the DD genotype. The ACE inhibitor captopril significantly enhanced the viability of DD cells, but it had little effect on II cells. Hamdi and Castellon (2004) concluded that ACE inhibitors protect DD cells by upregulating genes involved in cell survival and renewal.

Association with Coronary Artery Disease and Myocardial Infarction

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 (MI) with controls, Cambien et al. (1992) found association between coronary heart disease and the ACE/ID polymorphism. They determined that the frequency of the ACE/DD genotype in the 'general population' is approximately 0.27. The ACE polymorphism was unrelated to blood pressure and hypertension. Cambien et al. (1992) estimated that in the low-risk group, i.e., those without tobacco usage, high blood pressure, diabetes, obesity, or hypercholesterolemia, the ACE/DD genotype may account for 35% of cases of myocardial infarction. The results of these studies correlate with those of Pfeffer et al. (1992), which showed that administration of an ACE inhibitor not only decreased the risk of developing heart failure but also reduced the risk for recurrent myocardial infarction. Experimental studies had shown that ACE gene expression is increased in myocardial tissue after coronary artery occlusion.

Among 185 male and 49 female survivors of myocardial infarction below 56 and 61 years of age, respectively, Bohn et al. (1993) failed to find results similar to those reported by Cambien et al. (1992). They offered several possible explanations for the different results. Bohn et al. (1993) also studied the possible association between premature parental myocardial infarction (before age 61 in mothers and/or before age 56 years in fathers) and the I/D polymorphism in the ACE gene in 181 male and 48 female myocardial infarction survivors. In the total series, the frequency of premature parental MI was 14% in DD, 10.6% in ID, and 6.1% in II individuals. Thus, the ACE polymorphism may be an important genetic marker of MI risk and contribute to clustering of premature MI in families.

Schachter et al. (1994) undertook a case-control study of 338 centenarians in comparison with adults aged 20 to 70 years. Surprisingly, they found that the DD genotype, which predisposes to coronary heart disease, has an increased frequency in centenarians.

Ruiz et al. (1994) compared the frequency of the deletion polymorphism in 132 unrelated individuals with noninsulin-dependent diabetes mellitus (NIDDM; 125853) who had had myocardial infarction or significant coronary stenoses and 184 NIDDM individuals with no history of coronary heart disease. They found that the D allele was a strong and independent risk factor for coronary heart disease in NIDDM patients. It was associated with early-onset coronary heart disease in NIDDM, independently of hypertension and lipid values. A progressively increasing relative risk was observed in individuals heterozygous and homozygous for the D allele, suggesting a codominant effect. The percentage of coronary heart disease attributable to the ACE deletion allele was 24% in this NIDDM population.

Evans et al. (1994) determined the frequency of the ACE I/D polymorphism in 313 fatal cases of definite and possible myocardial infarction that came to autopsy in the Belfast, Northern Ireland area. In comparison to controls from the same population, the autopsy cases had an increased frequency of the ACE D allele (p less than 0.02). The overall odds ratios were 2.2 for DD versus II, and 1.8 for ID versus II.

Lindpaintner et al. (1995) were unable to confirm the association between the D allele and increased risk of ischemic heart disease or myocardial infarction in a large, prospectively followed population of U.S. male physicians.

In an angiographically defined study sample, Winkelmann et al. (1996) failed to find an association between ACE I/D gene polymorphism and coronary artery disease, although an effect on plasma ACE activity could be demonstrated. On the other hand, in a study of 388 white Italian patients of whom 255 had proven coronary atherosclerosis and 133 had angiographically normal coronary arteries, Arbustini et al. (1995) found that the deletion allele, whether homozygous or heterozygous, was the strongest risk factor for atherosclerosis, and that the D allele was significantly associated with the risk of infarction (although to a lesser extent than with permanent atherosclerosis). Hypertension proved to be unrelated with the ACE genotype.

Oike et al. (1995) suggested that the DD genotype relates to a greater risk for myocardial infarction in patients with coronary artery spasm (CAS). This would explain the greater risk for myocardial infarction of persons with the D allele, especially persons normally considered to be at low risk. Coronary artery spasm is considered to be one mechanism for developing MI. Oike et al. (1995) studied 150 angiographically assessed Japanese males, all more than 60 years of age. Coronary artery spasm was detected using intracoronary injection of ergonovine maleate. The subjects were divided into 3 groups: those with CAS, those without CAS but with fixed organic stenosis, and those without CAS and no organic stenosis. DD subjects were significantly represented in group 1 when compared with groups 2 and 3.

Ohishi et al. (1993) presented data indicating that the DD genotype is associated with an increased risk of restenosis after percutaneous transluminal angioplasty for widening the lumen of coronary arteries stenosed by atherosclerotic lesions. Amant et al. (1997) examined the relationship between the ACE I/D polymorphism and restenosis following coronary artery stenting in 146 consecutive patients. They found that restenosis was more than twice as common in those patients with the DD genotype than in those with the II genotype, possibly implicating the renin-angiotensin system in the pathogenesis of restenosis after coronary stenting.

In 2,267 male Caucasians, Gardemann et al. (1998) found an association of the D allele with coronary artery disease in subjects less than 61.7 years of age but not in patients 61.7 years or older. Exclusion of individuals with other cardiovascular risk factors (e.g., high body mass index) produced an even stronger association of the D allele with coronary artery disease.

Keavney et al. (2000) compared 4,629 myocardial infarction cases and 5,934 controls for presence or absence of the ACE I/D polymorphism. The ACE DD genotype was found in 1,359 (29.4%) of the myocardial infarction cases and in 1,637 (27.6%) of the controls (risk ratio 1.10 with a 95% confidence interval of 1.00 to 1.21). The association between myocardial infarction and the DD genotype did not seem to be stronger in the subgroup defined as low risk by previously used criteria or in any other subgroup. Nor was the ACE ID genotype predictive of subsequent survival. Keavney et al. (2000) also performed a metaanalysis of previously published studies, and found the risk ratio for myocardial infarction with the DD genotype to lie between 1.0 and 1.1. Although an increase in risk of up to 10 to 15% cannot be ruled out, substantially more extreme risks can be.

Sayed-Tabatabaei et al. (2005) determined the ACE I/D polymorphism and smoking status in 6,714 individuals and recorded fatal and nonfatal myocardial infarctions and mortality events. Among smokers, they found an increased risk of cardiovascular mortality for younger (below the median age of 68.2 years) carriers of the D allele (p = 0.03). No association was observed between ACE genotype and myocardial infarction.

Schurks et al. (2009) found no association between the ACE I/D polymorphism (rs1799752) and cardiovascular disease or migraine (157300) in a cohort of 25,000 white women.

Association with IgA Nephropathy

Yoshida et al. (1995) found that the deletion polymorphism in the ACE gene is a risk factor for progression to chronic renal failure in IgA nephropathy (161950), and that the deletion polymorphism predicts therapeutic efficacy of ACE inhibition on proteinuria and, potentially, on progressive deterioration of renal function. They found that 43% of patients who showed decline of renal function had the DD homozygous genotype, whereas it was present in only 7% of age-matched individuals without a history of the proteinuria and in only 16% of a group of patients with IgA nephropathy and stable renal function. After 48 weeks of ACE inhibitor administration, proteinuria significantly decreased in patients with the DD genotype but not in those with ID or II genotypes.

Using multivariant analysis, Pei et al. (1997) found that the presence of the ACE DD polymorphism adversely affected disease progression in IgA nephropathy only in patients with the met235/met235 (MM) genotype of the AGT gene (106150.0001).

Yoon et al. (2002) investigated the interdependent action of the insertion/deletion polymorphism of the ACE gene and the ala379-to-val polymorphism in exon 11 of PLA2G7 (601690.0003), which encodes a functional agonist of platelet-activating factor (PAF) on the progression of IgA nephropathy. They analyzed both polymorphisms in patients with primary IgA nephropathy who were followed up for longer than 3 years. During the follow-up, the disease progressed in 38 of the 191 patients. The D allele of the ACE gene in the absence of the T allele of the PLA2G7 gene did not affect the prognosis, nor did the T allele in the absence of the D allele. However, the presence of both was a significant prognostic factor. The results suggested that the interdependent effects of ACE and PLA2G7 polymorphisms on the progression of IgA nephropathy may be more important than the effect of the individual polymorphisms.

Association with Alzheimer Disease

Following reports that the DCP1*D allele of the common I/D polymorphism in the DCP1 gene is associated with increased longevity (Schachter et al., 1994), Kehoe et al. (1999) hypothesized that DCP1*D may protect against the development of Alzheimer disease (AD; 104300) and that, conversely, the DCP1*I allele may confer increased risk. They tested this hypothesis in samples from Cardiff, London, and Belfast. They reported findings suggesting that genetic variation at the DCP1 locus predisposes to AD in a manner that is independent of APOE variation. They considered the possibility that the low frequency of the DD homozygous genotype in AD may have been due to the exclusion of cases with cardiovascular disease. They thought this possibility unlikely for a number of reasons: first, the impact of the DD genotype on cardiovascular disease is controversial, relatively small, and restricted to specific geographic areas and to patient subgroups with highly heterogeneous clinical manifestations. Second, cases with vascular symptoms were only excluded from the groups of patients they studied if they had histories of obvious stepwise cognitive deterioration consistent with vascular dementia. Third, vascular dementia cases were also excluded from the screened age-matched control groups. Fourth, their control allele and genotype frequencies were similar to those reported for the general population by a number of studies, including 1 from a very similar geographic location. Finally, analysis of DCP1 genotypes in 15 additional vascular dementia cases, and in 21 dementia cases with a history of stroke excluded from the London sample, showed an excess of the DCP1*I allele rather than an excess of the DD genotype.

Hu et al. (1999) studied the ACE I/D polymorphism in 133 Japanese sporadic AD patients and 257 controls and found that the ACE II genotype was associated with susceptibility to AD. The frequency of the II genotype was 1.4 times higher in AD than controls, while that of the DD genotype was only 0.4 times higher in AD than controls.

Elkins et al. (2004) performed a metaanalysis of 23 independent published studies that investigated the association between Alzheimer disease and the ACE I/D polymorphism. Review of the data showed that the OR for AD in individuals with the I allele (II or ID genotype) was 1.27 compared to those with the DD genotype. The risk of AD was higher among Asians (OR of 2.44) and in patients younger than 75 years of age (OR of 1.54). Elkins et al. (2004) concluded that the ACE I allele is associated with an increased risk of late-onset AD, but noted that the risk is very small compared to the effects of other alleles, especially APOE4 (see 107741).

Association with Microvascular Complications of Diabetes 3

Marre et al. (1994) and Doria et al. (1994) reported that the I/D polymorphism of the ACE gene is associated with diabetic nephropathy (MVCD3; 612634), but this association was disputed by others, e.g., Tarnow et al. (1995) and Schmidt et al. (1995). Marre et al. (1997) undertook a large-scale, multicenter study on insulin-dependent diabetic subjects at risk of kidney complications due to long-term exposure to hyperglycemia, i.e., those who had developed proliferative diabetic retinopathy, to test the relationship between genetic factors and renal involvement in insulin-dependent diabetes mellitus (222100). The study concluded that the ACE gene is involved in both the susceptibility to diabetic nephropathy and its progression toward renal failure, and an interaction between ACE I/D and an M235T polymorphism in the AGT gene (106150.0001) was found that could account for the degree of renal involvement in the patients studied.

Vleming et al. (1999) studied the contribution of the I/D polymorphism in 79 patients with end-stage renal failure due to diabetic nephropathy and in 82 age-matched controls with 15 years of IDDM but without microalbuminuria. There was significant overrepresentation of the DD genotype with a significant increase of the D-allele frequency in the cases compared to controls. The presence of the DD genotype increased the risk of end-stage renal failure compared to other genotypes (odds ratio, 2.1; 95% CI, 1.1-4.0). However, the presence of 1 D-allele did not increase the risk.

In mice rendered diabetic, Huang et al. (2001) demonstrated that those mice who had a third copy of the Ace gene, and as a result higher enzyme levels (comparable to those associated with the variant D allele), developed increased blood pressures and overt proteinuria indicative of nephropathy.

Association with Type 2 Diabetes

The I allele of the I/D ACE polymorphism appears to be protective against the complications of type 2 diabetes (125853). Low birth weight, a marker of an adverse intrauterine environment, is associated with higher rates of type 2 diabetes. Kajantie et al. (2004) examined whether the ACE I/D polymorphism could explain or modify the association between low birth weight and adulthood glucose tolerance. They measured plasma glucose and insulin concentrations after an oral glucose challenge in a group of 423 men and women, ages 65 to 75 years, with measurements at birth recorded. The presence of the I allele was associated with shorter duration of gestation (p = 0.006) and, relative to gestational age, higher birth weight (p = 0.008) and length (p = 0.02). The I allele was associated with lower glucose at 120 minutes (p = 0.04) and a greater insulin response (p = 0.03 for insulin at 30 minutes and p = 0.06 for insulin area under the curve) to a standard oral glucose tolerance test. However, the associations between the ACE genotype and adulthood insulin secretion were present only in people with low birth weight. The authors concluded that the ACE I allele is associated with shorter duration of gestation and higher birth weight. The association between the presence of the ACE I allele and increased indices of adult insulin secretion is confined to subjects with low birth weight. The authors suggested that these findings reflect interactions between genotype and intrauterine environment with resulting changes in gene expression.

Association with Meningococcal Disease

Harding et al. (2002) recorded illness severity for 110 consecutive white pediatric patients with meningococcal disease and analyzed the results in terms of the ACE I/D polymorphism. Compared to children with an I allele, those with the DD genotype had a higher predicted risk of mortality (p = 0.01), worse Glasgow Meningococcal Septicemia Prognostic Scores (p = 0.014), greater need for inotropes (p = 0.034) and ventilation (p = 0.044), and longer stays in the pediatric intensive care unit (p = 0.021). DD genotype was 6% for the 18 children who did not require PICU care, 33% for the 84 PICU survivors, and 45% for those who died (p = 0.013). Harding et al. (2002) concluded that the ACE DD genotype is associated with increased illness severity in meningococcal disease.

Association with Preterm Cardiorespiratory Disease

Harding et al. (2003) determined ACE genotype in 148 preterm infants and prospectively obtained intensive care data. Infants with the DD genotype required higher oxygen (p = 0.028) and more blood pressure support (p = 0.039), and had worse base deficits (p = 0.020) than those with the ID or II genotype. Harding et al. (2003) concluded that ACE polymorphism has a role in the development of preterm cardiorespiratory disease and that the DD genotype, which encodes higher ACE activity, may adversely affect the early health status of preterm infants.

Association with Myophosphorylase Deficiency

In 47 patients with myophosphorylase deficiency (232600), Martinuzzi et al. (2003) found an association between increased clinical severity and the ACE D allele. The authors noted that because the ACE I/D polymorphism had been shown to be associated with muscle function, it may modulate some clinical aspects of myophosphorylase deficiency, accounting for some of the phenotypic variability of the disorder.

Association with Hemorrhagic Stroke

Slowik et al. (2004) found an association between the ACE DD genotype and spontaneous intracerebral hemorrhagic stroke (ICH; 614519) in deep brain structures in 58 Polish patients (OR of 2.46). No association was found between the DD genotype and 140 controls or 70 Polish patients with small vessel disease and ischemic stroke.

Association with Ischemic Stroke

In a comprehensive metaanalysis of 11 case-control studies including 2,990 white adult patients, Casas et al. (2004) found a statistically significant association between ischemic stroke (601367) and the ACE DD genotype compared to the II or ID genotypes (OR of 1.21).

Association with Severe Acute Respiratory Syndrome

Itoyama et al. (2004) genotyped 44 Vietnamese severe acute respiratory syndrome (SARS) cases along with 103 healthy exposed and 50 unexposed controls. They divided the SARS cases into hypoxemic and nonhypoxemic groups, both of which had 22 individuals. The frequency of the D allele of ACE1 was significantly higher in the hypoxemic group compared with the nonhypoxemic group (20 of 44 alleles vs 9 of 44 alleles), whereas there was no significant difference between the SARS cases and controls, regardless of contact history. Itoyama et al. (2004) proposed that ACE1 may influence the progression to pneumonia in SARS.

Association with Athletic Excellence

Gayagay et al. (1998) concluded that the ACE I allele may be a genetic marker associated with athletic excellence. They found that the I allele was present in excess (P less than 0.02), as was also the homozygous II genotype (p = 0.03), in 64 Australian national rowers, compared with a normal population. They proposed that the underlying mechanism related to a healthier cardiovascular system.