Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: ACE
SNOMEDCT: 702397002;
Cytogenetic location: 17q23.3 Genomic coordinates (GRCh38): 17:63,477,061-63,498,373 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q23.3 | [Angiotensin I-converting enzyme, benign serum increase] | 3 | ||
| {Microvascular complications of diabetes 3} | 612624 | 3 | ||
| {Myocardial infarction, susceptibility to} | 3 | |||
| {SARS, progression of} | 3 | |||
| {Stroke, hemorrhagic} | 614519 | 3 | ||
| Renal tubular dysgenesis | 267430 | Autosomal recessive | 3 |
Angiotensin I-converting enzyme (EC 3.4.15.1), or kininase II, is a dipeptidyl carboxypeptidase that plays an important role in blood pressure regulation and electrolyte balance by hydrolyzing angiotensin I into angiotensin II, a potent vasopressor, and aldosterone-stimulating peptide. The enzyme is also able to inactivate bradykinin, a potent vasodilator.
Ehlers et al. (1989) determined the cDNA sequence for human testicular ACE. The predicted protein is identical, from residue 37 to its C terminus, to the second half or C-terminal domain of the endothelial ACE sequence. The inferred protein sequence consists of a 732-residue preprotein including a 31-residue signal peptide. The mature polypeptide has a molecular weight of 80,073.
Although angiotensin-converting enzyme has been studied primarily in the context of its role in blood pressure regulation, this widely distributed enzyme has many other physiologic functions. The ACE gene encodes 2 isozymes. The somatic ACE isozyme is expressed in many tissues, including vascular endothelial cells, renal epithelial cells, and testicular Leydig cells, whereas the testicular or germinal ACE isozyme is expressed only in sperm (Ramaraj et al., 1998).
By quantitative RT-PCR, Harmer et al. (2002) found ACE1 expressed in all 72 tissues examined. Expression was particularly high in ileum, jejunum, duodenum, testis, lung, pulmonary blood vessels, and prostate.
Howard et al. (1990) found that the testis-specific form of ACE has its own promoter within intron 12, is encoded by the 3-prime region of the gene, and is found only in postmeiotic spermatogenic cells and sperm.
Brown et al. (1996) found an association between the use of certain ACE inhibitors (lisinopril or enalapril vs captopril) and emergent angioedema in the African American population of Tennessee. The adjusted relative risk of angioedema was 4.5 (95% CI, 2.9-6.8) in blacks compared to whites. The African American patients were more severely affected: 7 of the 8 patients admitted to the intensive care unit were black, as were all patients who required intubation. African American users of ACE inhibitors tended to be younger and female when compared to their white counterparts. The rate of angioedema was highest within the first 30 days of use (5.79 per 1,000 patient-years) compared to long-term use (1.04 per 1,000 patient-years).
Large-scale trials of therapy for heart failure showed improvements in outcome with ACE inhibitors and beta-blockers. These results led to the recommendation that all patients who have heart failure accompanied by a low ejection fraction and who can tolerate ACE inhibitors and beta-blockers should be treated with both agents. Exner et al. (2001) focused on the fact that black patients with heart failure have a poorer prognosis than white patients and performed a study comparing racial groups. They found that whereas therapy with enalapril is associated with significant reduction in the risk of hospitalization for heart failure among white patients with left ventricular function, it had no such effect in similar black patients. The explanation for the lesser response to the ACE inhibitor in black patients was not clear.
Use of ACE inhibitors during the second and third trimesters of pregnancy is contraindicated because of their association with an increased risk of fetopathy. In contrast, first-trimester use of ACE inhibitors had not been linked to adverse fetal outcomes. From a study of association between exposure to ACE inhibitors during the first trimester of pregnancy only and the risk of congenital malformations, Cooper et al. (2006) concluded that ACE inhibitors at that stage also cannot be considered safe and should be avoided.
Crystal Structure
Natesh et al. (2003) presented the x-ray structure of human testicular ACE and its complex with one of the most widely used inhibitors, lisinopril, at 2.0-angstrom resolution. Analysis of the 3-dimensional structure of ACE shows that it bears little similarity to that of carboxypeptidase A (see 114850), but instead resembles neurolysin (611530) and Pyrococcus furiosus carboxypeptidase, zinc metallopeptidases with no detectable sequence similarity to ACE.
ACE is an integral membrane protein that is proteolytically shed from the cell surface by a zinc metallosecretase. Alfalah et al. (2001) found that mutagenesis of asn631 to gln in the juxtamembrane stalk region of ACE did not affect the enzymatic activity of the protein, but it was more efficiently cleaved and secreted into the medium of transfected cells than wildtype ACE. In contrast to wildtype ACE, which is cleaved between asn638 and ser639 at the cell surface by a metalloprotease, the mutant protein was cleaved between asn635 and ser636 by a serine proteinase within the endoplasmic reticulum.
Hu et al. (1999) demonstrated an association between the ACE I/D polymorphism (106180.0001) and Alzheimer disease (AD; 104300) in the Japanese population. Hu et al. (2001) found that purified ACE inhibited aggregation of amyloid-beta peptide (A-beta) in a dose-dependent manner. Inhibition of A-beta aggregation was specifically blocked by an ACE inhibitor. ACE also significantly inhibited A-beta cytotoxicity in a rat neural precursor cell line. ACE degraded A-beta by cleaving the 40-amino acid peptide between asp7 and ser8. Compared with the 40-amino acid A-beta peptide, the degradation products, A-beta(1-7) and A-beta(8-40), showed reduced aggregation and cytotoxic effects. Hu et al. (2001) concluded that ACE alters susceptibility to AD by degrading A-beta and preventing accumulation of amyloid plaques in vivo.
In testicular germ cells, Kondoh et al. (2005) identified ACE as the glycosylphosphatidylinositol (GPI)-anchored protein-releasing (GPIase) factor. ACE GPIase activity was not inactivated by substitutions of core amino acid residues for peptidase activity, suggesting that the active site elements for GPIase differ from those for peptidase activity; analysis of the released products predicted the cleavage site at the mannose-mannose linkage within the GPI moiety. GPI-anchored proteins were released from the sperm membrane of wildtype mice but not in Ace-knockout sperm in vivo; peptidase-inactivated mutant ACE and bacterial phosphatidylinositol-specific phospholipase rescued the egg-binding deficiency of Ace-knockout sperm. Kondoh et al. (2005) concluded that ACE plays a crucial role in fertilization through its GPIase activity.
In the brain, ACE is especially abundant in striatal tissue. Trieu et al. (2022) found that ACE degrades an unconventional enkephalin heptapeptide, Met-enkephalin-Arg-Phe (MERF), which is encoded by the PENK gene (131330), in the nucleus accumbens of mice. ACE inhibition enhanced mu-opioid receptor activation by MERF, causing a cell type-specific long-term depression of glutamate release onto medium spiny projection neurons expressing the Drd1 (126449) dopamine receptor. Systemic ACE inhibition with captopril was not intrinsically rewarding, reduced the rewarding effects of fentanyl, and increased reciprocal social interaction.
Mattei et al. (1989) assigned the ACE gene to 17q23 by in situ hybridization. Using a DNA marker at the growth hormone gene locus (139250), which they characterized as 'extremely polymorphic' and which showed no recombination with ACE, Jeunemaitre et al. (1992) mapped ACE to 17q22-q24, consistent with the in situ hybridization mapping to 17q23. A demonstration of linkage between the ACE locus and elevated blood pressure in a rat model of hypertension (see 145500) pointed to ACE as a candidate gene in human hypertension. In studies of hypertensive families, they found no evidence to support linkage between the ACE locus and the disease, however. Using affected sib-pair analysis and parametric analysis with ascertainment correction, Julier et al. (1997) found evidence of linkage of familial essential hypertension to 2 closely linked microsatellite markers, D17S183 and D17S934, located on 17q; these markers are, however, 18 cM proximal to the ACE locus.
Benign Serum Increase of ACE
In affected members of 8 families with a 5-fold increase in serum ACE, Kramers et al. (2001) identified a heterozygous pro1199-to-leu mutation in the ACE gene (P1199L; 106180.0002). There were no other clinical abnormalities in any of the affected patients, indicating a benign phenotype. Functional analysis showed that the mutation resulted in increased shedding of the protein from the cell surface.
Renal Tubular Dysgenesis
Gribouval et al. (2005) studied 11 individuals with renal tubular dysgenesis (267430) belonging to 9 families and found that they had homozygous or compound heterozygous mutations in the genes encoding renin (REN; 179820), angiotensinogen (AGT; 106150), ACE, or angiotensin II receptor type 1 (AGTR1; 106165). They proposed that renal lesions and early anuria result from chronic low perfusion pressure of the fetal kidney, a consequence of renin-angiotensin system inactivity. This appeared to be the first identification of a renal mendelian disorder linked to genetic defects in the renin-angiotensin system, highlighting the crucial role of the renin-angiotensin system in human kidney development.
ACE Insertion/Deletion Polymorphism
The importance of ACE in circulatory homeostasis is well documented. Besides being present as a membrane-bound enzyme on the surface of vascular endothelial cells, ACE also circulates in plasma. The plasma enzyme may be synthesized in vascular endothelium. In normal individuals, plasma ACE levels can show as much as a 5-fold interindividual variation; on the other hand, intra-individual variation is small. Cambien et al. (1988) studied familial resemblance for plasma ACE activity in 87 healthy families. The mean levels were 34.1, 30.7, and 43.1 in fathers, mothers, and offspring, respectively. Plasma ACE was uncorrelated with age, height, weight, or blood pressure in the parents, but a negative correlation with age was observed in offspring. Results of genetic analysis suggested that a major gene may affect the interindividual variability of plasma ACE. Okabe et al. (1985) described a family in which an abnormal elevation in plasma ACE levels was transmitted apparently as an autosomal dominant trait. Plasma ACE levels in affected individuals in this kindred were much higher than the values observed in the 87 families studied by Cambien et al. (1988). Tiret et al. (1992) demonstrated that the interindividual variability of plasma ACE was 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 (106180.0001). 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.
Berge and Berg (1994) found no evidence of association between genotypes in the insertion/deletion polymorphism and level of systolic or diastolic blood pressure. In 2 series of monozygotic twin pairs, there was no difference between genotypes in within-pair variation in systolic or diastolic blood pressure. On the other hand, Schunkert et al. (1994) found an association between left ventricular hypertrophy, as assessed by electrocardiographic criteria, and the DD genotype of ACE. Epidemiologic studies had shown that left ventricular hypertrophy is often found in the absence of an elevated cardiac workload. The association with the D/D genotype was stronger in men than in women and was more prominent when blood pressure measurements were normal. The findings suggest that the D/D genotype is a genetic marker associated with an elevated risk of left ventricular hypertrophy in middle-aged men.
Lindpaintner et al. (1996) were unable to confirm an association between ACE genotype and electrocardiographically determined left ventricular mass (determined by echocardiography) and left ventricular hypertrophy (adjusted for clinical covariates) in an analysis of 2,439 subjects from the Framingham Heart Study. Montgomery et al. (1997) reported a prospective study of 460 normotensive Caucasian male military recruits undergoing an intensive 10-week physical training course. Echocardiographic indices of left ventricular mass increased by 18% during training (p less than 0.0001); those individuals with the D ACE allele showed a significantly greater response. In addition, Montgomery et al. (1997) found that electrocardiographic evidence of left ventricular hypertrophy occurred only in individuals with the DD genotype. The authors concluded that exercise-induced left ventricular growth in young males is strongly associated with the ACE I/D polymorphism.
Yoshida et al. (1995) presented evidence suggesting that the deletion polymorphism in the ACE gene, particularly the homozygote DD, is a risk factor for progression to chronic renal failure in IgA nephropathy (161950). Moreover, this deletion polymorphism appeared to predict the therapeutic efficacy of ACE inhibition on proteinuria and, potentially, on progressive deterioration of renal function in that disorder.
Marre et al. (1994) and Doria et al. (1994) reported that the I/D polymorphism of the ACE gene is associated with diabetic nephropathy (see 612624), but this association was disputed by others, e.g., Tarnow et al. (1995) and Schmidt et al. (1995). Marre et al. (1997) performed a large-scale, multicenter study on individuals with insulin-dependent diabetes mellitus (IDDM; 222100) 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 IDDM. The study, called GENEDIAB (GEnetique de la NEphropathie DIABetique), was conducted prospectively over 1 year. The degree of renal involvement of the patients was classified according to the genetic polymorphism of ACE and 2 other elements of the renin-angiotensin system, AGT (106150) and AT2R1 (106165). The study concluded that the ACE gene is involved in both the susceptibility to diabetic nephropathy and its progression toward renal failure. The other 2 polymorphisms were found not to be contributive alone, but an interaction between the ACE I/D and AGT M235T (106150.0001) polymorphisms was found that could account for the degree of renal involvement in the patients studied.
Yoshioka et al. (1998) studied the influence of the I/D polymorphism in intron 16 of the ACE gene on the clinical manifestations of childhood Henoch-Schonlein purpura nephritis (HSPN). One-fifth of patients with HSPN had the DD genotype. The incidence of persisting proteinuria in this group was significantly greater in DD homozygotes than in II homozygotes, with an intermediate incidence in heterozygotes. This effect was not seen in a control group of patients with IgA nephropathy. The authors suggested that persisting proteinuria may be related to a defective angiotensin system genetically determined by the I/D polymorphism.
Singer et al. (1996) provided a review of the clinical literature.
There is evidence for a skeletal muscle renin-angiotensin system, suggesting that muscle growth, and thus physical performance, might be possibly associated with the D allele of the ACE insertion/deletion polymorphism. However, in initial studies, Montgomery et al. (1998) found that the ACE I allele was associated with improved endurance performance. This association was investigated in 2 parallel experiments. A relative excess of II genotype and a deficiency of DD genotype was found in 25 elite unrelated male British mountaineers, with a history of ascending beyond 7,000 meters without using supplementary oxygen, as compared with 1,906 British males free from clinical cardiovascular disease. Among 15 climbers who had ascended beyond 8,000 meters without oxygen, none was homozygous for the D allele.
In a second study, Montgomery et al. (1998) determined ACE genotype in 123 Caucasian males recruited to the U.K. Army consecutively. The maximum duration (in seconds) for which they could perform repetitive elbow flexion while holding a 15-kg barbell was assessed both before and after the training period. Pre-training performance was independent of insertion/deletion genotype. Duration of exercise improved significantly for the 66 individuals of II and ID genotypes but not for the 12 of D/D genotype. Improvement was 11-fold greater for those of II than for those of DD genotype. The mechanism of the association of the I allele with improved endurance was discussed.
Williams et al. (2000) examined training-related changes in the mechanical efficiency of human skeletal muscle and found that the presence of the II genotype confers an enhanced mechanical efficiency in trained muscle over the DD genotype. Williams et al. (2000) concluded that such benefits could be associated with the lower ACE activity of the I allele, an idea that may partly explain the beneficial effects of ACE inhibitors on myocardial cell survival during ischemia and on the survival of patients with cardiac dysfunction.
Zhang et al. (2003) demonstrated that the ACE I allele was associated with increased type I skeletal muscle fibers and suggested that this may be a mechanism for the association between the ACE genotype and endurance performance.
Winnicki et al. (2004) studied the relationship between the ACE I/D polymorphism and physical activity status in 355 mild hypertensives in whom power exercise was contraindicated. They found that a sedentary lifestyle was more common among DD than II hypertensives, with ID subjects having intermediate values (chi square = 13.9, p = 0.001). Winnicki et al. (2004) suggested that the increased risk for the development of cardiovascular complications associated with a deletion polymorphism of the ACE gene could be partially explained by the sedentary lifestyle of these subjects.
Keramatipour et al. (2000) provided genotype data on 258 subjects with ruptured intracranial aneurysm and 299 controls from the same geographic region. ACE allele frequencies were significantly different between the cases and controls (chi square = 4.67, p = 0.03)(odds ratio for I allele vs D allele = 1.3; odds ratio for II vs DD genotype = 1.67).
Low bone mineral density and muscle weakness are major risk factors for postmenopausal osteoporotic fracture. Hormone replacement therapy reverses the menopausal decline in maximum voluntary force of the adductor pollicis and reduces serum ACE levels. The I allele of the ACE gene polymorphism is associated with lower ACE activity and improved muscle efficiency in response to physical training. Woods et al. (2001) investigated whether the presence of the I allele in postmenopausal women would affect the muscle response to hormone replacement therapy. Those taking hormone replacement therapy showed a significant gain in normalized muscle maximum voluntary force slope, the rate of which was strongly influenced by ACE genotype (16.0 +/- 1.53%, 14.3 +/- 2.67%, and 7.76 +/- 4.13%, mean +/- SEM for II, ID, and DD genotype, respectively; p = 0.017 for gene effect, p = 0.004 for I allele effect). There was also a significant ACE gene effect in the response of bone mineral density to hormone replacement therapy in the Ward triangle and a significant I allele effect in the spine, but not in the neck of femur or total hip. The authors concluded that low ACE activity associated with the I allele confers an improved muscle and bone mineral density response in postmenopausal women treated with hormone replacement therapy.
Dynamic exercise is effective in lowering resting blood pressure, in both the long- and short-term, and has been advocated as a primary treatment for mild hypertension or as an adjunct therapy for more severe hypertension, in part because of its low cost and few side effects. An inverse relationship between baseline plasma renin activity and the depressor effect of mild exercise has been observed. Furthermore, resting diastolic blood pressure after upright bicycle exercise decreased in children and young adults of normotensive parents but not in those of hypertensive parents (Seguro et al., 1995). A twin study by van den Bree et al. (1996) showed that blood pressure during dynamic exercise is regulated by genetic factors. Zhang et al. (2002) studied the association of the ACE ID polymorphism with the depressor response to exercise therapy in 64 Japanese subjects with mild to moderate essential hypertension. Each subject performed 10 weeks of mild exercise therapy on a bicycle ergometer. Systolic blood pressure, diastolic blood pressure, and mean arterial pressure were significantly decreased by exercise therapy in subjects with the homozygous II and heterozygous ID genotypes, but not in homozygous DD subjects.
Age-related macular degeneration-1 (ARMD1; 603075) is the leading cause of blindness in the elderly. Hamdi et al. (2002) reported an association between an Alu polymorphism in the ACE gene with the dry/atrophic form of ARMD1. Using PCR on genomic DNA isolated from 173 patients with ARMD1 and 189 age-matched controls, they amplified a region polymorphic for an Alu element insertion in the ACE gene. The Alu +/+ genotype (i.e., the II genotype) occurred 4.5 times more frequently in the control population than in the dry/atrophic ARMD1 patient population (p = 0.004). The predominance of the Alu +/+ genotype within the unaffected control group represented a protective insertion with respect to dry/atrophic ARMD1. This was the first demonstration of an Alu element insertion exerting protective effects against a known human disease.
Kehoe et al. (2003) performed a large-scale study involving multiple markers spanning ACE, in conjunction with a metaanalysis of previously published data on a common Alu insertion/deletion polymorphism, which supported the finding of Kehoe et al. (1999) that one or more alleles of ACE contribute to Alzheimer disease (AD; 104300).
Suehiro et al. (2004) demonstrated that the D allele of the ACE I/D polymorphism leads to higher expression of the ACE mRNA and may affect the renin-angiotensin system in local regions.
Other ACE Polymorphisms
Pedigree analyses showed that ACE levels are influenced by a quantitative trait locus (QTL) located within or close to the ACE gene and most likely residing in the 3-prime region of this locus. Zhu et al. (2000) evaluated linkage disequilibrium involving 7 polymorphisms spanning 13 kb in the 3-prime end of the ACE gene to narrow the genomic region associated with elevated ACE levels using a cladistic analysis.
In a study in 332 Nigerian families, using 13 polymorphisms in the ACE gene, Zhu et al. (2001) found strong linkage between the circulating levels of ACE and the 17q23 region (maximum lod score 7.5). Likewise, most of the polymorphisms in the ACE gene were significantly associated with ACE concentration. They also found that the 2 polymorphisms explaining the greatest variation in ACE concentration, ACE4 (A-240T) and ACE8 (A2350G), were significantly associated with blood pressure, through interaction, in this African population sample.
Kehoe et al. (2004) explored the potential influence of ACE on age at onset (AAO) of AD. They examined 2,861 individuals from 3 European populations, including 6 independent AD samples. A strong effect upon AAO was observed for 1 marker in exon 17 and evidence was also obtained indicating a possible independent effect of a second marker located in the ACE promoter. Effects were consistent with data from previous studies suggesting that alleles that confer risk to disease also appear to reduce AAO. Equivalent effects were evident regardless of APOE4 (see 107741) carrier status and in both males and females.
In 4,000 Swedish individuals, Katzov et al. (2004) demonstrated associations in males exclusively between ACE SNPs and several metabolic traits, including fasting plasma glucose levels, insulin levels, and measures of obesity (601665). Extending cladistic models to the study of myocardial infarction (608446) and Alzheimer disease (AD; 104300), significant associations were observed with greater effect sizes than those typically obtained in large-scale metaanalyses based on the Alu indel. Population frequencies of ACE genotypes changed with age, congruent with previous data suggesting effects upon longevity. Clade models consistently outperformed those based upon single markers, reinforcing the importance of taking into consideration the possible confounding effects of allelic heterogeneity in this genomic region.
Catarsi et al. (2005) studied 227 Italian nephrotic syndrome patients in whom hypertension was the major side effect of treatment by cyclosporine A (CsA). ACE haplotypes were determined in 304 Italian blood donors and assembled in clades (A, B, C) that include 95% of observed haplotypes. The association between ACE clade combinations and serum enzymatic levels reconfirmed the role of a genetic variant in the intragenic recombination site near intron 7. Haplotyping patients revealed that ACE genotype and responsiveness to CsA were strictly associated, because homozygosity for ACE B clade was able to influence CsA sensitivity. This highlights the role of 5-prime variants that differentiate clades B and C. Catarsi et al. (2005) hypothesized that the effect of ACE polymorphisms on blood pressure may be detectable once environmental factors, like CsA treatment, overcome physiologic homeostatic mechanisms.
Meng et al. (2006) evaluated the association between 15 SNPs in the ACE gene and AD in a sample of 92 patients with AD and 166 nondemented controls from an inbred Israeli Arab community. They observed significant association with 2 adjacent SNPs and with a combination of the 2. Their haplotype 'GA' had a frequency of 0.21 in cases and 0.01 in controls. Individuals with this haplotype had a 45-fold increased risk of developing AD compared with those possessing any of the other 3 haplotypes. Longer range haplotypes including I/D were even more significant.
Krege et al. (1995) investigated the role of the ACE gene in blood pressure control and reproduction using mice generated to carry an insertional mutation that was designed to inactivate both forms of Ace. All homozygous female mutants were found to be fertile, but the fertility of homozygous male mutants was greatly reduced. Heterozygous males but not females had blood pressures that were 15 to 20 mm Hg less than normal, although both male and female heterozygotes had reduced serum Ace activity.
Although significant ACE activity is found in plasma, the majority of the enzyme is bound to tissue such as vascular endothelium. Esther et al. (1997) used targeted homologous recombination to create mice expressing a form of ACE that lacks the C-terminal half of the molecule. This modified ACE protein was catalytically active but entirely secreted from cells. Mice that expressed only this modified ACE had significant plasma ACE activity but no tissue-bound enzyme. These animals had low blood pressure, renal vascular thickening, and a urine-concentrating defect. The phenotype was very similar to that of completely ACE-deficient mice previously reported, except that the renal pathology was less severe. These studies strongly supported the concept that the tissue-bound ACE is essential for the control of blood pressure and the structure and function of the kidney.
ACE gene knockout mice lack both isozymes and exhibit low blood pressure, kidney dysfunctions, and male infertility. Ramaraj et al. (1998) reported the use of a sperm-specific promoter and interbreeding of transgenic and gene knockout mice for generating a mouse strain that expressed ACE only in sperm. The experimental mice maintained the kidney defects of ACE -/- mice, but unlike the knockout strain, the males were fertile. Thus, Ramaraj et al. (1998) established that the role of ACE in male fertility is completely dependent on its exclusive expression in sperm. Their study demonstrated how transgenic and knockout techniques can be combined for ascribing a specific physiologic function to the expression of a multifunctional protein in a given tissue.
Hagaman et al. (1998) used transgenic mice lacking somatic and testis ACE to investigate the male fertility defect. They demonstrated that mice lacking both somatic and testis ACE isozymes have defects in sperm transport within the oviducts and in binding to zonae pellucidae. Males generated by gene targeting experiments that lack somatic ACE but retain testis ACE are fertile. Both male and female mice lacking angiotensinogen have normal fertility. The authors found that males heterozygous for the mutation inactivating both ACE enzymes had offspring of wildtype and heterozygous genotypes at the same frequency, suggesting that sperm carrying the mutation are not at a selective disadvantage.
As indicated by the work of Marre et al. (1994), Doria et al. (1994) and others, nephropathy of type 1 diabetes (222100) is associated with the D allele of the insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene. The D allele determines higher enzyme levels. To address causality underlying this association, Huang et al. (2001) induced diabetes in mice having 1, 2, or 3 copies of the Ace gene, normal blood pressure, and an enzyme level range (65-162% of wildtype) comparable to that seen in humans. Twelve weeks later, the 3-copy diabetic mice had increased blood pressures and overt proteinuria. Proteinuria was correlated to plasma ACE level in the 3-copy diabetic mice. Thus, a modest genetic increase in ACE levels was sufficient to cause nephropathy in diabetic mice.
Kessler et al. (2003) generated 2 strains of mice that express ACE in only vascular endothelial cells or renal proximal tubules. Both strains had equivalent serum ACE and angiotensin II levels and renal function, but only the group that expressed ACE in vascular endothelial cells had normal blood pressure. Kessler et al. (2003) concluded that ACE-mediated blood pressure maintenance can be dissociated from its role in maintaining renal structure and function, supporting the hypothesis that specific physiologic functions of ACE are mediated by its expression in specific tissues.
Because experiments in mice and computer simulations indicated that modest increases in ACE have minimal effects on blood pressure and angiotensin II levels but cause a significant decrease in bradykinin levels (see 113503), Kakoki et al. (2004) hypothesized that bradykinin is critical for protecting the kidney in diabetics. They confirmed this by demonstrating that Akita diabetic mice lacking the bradykinin B2 receptor (BDKRB2; 113503) developed overt albuminuria, excreting the equivalent of more than 550 mg/day of albumin in humans, which contrasted with the microalbuminuria (equivalent to less than 150 mg/day) seen in their simply diabetic littermates. The overt albuminuria was accompanied by a marked increase in glomerular mesangial sclerosis.
Tian et al. (2004) generated a transgenic rat model with selective overexpression of human ACE1 in the cardiac ventricles. The left ventricular ACE1 activity was elevated about 50-fold in transgenic rats. Angiotensin-1 perfusion of isolated hearts demonstrated a significant decrease in coronary artery flow compared with nontransgenic littermates, suggesting that the transgenic ACE1 is functional. Neither cardiac hypertrophy nor other morphologic abnormalities were observed in transgenic rats under standard living conditions. After induction of hypertension by suprarenal aortic banding, the degree of cardiac hypertrophy in transgenic rats was significantly higher than that of banded control rats. The expressions of both ANF (108780) and collagen III (see 120180), molecular markers of cardiac hypertrophy, were also increased in banded transgenic rats compared with banded control. Tian et al. (2004) concluded that increased cardiac ACE1 does not trigger but augments cardiac hypertrophy.
Jayasooriya et al. (2008) stated that Ace -/- mice have lower body weight than wildtype mice, and they found that the reduced weight was due to greater fed-state total energy expenditure and resting energy expenditure. In addition, livers of Ace -/- mice showed pronounced expression of genes related to lipolysis and fatty acid oxidation, and plasma leptin (164160) levels were reduced. Jayasooriya et al. (2008) concluded that reduced Ace activity causes increased metabolism of fatty acids in the liver, with additional effect of increased glucose tolerance.
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.
In affected members of 8 families with an autosomal dominant increase in serum ACE activity, Kramers et al. (2001) identified a heterozygous 3705C-T transition in the ACE gene, resulting in a pro1199-to-leu (P1199L) substitution in the stalk region of the protein. In all families, the proband was investigated for ACE activity because of a suspicion of sarcoidosis; the diagnosis was not made in any of the individuals. ACE values in affected members from the 8 families showed a 5-fold increase compared to normal. Elevated ACE was not accompanied by any apparent clinical abnormality. Analysis of leukocytes and dendritic cells from individuals with the mutation showed a normal amount of ACE on the cell surface, but there was a significant increase in the amount of secreted ACE. Kramers et al. (2001) suggested that the P1199L mutation results in more efficient cleavage of somatic ACE.
In 3 unrelated patients with high plasma ACE levels, Eyries et al. (2001) identified the P1199L mutation. In vitro analysis revealed that the shedding of the mutant protein was enhanced compared to wildtype; the rate of solubilization was on average 2.5-fold higher than wildtype. Two-dimensional structural analyses showed that the mutated residue was critical for the positioning of a specific loop containing the cleavage site, leading to more accessibility at the stalk region.
Linnebank et al. (2003) reported a 49-year-old woman with arterial hypertension, transitory neurologic symptoms, and suspected neurosarcoidosis based on elevated plasma and CSF levels of ACE. The P1199L mutation was identified in the patient, as well as in her mother and daughter who also had elevated serum ACE. There was no evidence of neurosarcoidosis in the proband. Linnebank et al. (2003) emphasized the importance of considering this benign inherited phenotype in order to avoid unnecessary and potentially harmful treatment.
In 2 sibs with renal tubular dysgenesis (267430) in a family of Italian and French origin, Gribouval et al. (2005) found a tyr266-to-ter (Y266X) mutation in the ACE gene, arising from a 798C-G transversion in exon 5. It was the only mutation found, inherited from the father.
In 2 sibs with renal tubular dysgenesis (267430) from a consanguineous Turkish family, Gribouval et al. (2005) found homozygosity for a frameshift mutation in exon 8 of the ACE gene. Deletion of 4 nucleotides, 1319_1322del TGGA, resulted in a frameshift at leucine-440 and a premature stop at codon 455.
In a girl with renal tubular dysgenesis (267430), who was born to consanguineous Swiss parents, Gribouval et al. (2012) identified a homozygous c.1486C-T transition in exon 9 of the ACE gene, resulting in an arg496-to-ter (R496X) substitution. She died in the second hour of life.
In an Italian boy with renal tubular dysgenesis (267430), who was born to consanguineous parents, Gribouval et al. (2012) identified a homozygous c.2371C-T transition in exon 16 of ACE gene, resulting in an arg791-to-ter (R791X) substitution. He died on the seventh day of life.
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