Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders
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angiotensin I-converting enzyme

The ACE gene to be involved in hypertension, hypertensive complications, and diabetic nephropathy is discussed by several publications.

Epidemiology

This polymorphism is common wordwide. In general population the following allel frequencies are reported. DD 34% DI 44% II 22%

Gene Structure

The gene of the angiotensin converting enzyme (ACE) is localized on chromosome 17 (17q23). Size is about 20kb. It consists of 25 exons.

Protein Structure

ACE is an enzyme, a zinc metalloendopeptidase that functions as a carboxyl directed dipeptidase.

Phenotype

Hypertension is a very common disease. It is influenced by many genes. ACE polymorphism has an imoprtance in modifying the expression and maybe on renal and cardiac hypertensive injuries.

Pathology

The function of the protein product of this gene is the conversion of angiotensin I to angiotensin II. The latter is a potent vasoconstrictor. The importance of ACE is in blood pressure regulation by the mean of the activation of angiotensinogen (AGT) wich is secreted as a prohormone. ACE fulfills the last step of activation. The gene exists in two different variants. One form is chracterized by additional 250bp in intron 16. This variant is called I (insertion) and it will be distinguished from D deletion. Because these changes are localized in the intron there is no direct influence expected on protein structure. But this polymorphism can have an influence on gene regulation or may be in linkage dysequilibrium with other more importen changes on the same gene.

Gene Regulation

ACE not only cleaves angiotensin I to angiotensin II, but also

Test Strategy

Patients with hypertension with a known family risk for hypertensive injuries.

Interpretation

The higher frequency of D allel suggests that this had some benefit in past. But it seems that in modern times carier are more succeptable to the common diseases of modern countries. There is a doese dependent risk for cardiovascular disesase connected to the D allel.

Genetests:

Clinic Method Carrier testing
Turnaround 5 days
Specimen type genomic DNA
Clinic Method Massive parallel sequencing
Turnaround 25 days
Specimen type genomic DNA
Clinic Method Genomic sequencing of the entire coding region
Turnaround 20 days
Specimen type genomic DNA
Clinic Method Target mutation analysis
Turnaround 20 days
Specimen type genomic DNA

Related Diseases:

Diabetic nephropathy
ACE
AGT
AKR1B1
Hypertension
ACE
ACE2
AGT
Benign hyperproreninemia
REN
Monogenic hypertension
Apparent mineralocorticoid excess
HSD11B2
Glucocorticoid triggered hypertension
NR3C1
Hyperaldosteronism
Conn syndrome
ATP1A1
ATP2B3
CACNA1D
CACNA1H
CTNNB1
KCNJ5
Glucocorticoid triggered hypertension
NR3C1
Hyperaldosteronism type 1
CYP11B1
CYP11B2
Hyperaldosteronism type 2
Hyperaldosteronism type 3
KCNJ5
Hyperaldosteronism type 4
CACNA1D
CACNA1H
Hypertension and brachydactyly syndrome
PDE3A
Liddle syndrome
NEDD4
NEDD4L
NR3C2
OXSR1
SCNN1B
SCNN1G
STK39
Pseudohypoaldosteronism
Pseudohypoaldosteronism type 2
CUL3
KLHL3
WNK1
WNK4
Pseudohypoaldosteronism type1
NR3C2
SCNN1A
SCNN1B
SCNN1G
Preeclampsia
APOL1
Preeclampsia 1
Preeclampsia 2
Preeclampsia 3
Preeclampsia 4
STOX1
Preeclampsia 5
CORIN
Salt-sensitive essential hypertension
CYP3A5
VEGFC
Renal tubular dysgenesis
ACE
AGT
AGTR1
REN

References:

1.

Pei Y et al. (1997) Association of angiotensinogen gene T235 variant with progression of immunoglobin A nephropathy in Caucasian patients.

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2.

Gribouval O et al. (2005) Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis.

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3.

Lalouel JM et al. (2001) Angiotensinogen in essential hypertension: from genetics to nephrology.

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4.

Lovati E et al. (2001) Genetic polymorphisms of the renin-angiotensin-aldosterone system in end-stage renal disease.

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5.

Pereira AC et al. (2001) Effect of race, genetic population structure, and genetic models in two-locus association studies: clustering of functional renin-angiotensin system gene variants in hypertension association studies.

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6.

Marre M et al. (1997) Contribution of genetic polymorphism in the renin-angiotensin system to the development of renal complications in insulin-dependent diabetes: Genetique de la Nephropathie Diabetique (GENEDIAB) study group.

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7.

Chaves FJ et al. (2004) Polymorphisms of the renin-angiotensin system influence height in normotensive women in a Spanish population.

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8.

Schächter F et al. (1994) Genetic associations with human longevity at the APOE and ACE loci.

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9.

Yoshida H et al. (1995) Role of the deletion of polymorphism of the angiotensin converting enzyme gene in the progression and therapeutic responsiveness of IgA nephropathy.

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10.

Julier C et al. (1997) Genetic susceptibility for human familial essential hypertension in a region of homology with blood pressure linkage on rat chromosome 10.

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11.

Vleming LJ et al. (1999) The DD genotype of the ACE gene polymorphism is associated with progression of diabetic nephropathy to end stage renal failure in IDDM.

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12.

Yoshioka T et al. (1998) Deletion polymorphism of the angiotensin converting enzyme gene predicts persistent proteinuria in Henoch-Schönlein purpura nephritis.

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13.

Jeffery S et al. (1999) A dominant relationship between the ACE D allele and serum ACE levels in a Ghanaian population.

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14.

Hu J et al. (1999) Angiotensin-converting enzyme genotype is associated with Alzheimer disease in the Japanese population.

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15.

Williams AG et al. (2000) The ACE gene and muscle performance.

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16.

Keavney B et al. (2000) Large-scale test of hypothesised associations between the angiotensin-converting-enzyme insertion/deletion polymorphism and myocardial infarction in about 5000 cases and 6000 controls. International Studies of Infarct Survival (ISIS) Collaborators.

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17.

Keramatipour M et al. (2000) The ACE I allele is associated with increased risk for ruptured intracranial aneurysms.

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18.

Zhu X et al. (2000) Localization of a small genomic region associated with elevated ACE.

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19.

Eyries M et al. (2001) Increased shedding of angiotensin-converting enzyme by a mutation identified in the stalk region.

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20.

Alfalah M et al. (2001) A point mutation in the juxtamembrane stalk of human angiotensin I-converting enzyme invokes the action of a distinct secretase.

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21.

Zhu X et al. (2001) Linkage and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure.

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22.

Exner DV et al. (2001) Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction.

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23.

Woods D et al. (2001) Angiotensin-I converting enzyme genotype-dependent benefit from hormone replacement therapy in isometric muscle strength and bone mineral density.

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24.

Kramers C et al. (2001) Point mutation in the stalk of angiotensin-converting enzyme causes a dramatic increase in serum angiotensin-converting enzyme but no cardiovascular disease.

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25.

Hu J et al. (2001) Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta ); retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity.

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26.

Huang W et al. (2001) Genetically increased angiotensin I-converting enzyme level and renal complications in the diabetic mouse.

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27.

Harding D et al. (2002) Severity of meningococcal disease in children and the angiotensin-converting enzyme insertion/deletion polymorphism.

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28.

Hamdi HK et al. (2002) Alu DNA polymorphism in ACE gene is protective for age-related macular degeneration.

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29.

Yoon HJ et al. (2002) Interdependent effect of angiotensin-converting enzyme and platelet-activating factor acetylhydrolase gene polymorphisms on the progression of immunoglobulin A nephropathy.

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30.

Zhang B et al. (2002) Association of angiotensin-converting-enzyme gene polymorphism with the depressor response to mild exercise therapy in patients with mild to moderate essential hypertension.

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31.

Harmer D et al. (2002) Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme.

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32.

Natesh R et al. (2003) Crystal structure of the human angiotensin-converting enzyme-lisinopril complex.

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33.

Zhang B et al. (2003) The I allele of the angiotensin-converting enzyme gene is associated with an increased percentage of slow-twitch type I fibers in human skeletal muscle.

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34.

Martinuzzi A et al. (2003) Phenotype modulators in myophosphorylase deficiency.

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35.

Kehoe PG et al. (2003) Haplotypes extending across ACE are associated with Alzheimer's disease.

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36.

Kessler SP et al. (2003) Maintenance of normal blood pressure and renal functions are independent effects of angiotensin-converting enzyme.

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37.

Rigat B et al. (1992) PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1).

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38.

Tiret L et al. (1992) Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels.

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39.

None (1992) Myocardial infarction. The ACE of hearts.

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40.

Cambien F et al. (1992) Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction.

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41.

Jeunemaitre X et al. (1992) Absence of linkage between the angiotensin converting enzyme locus and human essential hypertension.

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42.

Pfeffer MA et al. (1992) Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators.

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43.

Harding D et al. (2003) Angiotensin-converting enzyme DD genotype is associated with worse perinatal cardiorespiratory adaptation in preterm infants.

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44.

Linnebank M et al. (2003) Hereditary elevation of angiotensin converting enzyme suggesting neurosarcoidosis.

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45.

Winnicki M et al. (2004) Physical activity and angiotensin-converting enzyme gene polymorphism in mild hypertensives.

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46.

Elkins JS et al. (2004) Alzheimer disease risk and genetic variation in ACE: a meta-analysis.

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47.

Kehoe PG et al. (2004) Common variants of ACE contribute to variable age-at-onset of Alzheimer's disease.

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48.

Hamdi HK et al. (2004) A genetic variant of ACE increases cell survival: a new paradigm for biology and disease.

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49.

Tian XL et al. (2004) Over-expression of angiotensin converting enzyme-1 augments cardiac hypertrophy in transgenic rats.

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50.

Suehiro T et al. (2004) Increased amount of the angiotensin-converting enzyme (ACE) mRNA originating from the ACE allele with deletion.

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51.

Slowik A et al. (2004) DD genotype of ACE gene is a risk factor for intracerebral hemorrhage.

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52.

Kakoki M et al. (2004) Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor.

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53.

Katzov H et al. (2004) A cladistic model of ACE sequence variation with implications for myocardial infarction, Alzheimer disease and obesity.

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54.

Itoyama S et al. (2004) ACE1 polymorphism and progression of SARS.

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55.

Kajantie E et al. (2004) The effects of the ACE gene insertion/deletion polymorphism on glucose tolerance and insulin secretion in elderly people are modified by birth weight.

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56.

Casas JP et al. (2004) Meta-analysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18,000 cases and 58,000 controls.

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57.

Sayed-Tabatabaei FA et al. (2005) Angiotensin converting enzyme gene polymorphism and cardiovascular morbidity and mortality: the Rotterdam Study.

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58.

Kondoh G et al. (2005) Angiotensin-converting enzyme is a GPI-anchored protein releasing factor crucial for fertilization.

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59.

Catarsi P et al. (2005) Angiotensin-converting enzyme (ACE) haplotypes and cyclosporine A (CsA) response: a model of the complex relationship between ACE quantitative trait locus and pathological phenotypes.

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60.

Meng Y et al. (2006) Association of polymorphisms in the Angiotensin-converting enzyme gene with Alzheimer disease in an Israeli Arab community.

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61.

Cooper WO et al. (2006) Major congenital malformations after first-trimester exposure to ACE inhibitors.

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62.

Chappel MC et al. (2006) ACE and ACE2: their role to balance the expression of angiotensin II and angiotensin-(1-7).

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63.

Jayasooriya AP et al. (2008) Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance.

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64.

Schürks M et al. (2009) ACE D/I polymorphism, migraine, and cardiovascular disease in women.

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65.

Rigat B et al. (1990) An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels.

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66.

Howard TE et al. (1990) Transcription of testicular angiotensin-converting enzyme (ACE) is initiated within the 12th intron of the somatic ACE gene.

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67.

Ehlers MR et al. (1989) Molecular cloning of human testicular angiotensin-converting enzyme: the testis isozyme is identical to the C-terminal half of endothelial angiotensin-converting enzyme.

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68.

Cambien F et al. (1988) Familial resemblance of plasma angiotensin-converting enzyme level: the Nancy Study.

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69.

Soubrier F et al. (1988) Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning.

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70.

Tarnow L et al. (1995) Lack of relationship between an insertion/deletion polymorphism in the angiotensin I-converting enzyme gene and diabetic nephropathy and proliferative retinopathy in IDDM patients.

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71.

Krege JH et al. (1995) Male-female differences in fertility and blood pressure in ACE-deficient mice.

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72.

Schmidt S et al. (1995) Association of ACE gene polymorphism and diabetic nephropathy? The Diabetic Nephropathy Study Group.

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73.

Lindpaintner K et al. (1995) A prospective evaluation of an angiotensin-converting-enzyme gene polymorphism and the risk of ischemic heart disease.

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74.

Doria A et al. (1994) Genetic predisposition to diabetic nephropathy. Evidence for a role of the angiotensin I--converting enzyme gene.

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75.

Berge KE et al. (1994) No effect of insertion/deletion polymorphism at the ACE locus on normal blood pressure level or variability.

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76.

Bøhn M et al. (1993) Insertion/deletion (I/D) polymorphism at the locus for angiotensin I-converting enzyme and myocardial infarction.

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77.

Bøhn M et al. (1993) Insertion/deletion (I/D) polymorphism at the locus for angiotensin I-converting enzyme and parental history of myocardial infarction.

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78.

Ruiz J et al. (1994) Insertion/deletion polymorphism of the angiotensin-converting enzyme gene is strongly associated with coronary heart disease in non-insulin-dependent diabetes mellitus.

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79.

Schunkert H et al. (1994) Association between a deletion polymorphism of the angiotensin-converting-enzyme gene and left ventricular hypertrophy.

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80.

Evans AE et al. (1994) Polymorphisms of the angiotensin-converting-enzyme gene in subjects who die from coronary heart disease.

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81.

Ohishi M et al. (1993) A potent genetic risk factor for restenosis.

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82.

Marre M et al. (1994) Relationships between angiotensin I converting enzyme gene polymorphism, plasma levels, and diabetic retinal and renal complications.

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83.

Arbustini E et al. (1995) Angiotensin converting enzyme gene deletion allele is independently and strongly associated with coronary atherosclerosis and myocardial infarction.

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84.

Lindpaintner K et al. (1996) Absence of association or genetic linkage between the angiotensin-converting-enzyme gene and left ventricular mass.

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85.

Seguro C et al. (1995) [Hemodynamic assessment at rest and during dynamic physical exercise in young subjects with and without hypertensive parents]

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86.

Winkelmann BR et al. (1996) Deletion polymorphism of the angiotensin I-converting enzyme gene is associated with increased plasma angiotensin-converting enzyme activity but not with increased risk for myocardial infarction and coronary artery disease.

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87.

Oike Y et al. (1995) Angiotensin converting enzyme as a genetic risk factor for coronary artery spasm. Implication in the pathogenesis of myocardial infarction.

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88.

Singer DR et al. (1996) Angiotensin-converting enzyme gene polymorphism. What to do about all the confusion.

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89.

van den Bree MB et al. (1996) Genetic regulation of hemodynamic variables during dynamic exercise. The MCV twin study.

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90.

Esther CR et al. (1997) The critical role of tissue angiotensin-converting enzyme as revealed by gene targeting in mice.

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91.

Amant C et al. (1997) D allele of the angiotensin I-converting enzyme is a major risk factor for restenosis after coronary stenting.

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92.

Montgomery HE et al. (1997) Association of angiotensin-converting enzyme gene I/D polymorphism with change in left ventricular mass in response to physical training.

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93.

Hagaman JR et al. (1998) Angiotensin-converting enzyme and male fertility.

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94.

Montgomery HE et al. (1998) Human gene for physical performance.

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95.

Ramaraj P et al. (1998) Selective restoration of male fertility in mice lacking angiotensin-converting enzymes by sperm-specific expression of the testicular isozyme.

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96.

Gardemann A et al. (1998) ACE I/D gene polymorphism: presence of the ACE D allele increases the risk of coronary artery disease in younger individuals.

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97.

Gayagay G et al. (1998) Elite endurance athletes and the ACE I allele--the role of genes in athletic performance.

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98.

Kehoe PG et al. (1999) Variation in DCP1, encoding ACE, is associated with susceptibility to Alzheimer disease.

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99.

NCBI article

NCBI 1636 external link
100.

OMIM.ORG article

Omim 106180 external link
101.

Orphanet article

Orphanet ID 117728 external link
102.

Wikipedia article

Wikipedia EN (Angiotensin-converting_enzyme) external link
Update: Aug. 14, 2020
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