Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Angiotensinogen

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

Epidemiology

The mutation is very common worldwide. The frequency of the T-allel wird in caucasien is 36%. It seems to exist race differences in allel frequencies and its influence on the development of hypertensive injuries.

Gene Structure

The gene AGT is 12kb in size. It consists of 4 exons. Gen locus is on chromosome 1 (1q42-q43).

Phenotype

Hypertension is a very common disease. It is influenced by many genes. The angiontensinogene mutation has a modifying function. It is suggested that hypertensive injuries especially in kidney and heart develop earlier. It is suggestive too that these patients will have a good benefit from ACE-inhibitor therapy.

Pathology

Angiotensinogen is a peptide hormone. It is secreted as a prohormone and will be activated extracellulary by renin (REN) and angiotensin-converting-enzyme (ACE). These extracallular activators have an important function in regulating the hormone.The renin-agiotensin-system (RAS) playes an important role in boo pressure regulation: Activated angiotensinogen, angiotensin II, is a potent vasoconstrictor and a stimulator of the synthesis of aldosterone. In the kidney microcirculation and glomerular filtrationsrate will be influenced. in clinical studies the influence on the development of hypertensive injuries could be shown.In case of M235T mutation plasma levels of angiotensinogen are elevated. According the enzyme kinetics a higher substrate concentration will result in a higher concentration of product. This way the hypertensive angiotensin II is elevated too. This can explaine the correlation of this mutation to hypertension.

Test Strategy

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

Interpretation

The importance of the genetic test lays in the estimation of the prognosis an the decision to ACE inhibitor therapy.

Genetests:

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

Wang WY et al. (1999) Exclusion of angiotensinogen gene in molecular basis of human hypertension: sibpair linkage and association analyses in Australian anglo-caucasians.

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2.

Nakajima T et al. (1999) Functional analysis of a mutation occurring between the two in-frame AUG codons of human angiotensinogen.

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3.

Guo X et al. (1999) Evidence of a major gene effect for angiotensinogen among Nigerians.

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4.

Azizi M et al. (2000) Influence of the M235T polymorphism of human angiotensinogen (AGT) on plasma AGT and renin concentrations after ethinylestradiol administration.

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5.

Ding Y et al. (2001) Genetic evidence that lethality in angiotensinogen-deficient mice is due to loss of systemic but not renal angiotensinogen.

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6.

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

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7.

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

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8.

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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9.

Nakajima T et al. (2002) Nucleotide diversity and haplotype structure of the human angiotensinogen gene in two populations.

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10.

Kemper MJ et al. (2001) Antenatal oligohydramnios of renal origin: postnatal therapeutic and prognostic challenges.

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11.

Nakajima T et al. (2002) Molecular cloning and functional analysis of a factor that binds to the proximal promoter of human angiotensinogen.

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12.

Kim HS et al. (2002) Molecular phenotyping for analyzing subtle genetic effects in mice: application to an angiotensinogen gene titration.

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13.

Lochard N et al. (2003) Brain-specific restoration of angiotensin II corrects renal defects seen in angiotensinogen-deficient mice.

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14.

Brand E et al. (2002) Detection of putative functional angiotensinogen (AGT) gene variants controlling plasma AGT levels by combined segregation-linkage analysis.

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15.

Sawathiparnich P et. al. (2003) Effect of combined AT1 receptor and aldosterone receptor antagonism on plasminogen activator inhibitor-1.

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16.

TAKAHASHI E et al. (1957) The geographic distribution of cerebral hemorrhage and hypertension in Japan.

[^]
17.

None (1962) Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"?

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18.

SASAKI N et al. (1964) THE RELATIONSHIP OF SALT INTAKE TO HYPERTENSION IN THE JAPANESE.

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19.

Tsai CT et al. (2004) Renin-angiotensin system gene polymorphisms and atrial fibrillation.

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20.

Nakajima T et al. (2004) Natural selection and population history in the human angiotensinogen gene (AGT): 736 complete AGT sequences in chromosomes from around the world.

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21.

Montiel M et al. (2005) Angiotensin II induces focal adhesion kinase/paxillin phosphorylation and cell migration in human umbilical vein endothelial cells.

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22.

Lautrette A et al. (2005) Angiotensin II and EGF receptor cross-talk in chronic kidney diseases: a new therapeutic approach.

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23.

Hillermann R et. al. (2005) The Glu298Asp variant of the endothelial nitric oxide synthase gene is associated with an increased risk for abruptio placentae in pre-eclampsia.

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24.

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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25.

Zhan Y et al. (2005) Ets-1 is a critical regulator of Ang II-mediated vascular inflammation and remodeling.

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26.

Markovic D et al. (2005) Association of angiotensinogen gene polymorphisms with essential hypertension in African-Americans and Caucasians.

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27.

Caruso-Neves C et. al. (2005) Albumin endocytosis in proximal tubule cells is modulated by angiotensin II through an AT2 receptor-mediated protein kinase B activation.

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28.

Gu CC et al. (2005) Haplotype association analysis of AGT variants with hypertension-related traits: the HyperGEN study.

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29.

Hume GE et al. (2006) Angiotensinogen and transforming growth factor beta1: novel genes in the pathogenesis of Crohn's disease.

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30.

Frank D et al. (2007) Calsarcin-1 protects against angiotensin-II induced cardiac hypertrophy.

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31.

Isa MN et al. (1990) Assignment of the human angiotensinogen gene to chromosome 1q42-q43 by nonisotopic in situ hybridization [corrected]

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32.

Gaillard-Sanchez I et al. (1990) Assignment by in situ hybridization of the angiotensinogen gene to chromosome band 1q4, the same region as the human renin gene.

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33.

Gaillard I et al. (1989) Structure of human angiotensinogen gene.

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34.

Kunapuli SP et al. (1987) Expression of human angiotensinogen cDNA in Escherichia coli.

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35.

Weeks DE et al. (1988) The affected-pedigree-member method of linkage analysis.

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36.

Arakawa K et al. (1968) Enzymatic degradation and electrophoresis of human angiotensin I.

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37.

Kageyama R et al. (1984) Primary structure of human preangiotensinogen deduced from the cloned cDNA sequence.

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38.

Ohkubo H et al. (1983) Cloning and sequence analysis of cDNA for rat angiotensinogen.

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39.

Caulfield M et al. (1995) Linkage of the angiotensinogen gene locus to human essential hypertension in African Caribbeans.

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40.

Fornage M et al. (1995) Variation at the M235T locus of the angiotensinogen gene and essential hypertension: a population-based case-control study from Rochester, Minnesota.

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41.

Katsuya T et al. (1995) Association of angiotensinogen gene T235 variant with increased risk of coronary heart disease.

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42.

Bloem LJ et al. (1995) The serum angiotensinogen concentration and variants of the angiotensinogen gene in white and black children.

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43.

Hegele RA et al. (1994) A polymorphism of the angiotensinogen gene associated with variation in blood pressure in a genetic isolate.

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44.

Tanimoto K et al. (1994) Angiotensinogen-deficient mice with hypotension.

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45.

Abonia JP et al. (1993) Linkage of Agt and Actsk-1 to distal mouse chromosome 8 loci: a new conserved linkage.

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46.

Hata A et al. (1994) Angiotensinogen as a risk factor for essential hypertension in Japan.

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47.

Caulfield M et. al. (1994) Linkage of the angiotensinogen gene to essential hypertension.

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48.

Sadoshima J et al. (1993) Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro.

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49.

Arngrímsson R et al. (1993) Angiotensinogen: a candidate gene involved in preeclampsia?

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50.

Ward K et al. (1993) A molecular variant of angiotensinogen associated with preeclampsia.

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51.

Russ AP et al. (1993) Rapid detection of the hypertension-associated Met235-->Thr allele of the human angiotensinogen gene.

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52.

Hegele RA et al. (1996) Genetic and biochemical factors associated with variation in blood pressure in a genetic isolate.

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53.

Davisson RL et al. (1997) Complementation of reduced survival, hypotension, and renal abnormalities in angiotensinogen-deficient mice by the human renin and human angiotensinogen genes.

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54.

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.

[^]
55.

Inoue I et al. (1997) A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro.

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56.

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

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57.

Niu T et al. (1998) Angiotensinogen gene and hypertension in Chinese.

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58.

Karlsson C et al. (1998) Human adipose tissue expresses angiotensinogen and enzymes required for its conversion to angiotensin II.

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59.

Frossard PM et al. (1998) Associations of angiotensinogen gene mutations with hypertension and myocardial infarction in a gulf population.

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60.

Neel JV et. al. (1998) Type II diabetes, essential hypertension, and obesity as "syndromes of impaired genetic homeostasis": the "thrifty genotype" hypothesis enters the 21st century.

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Update: Sept. 26, 2018