Scientific background:

Summary: This gene to be involved in hypertension, hypertensive complications, and diabetic nephropathy is discussed by several publications.

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

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.

Clinical signs: 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.

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.

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

Test strategy: Patients with hypertension with a known family risk for hypertensive injuries.

Methodology:

	research test	Method		Hotspot sequencing
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	Only in the region of interest, known and new missense, nonsense and splice mutations can be detected.
	research test	Method		Fragment analysis
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	Only the target mutation is detected all other genetic variations, though possibly important they may be, are missed.

Literature: 

Nagel M, BMC Nephrol. 2005 Jan 11;6(1):1
Lalouel JM et al. (2001) Angiotensinogen in essential hypertension: from genetics to nephrology.
Lovati E et al. (2001) Genetic polymorphisms of the renin-angiotensin-aldosterone system in end-stage renal disease.
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.
Abonia JP et al. (1993) Linkage of Agt and Actsk-1 to distal mouse chromosome 8 loci: a new conserved linkage.
Arakawa K et al. (1968) Enzymatic degradation and electrophoresis of human angiotensin I.
Arngrímsson R et al. (1993) Angiotensinogen: a candidate gene involved in preeclampsia?
Azizi M et al. (2000) Influence of the M235T polymorphism of human angiotensinogen (AGT) on plasma AGT and renin concentrations after ethinylestradiol administration.
Bloem LJ et al. (1995) The serum angiotensinogen concentration and variants of the angiotensinogen gene in white and black children.
Brand E et al. (2002) Detection of putative functional angiotensinogen (AGT) gene variants controlling plasma AGT levels by combined segregation-linkage analysis.
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.
Caulfield M et al. (1994) Linkage of the angiotensinogen gene to essential hypertension.
Caulfield M et al. (1995) Linkage of the angiotensinogen gene locus to human essential hypertension in African Caribbeans.
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.
Ding Y et al. (2001) Genetic evidence that lethality in angiotensinogen-deficient mice is due to loss of systemic but not renal angiotensinogen.
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.
Frank D et al. (2007) Calsarcin-1 protects against angiotensin-II induced cardiac hypertrophy.
Frossard PM et al. (1998) Associations of angiotensinogen gene mutations with hypertension and myocardial infarction in a gulf population.
Gaillard I et al. (1989) Structure of human angiotensinogen gene.
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.
Gribouval O et al. (2005) Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis.
Gu CC et al. (2005) Haplotype association analysis of AGT variants with hypertension-related traits: the HyperGEN study.
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