Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: AGT
SNOMEDCT: 702397002;
Cytogenetic location: 1q42.2 Genomic coordinates (GRCh38): 1:230,702,523-230,745,583 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q42.2 | {Hypertension, essential, susceptibility to} | 145500 | Multifactorial | 3 |
| {Preeclampsia, susceptibility to} | 3 | |||
| Renal tubular dysgenesis | 267430 | Autosomal recessive | 3 |
Angiotensin is formed from a precursor, angiotensinogen, which is produced by the liver and found in the alpha-globulin fraction of plasma. The lowering of blood pressure is a stimulus to secretion of renin (179820) by the kidney into the blood. Renin cleaves from angiotensinogen a terminal decapeptide, angiotensin I. This is further altered by the enzymatic removal of a dipeptide to form angiotensin II.
Ohkubo et al. (1983) determined the sequence of the cloned rat angiotensinogen gene. The human angiotensinogen molecule has a molecular mass of about 50 kD. The angiotensin I decapeptide is located in its N-terminal part. Kageyama et al. (1984) reported the complete nucleotide sequence of human angiotensinogen mRNA. Similarly, Kunapuli et al. (1987) isolated cDNA clones for human angiotensinogen from a human liver library. The determined nucleotide sequence corroborated the sequence published by Kageyama et al. (1984), with the exception of a single nucleotide change which may represent a simple genetic polymorphism. Kunapuli et al. (1987) constructed a full-length angiotensinogen cDNA which enabled the in vitro synthesis of human angiotensinogen in E. coli. Gaillard et al. (1989) observed that the primary amino acid sequence shows similarities to that of alpha-1-antitrypsin (AAT; 107400) and antithrombin III (AT3; 107300).
Gaillard et al. (1989) found that the human angiotensinogen gene contains 5 exons. The angiotensinogen gene shows organization identical to that of the AAT gene, but different from that of the AT3 gene.
By in situ hybridization, Gaillard-Sanchez et al. (1990) assigned the angiotensinogen gene to 1q4 in the same region as the renin gene. Isa et al. (1989, 1990) used a human angiotensinogen cDNA plasmid probe to localize the gene by nonisotopic in situ hybridization; the location was determined to be 1q42-q43. By screening a panel of human-mouse somatic cell hybrids, Abonia et al. (1993) confirmed the assignment of the AGT locus to chromosome 1. They showed, furthermore, that the homologous gene in the mouse is on the distal end of chromosome 8; a short region of conserved linkage homology between mouse chromosome 8 and human chromosome 1 was indicated by the mapping also of the skeletal alpha-actin locus (102610) to mouse chromosome 8 and human chromosome 1.
Karlsson et al. (1998) analyzed the expression of angiotensinogen and enzymes required for its conversion to angiotensin II in human adipose tissue. Northern blot analysis demonstrated angiotensinogen expression in adipose tissue from 9 obese subjects. Western blot analysis showed a distinct band of expected size of the angiotensinogen protein (61 kD) in isolated adipocytes. RT-PCR and Southern blot analysis demonstrated renin expression in human adipose tissue. Angiotensin-converting enzyme mRNA was detected by RT-PCR, and the identity of the PCR products was verified by restriction enzyme cleavage. Transcripts for cathepsin D (116840) and cathepsin G (116830), components of the nonrenin-angiotensin systems, were detected by RT-PCR and verified by restriction enzyme cleavage. The authors concluded that human adipose tissue expresses angiotensinogen and enzymes of renin- and nonrenin-angiotensin systems.
Hypertrophy is a fundamental adaptive process occurring in postmitotic cardiac and skeletal muscle in response to mechanical load. Using an in vitro model of load-induced cardiac hypertrophy, Sadoshima et al. (1993) demonstrated that mechanical stress causes release of angiotensin II from cardiac myocytes and that angiotensin II acts as an initial mediator of the hypertrophic response. The results not only provided direct evidence for the autocrine mechanism in load-induced growth of cardiac muscle cells, but also defined a pathophysiologic role of the local (cardiac) renin-angiotensin system.
To analyze the influence of the M235T polymorphism (106150.0001) on the ethinylestradiol-induced increase in plasma AGT concentration and on the resulting generation of Ang I and Ang II in plasma, Azizi et al. (2000) compared changes in the circulating renin-angiotensin system after short-term (2 days) and repeated (7 days) administration of 50 microg ethinylestradiol in homozygous normotensive men (TT and MM). In the 7-day study, TT subjects had higher peak plasma AGT concentrations than did MM subjects. The more pronounced AGT increase in TT subjects resulted in similar plasma renin activity at a lower plasma active renin concentration, with a higher plasma renin activity/active renin ratio. The authors concluded that the T235 AGT allele is associated with increased AGT secretion in plasma after ethinylestradiol administration. In the short term, complete readjustment of the circulating renin-angiotensin system occurs, through a decrease in renin release, which blunts the effects of the increase in AGT concentration.
Aldosterone enhances angiotensin II-induced PAI1 (173360) expression in vitro. Sawathiparnich et al. (2003) tested the hypothesis that angiotensin II type 1 and aldosterone receptor (600983) antagonism interact to decrease PAI1 in humans. Effects of candesartan, spironolactone, or combined candesartan/spironolactone on mean arterial pressure, endocrine, and fibrinolytic variables were measured in 18 normotensive subjects in whom the renin-angiotensin-aldosterone system was activated by furosemide. This study evidenced an interactive effect of endogenous angiotensin II and aldosterone on PAI1 production in humans.
Albumin (ALB; 103600) endocytosis in renal proximal tubule cells through a clathrin- and receptor-mediated mechanism initiates or promotes tubule-interstitial disease in several pathophysiologic conditions. Using LLC-PK1 porcine proximal tubule cells, Caruso-Neves et al. (2005) showed that Ang II increased albumin endocytosis through Agtr2 (300034)-mediated activation of protein kinase B (AKT1; 164730) in the plasma membrane, which depended on the basal activity of phosphatidylinositol 3-kinase (PI3K; see 601232).
Montiel et al. (2005) found that ANG II enhanced FAK (PTK2; 600758) and paxillin (PXN; 602505) phosphorylation in human umbilical endothelial cells (HUVECs). ANG II induced a time- and dose-dependent augmentation of cell migration, but it did not affect HUVEC proliferation. Inhibitor studies indicated that FAK and paxillin phosphorylation induced HUVEC migration through signaling pathways dependent on PI3K and SRC family kinases (see 190090) and EGFR phosphorylation.
Brand et al. (2002) measured plasma AGT levels and analyzed 7 biallelic AGT variants as candidate functional variants in 545 healthy French volunteers in 130 nuclear families that included 285 offspring. Analysis with the class D regressive model showed the most significant result at -532C-T (p = 0.000001), accounting for 4.3% of total plasma AGT variability in parents and 5.5% in offspring. Maximum likelihood estimates of haplotype frequencies and tests of linkage disequilibrium between each AGT polymorphism and a putative QTL were in agreement with a complete confounding of -532C-T with the QTL, when taking into account sex- and generation-specific effects of the QTL. However, further combined segregation-linkage analyses showed significant evidence for additional effects of the -6G-A, M235T (106150.0001), and 2054C-A polymorphisms after accounting for -532C-T, which supports a complex model with at least 2 functional variants within the AGT gene controlling AGT levels.
Renal Tubular Dysgenesis
Gribouval et al. (2005) studied 11 individuals with renal tubular dysgenesis (RTD; 267430) belonging to 9 families and found that they had homozygous or compound heterozygous mutations in the genes encoding angiotensinogen (see 106150.0003-106150.0005), renin (REN; 179820), angiotensin-converting enzyme (ACE; 106180), 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.
Association with Hypertension
Jeunemaitre et al. (1992) reported results from a collaborative study of AGT in 215 sibships, each with 2 or more hypertensive subjects ascertained from American and French study populations, a total of 379 sib pairs. The study provided evidence for involvement of AGT in the pathogenesis of essential hypertension (145500). In each of the samples, they found genetic linkage between essential hypertension and AGT in affected sibs, association between hypertension and certain molecular variants of AGT as revealed by a comparison between cases and controls, and increased concentrations of plasma angiotensinogen in hypertensive subjects who carry a common variant of AGT strongly associated with hypertension. Among the 15 molecular variants of AGT that had been identified, significant association with hypertension was observed with 2 amino acid substitutions, M235T (106150.0001) and T174M. These 2 variants exhibited complete linkage disequilibrium, as T174M occurred on a subset of the haplotypes carrying the M235T variant, and both haplotypes were observed at higher frequency among hypertensives. Several interpretations can be proposed to account for this observation: M235T directly mediates a predisposition to hypertension; an unidentified risk factor is common to both haplotypes; or each haplotype harbors a distinct risk factor.
Caulfield et al. (1994) could find no association between essential hypertension and either the M235T or the T174M variant. On the other hand, studies in a distinct, ethnically homogeneous population, namely Japanese, showed that the same variant, T235, is associated with essential hypertension (Hata et al., 1994). In the Japanese study, the population frequency of the T235 variant was found to be higher than among Caucasian subjects. Because of the involvement of angiotensinogen in salt homeostasis, T235 may be a marker for a salt-sensitive form of essential hypertension. Epidemiologic studies documented a striking gradient of increasing prevalence of hypertension and stroke mortality from south to north Japan (Takahashi et al., 1957), which correlates with a parallel rise in average daily salt intake (Sasaki, 1964).
The observation that plasma and angiotensinogen levels correlate with blood pressure and track through families suggested that angiotensinogen may have a role in essential hypertension. Caulfield et al. (1994) therefore investigated linkage between the AGT gene and essential hypertension in 63 white European families in which 2 or more members had essential hypertension. To test for linkage they used a dinucleotide repeat marker flanking the gene on 1q42-q43 and adopted the affected-pedigree-member method of linkage analysis (Weeks and Lange, 1988). In this approach, a t-statistic is computed that tests whether affected relatives share alleles at the AGT locus more often than would be expected by chance. Linkage was detected (t = 5.00, p less than 0.001).
Among the Hutterites, a North American religious genetic isolate (Hostetler, 1974), Hegele et al. (1994) tested for association between variation in systolic and diastolic blood pressures and the insertion/deletion polymorphism of ACE (106180) and 2 protein polymorphisms of AGT, namely, M235T and T174M. The genotypes of AGT codon 174 were significantly associated with variation in systolic blood pressure in men and accounted for 3.1% of the total variation. Hegele et al. (1996) provided further information on this association and that of the genotype of apoB codon 4154 (107730) in association with variation in systolic blood pressure in Hutterites.
In a study in African Caribbeans from St. Vincent and the Grenadines, Caulfield et al. (1995) tested for linkage between the AGT gene and hypertension by analyzing 63 affected sib pairs for an excess of allele sharing, using an AGT dinucleotide repeat sequence as an indicator. There was significant support for linkage (p = 0.001) and association (p less than 0.001) of AGT to hypertension. However, they found no association of the M235T variant (106150.0001) with hypertension in this study of African Caribbeans.
As outlined earlier, the strongest evidence implicating a gene as the cause of human essential hypertension is for the AGT gene (Jeunemaitre et al., 1992). Davisson et al. (1997) reported studies designed to determine whether elements of the human renin-angiotensin system could functionally replace elements of the mouse renin-angiotensin system by complementing the reduced survival and renal abnormalities observed in mice carrying a gene-targeted deletion of the mouse angiotensinogen gene. These studies established that the human renin and angiotensinogen genes can functionally replace the mouse angiotensinogen gene, and provided proof that, in principle, one can examine the regulation of elements of the human renin-angiotensin system, and test the significance of human renin-angiotensin system gene variants, by a combined transgenic and gene-targeting approach.
Because of previous demonstrations of association between angiotensinogen and essential hypertension in white Europeans, African-Caribbeans, and Japanese, Niu et al. (1998) investigated whether the ATG gene is similarly implicated in the pathogenesis of essential hypertension in Chinese by carrying out linkage analysis in 310 hypertensive sib pairs. Genotypes were determined for 2 diallelic DNA polymorphisms observed at amino acid residues 174 (thr174 to met; T174M) and 235 (met235 to thr; M235T; 106150.0001) within the coding sequence and for 2 highly informative dinucleotide (GT)-repeat sequences (1 in the 3-prime flanking region and 1 at a distance of 6.1 cM from the gene). Affected sib-pair analysis conducted according to 3 different algorithms revealed no evidence for linkage of the AGT gene to hypertension. Niu et al. (1998) suggested that ethnicity may make a significant difference in the role of various genes in certain complex traits.
Nakajima et al. (2002) determined the complete genomic sequence of AGT and performed a scan of 14.4 kb for sequence variation in AGT. They found 44 single-nucleotide polymorphisms (SNPs) and a microsatellite in whites and Japanese. To infer the ancestral state of each SNP, the chimpanzee sequence was also completed. They evaluated haplotypes and the pattern of linkage disequilibrium (LD) in AGT to provide empirical information on the utility of LD for detection of disease genes. Despite an overall similarity in LD patterns in the 2 populations, they found a much higher frequency of the M235-associated haplotype in the white population.
Wang et al. (1999) evaluated AGT as a candidate gene for hypertension by means of sib pair analysis with multiple microsatellite markers surrounding this locus. They also performed an association study of the AGT variants in unrelated subjects with a strong family history (2 affected parents). For the linkage study, single and multiplex PCR and automated gene scan analysis were conducted on DNA from 175 Australian Anglo-Celtic Caucasian hypertensives. Statistical evaluation of genotype data by nonparametric methods resulted in exclusion scores. In this study, Wang et al. (1999) excluded AGT in the etiology of hypertension, at least in the population of Australian Anglo-Celtic Caucasians studied.
In a study of hypertensive patients, Nakajima et al. (1999) identified a mutation at the -30 amino acid position of the angiotensinogen signal peptide, in which an arginine was replaced by a proline (R-30P). Heterozygous individuals with R-30P showed a tendency to lowered plasma angiotensinogen levels compared with normal individuals in the family. Because of the small number of family members available for study, a possible relationship between the mutation and essential hypertension could not be addressed. Human angiotensinogen mRNA has 2 in-phase translation initiation codons (AUG) starting upstream 39 and 66 nucleotides from the cap site. R-30P occurs in a cluster of basic residues adjacent to the first AUG codon that may affect intracellular sorting of the nascent protein.
To dissect the genetic pathway of hypertension, Guo et al. (1999) measured angiotensinogen in 685 members of 186 families from a rural community in southwest Nigeria. Commingling and segregation analyses were performed. A mixture of 2 and/or 3 distributions fitted the data significantly better than a single distribution in commingling analysis, suggesting a major gene effect. Segregation analysis confirmed that a recessive major gene model for low values of angiotensinogen provided the best fit to the data and about 13% of the variance was due to the recessive gene segregation.
Nakajima et al. (2002) examined the potential impact of the G-A polymorphism 6-bp upstream from the initiation site of transcription (-6G-A; 106150.0002) on AGT promoter function. Screening an expression library with a double-stranded DNA segment centered on -6 led to the isolation of cDNA clones encoding the YB1 protein (NSEP1; 154030). The specificity of the interaction of YB1 with the proximal promoter of AGT was verified by Southwestern blotting and gel mobility shift assays. In cotransfection experiments, YB1 reduced basal AGT promoter activity in a dose-dependent manner. Although these observations suggested a possible role for YB1 in modulating AGT expression, this function was thought likely to occur in the context of complex interactions involving other nuclear factors.
In a case-control study of 186 African American and 127 Caucasian patients with hypertension and 156 African American and 135 Caucasian normotensive controls, Markovic et al. (2005) found that subjects with the AA or AG genotype of the -793A-G promoter SNP were significantly more likely to have hypertension (OR = 1.88). Additionally, the differences in haplotype frequency distributions between cases and controls were significant at the 7% level for all 4 subgroups (stratified by race and sex).
Gu et al. (2005) examined a hypothesis that multiple genetic variants in the renin-angiotensin system act together in blood pressure regulation, via intermediate phenotypes such as blood pressure reactivity. They found that genetic variants in regulatory regions of the AGT gene showed strong association with blood pressure reactivity.
Association with Coronary Heart Disease
In a New Zealand study of 422 patients with documented coronary heart disease and 406 controls without known coronary heart disease (matched to cases by age and sex), Katsuya et al. (1995) concluded that the T235 of AGT is an independent risk factor that carries an approximately 2-fold increased risk of coronary heart disease. In that study, however, ACE DD (106180.0001) is not associated with any detectable increase in coronary heart disease risk.
Association with Nonfamilial Structural Atrial Fibrillation
Tsai et al. (2004) analyzed polymorphisms of the AGT, ACE, and angiotensin II type I receptor (AGTR1; 106165) genes in 250 patients with documented nonfamilial structural atrial fibrillation and 250 controls matched for age, sex, presence of left ventricular dysfunction, and presence of significant valvular heart disease. In multilocus haplotype analysis, the AGT gene haplotype profile was significantly different between cases and controls (p = 0.0002). In single-locus analysis, the M235T, -6G-A, and -217G-A polymorphisms of the AGT gene were significantly associated with atrial fibrillation. Significant gene-gene interactions between the ACE insertion/deletion (106180.0001) and AGT and AGTR1 polymorphisms were detected. Tsai et al. (2004) concluded that renin-angiotensin system gene polymorphisms are associated with nonfamilial structural atrial fibrillation.
Association with Inflammatory Bowel Disease
Hume et al. (2006) analyzed 2 cohorts of Australian patients with inflammatory bowel disease (see 266600) and sex- and age-matched controls for the -6G-A promoter polymorphism of the AGT gene (106150.0002) and found a significant association between the -6 AA genotype and Crohn disease in 1 cohort (p = 0.007) and in the 2 cohorts combined (p = 0.008).
Association with Susceptibility to Microvascular Complications of Diabetes 3
In a study of patients with insulin-dependent diabetes mellitus (IDDM; 222100) who had developed proliferative retinopathy (MVCD3, 612624), Marre et al. (1997) found evidence of an interaction between the ACE I/D (106180.0001) and AGT M235T (106150.0001) polymorphisms that could account for the degree of renal involvement, although M235T was not contributive alone.
Crystal Structure
Zhou et al. (2010) solved the crystal structure of angiotensinogen to 2.1-angstrom resolution and showed that the angiotensin cleavage site is inaccessibly buried in its amino-terminal tail. The conformational rearrangement that makes this site accessible for proteolysis was revealed in a 4.4-angstrom structure of the complex of human angiotensinogen with renin (179820). The coordinated changes involved are critically linked by a conserved but labile disulfide bridge. Zhou et al. (2010) showed that the reduced unbridged form of angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized sulfydryl-bridged form, which preferentially interacts with receptor-bound renin. Zhou et al. (2010) proposed that this redox-responsive transition of angiotensinogen to a form that will more effectively release angiotensin at a cellular level contributes to the modulation of blood pressure. Specifically, Zhou et al. (2010) demonstrated the oxidative switch of angiotensinogen to its more active sulfydryl-bridged form in the maternal circulation in preeclampsia (see 189800).
Tanimoto et al. (1994) generated angiotensinogen-deficient mice by homologous recombination in mouse embryonic stem cells. These mice do not produce angiotensinogen in the liver, resulting in the complete loss of plasma immunoreactive angiotensin I. The systolic blood pressure of the homozygous mutant mice was 66.9 +/- 4.1 mm Hg, as compared with 100.4 +/- 4.4 mm Hg in wildtype mice. The findings demonstrated an indispensable role for the renin-angiotensin system in maintaining blood pressure.
Ding et al. (2001) supplied human renin and the kidney-specific angiotensinogen transgene to Agt -/- mice but could not rescue lethality. Angiotensinogen protein and functional angiotensin II was generated in the kidney, and the kidney-specific transgene was temporally expressed during renal development similar to the endogenous AGT gene. Ding et al. (2001) concluded that their data strongly support the notion that the loss of systemic AGT, but not intrarenal AGT, is responsible for death in the Agt -/- mouse model. Ding et al. (2001) also concluded that the intrarenal renin-angiotensin system located in the proximal tubule plays an important role in blood pressure regulation and may cause hypertension if overexpressed, but may not be required for continued development of the kidney after birth.
The angiotensinogen M235T polymorphism (106150.0001) in humans is linked to differential expression of the AGT gene and hypertension. Kim et al. (2002) investigated how mice responded to 5 genetically determined levels of mouse Agt gene expression covering the range associated with the M235T variants. By using high-throughput molecular phenotyping, tissue RNAs were assayed for expression of 10 genes important in hypertension. Significant positive and negative responses occurred in both sexes as Agt expression increased 2-fold, including a 3-fold increase in aldosterone synthase (ALDOS; 124080) expression in adrenal gland, and a 2-fold decrease in renin expression in kidney. In males, cardiac expression of the precursor of atrial natriuretic peptide B (600295) and of adrenomedullin (ADM; 103275) also increased approximately 2-fold. The relative expression of all genes studied, except Agt, differed significantly in the 2 sexes, and several unexpected relationships were encountered. The correlation between blood pressure and liver Agt expression within the 5 Agt genotypes was significant in females but not in males, whereas correlation of blood pressure with differences between the genotypes was less in females than in males. Kim et al. (2002) concluded that the marked gender differences in gene expression in wildtype mice and the changes induced by moderate alterations in Agt expression and blood pressure emphasized the need to look for similar differences in humans.
Using a transgenic strategy, Lochard et al. (2003) restored angiotensin II exclusively in the brains of Agt-deficient mice. Restoration of brain angiotensin II corrected the hydronephrosis and partially corrected the renal dysfunction associated with loss of Agt expression. Lochard et al. (2003) concluded that the renin-angiotensin system affects renal development and function through systemically accessible targets in the brain.
Lautrette et al. (2005) found that angiotensin II infusion in mice over 2 months produced severe renal lesions, mainly glomerulosclerosis, tubular atrophy and/or dilation with little microcyst formation, mild interstitial fibrosis, and multifocal mononuclear cell infiltration. In contrast, mice overexpressing a dominant-negative isoform of EGFR (131550) were protected from renal lesions during chronic angiotensin II infusion. Tgf-alpha (TGFA; 190170) and its sheddase, Tace (ADAM17; 603639), were induced by angiotensin II treatment, Tace was redistributed to apical membranes, and Egfr was phosphorylated. Angiotensin II-induced lesions were reduced in mice lacking Tgfa or in mice given a Tace inhibitor. Inhibition of angiotensin II prevented Tgfa and Tace accumulation and renal lesions after nephron reduction. Lautrette et al. (2005) concluded that EGFR transactivation is crucial for angiotensin II-associated renal deterioration.
In Ets1 (164720)-null mice, Zhan et al. (2005) observed significantly reduced arterial wall thickening, perivascular fibrosis, and cardiac hypertrophy compared to wildtype mice in response to angiotensin II. The induction of 2 known targets of ETS1, CDKN1A (116899) and PAI1 (173360), by angiotensin II was markedly blunted in the aorta of Ets1-null mice compared with wildtype controls. Expression of MCP1 (CCL2; 158105) was similarly reduced, resulting in significantly diminished recruitment of T cells and macrophages to the vessel wall. Zhan et al. (2005) concluded that ETS1 has a critical role as a transcriptional mediator of vascular inflammation and remodeling in response to angiotensin II.
Frank et al. (2007) generated Myoz2 (605602)-overexpressing transgenic mice, which did not exhibit a pathologic phenotype when unchallenged. Long-term infusion of angiotensin II resulted in a similar degree of hypertension in both transgenic and wildtype mice; in contrast to wildtype, however, the Myoz2-overexpressing mice did not develop cardiac hypertrophy, yet had no impairment of contractile function by cardiac catheterization and echocardiography. Induction of the hypertrophic gene program was markedly blunted and expression of the calcineurin-dependent gene MCIP1 (RCAN1; 602917) was significantly reduced in transgenic mice. Frank et al. (2007) concluded that the calsarcin-1 protein prevents angiotensin II-induced cardiomyocyte hypertrophy at least in part via inhibition of calcineurin signaling.
By 3 sets of observations, i.e., genetic linkage, allelic associations, and differences in plasma angiotensinogen concentrations among AGT genotypes, in a sample of families from 2 different populations, Salt Lake City and Paris, Jeunemaitre et al. (1992) demonstrated involvement of the AGT gene in essential hypertension. Hypertension showed association with 2 distinct amino acid substitutions, M235T and T174M. The 2 variants showed complete linkage disequilibrium; T174M occurred on a subset of the haplotypes carrying the M235T variant, and both haplotypes were observed at higher frequency among hypertensives. Whether M235T directly mediates a predisposition to hypertension, or an unidentified risk factor is common to both haplotypes, or each haplotype harbors a distinct factor is uncertain.
Lifton et al. (1993) found the M235T variant to be very frequent among African Americans who as a group have a high prevalence of hypertension. The frequency of T235 homozygotes was 70%, with 28% for T235 heterozygotes and only 2% for M235 homozygotes; the corresponding figures were 12%, 46%, and 42% in Caucasians. Lifton et al. (1993) suggested that the T235 allele may have been the ancestral form, and, in an earlier period of salt scarcity, increased salt and water retention associated with T235 may have been an advantage. After the Diaspora from Africa to salt-rich areas, M235 may have become fixed or had some advantage.
Russ et al. (1993) described a rapid method for detection of the M235T polymorphism.
It is well known that blood pressure increases faster over time in black children than in white children and that in adults, hypertension is more prevalent in blacks. In a study of 148 white and 62 black normotensive children, Bloem et al. (1995) found that the frequency of the T235 allele was 0.81 in blacks and 0.42 in whites. The mean angiotensinogen level was 19% higher in blacks than in whites. This racial difference in the renin-angiotensin system may contribute to the disparity in blood pressure levels in white and black young people.
In Rochester, Minnesota, Fornage et al. (1995) studied a population-based sample consisting of 104 subjects diagnosed with hypertension before age 60 and 195 matched normotensive individuals to determine the relationship between M235T and essential hypertension. The authors used 2 methods: contingency chi-square analysis of association and a multivariable conditional logistic regression for variation at the M235T polymorphism as a significant predictor of the probability of having essential hypertension. They detected no statistically significant association in either gender or in a subset of severely hypertensive subjects requiring 2 or more antihypertensive medications. Furthermore, variation in the number of M235T alleles made no significant contribution to predicting the probability of having hypertension, either alone or in conjunction with other predictor variables. See also Niu et al. (1998).
Frossard et al. (1998) studied the association between the M235T and T174M variants in residents of the United Arab Emirates (Emirati), an ethnic group characterized by no alcohol intake and no cigarette smoking. T174M showed no correlation with any of the 4 clinical entities included in the study (essential hypertension, left ventricular hypertrophy, ischemic heart disease, and myocardial infarction), but the T235 allele occurred more frequently in the essential hypertension group and less frequently in the group of myocardial infarction survivors. They also found that the T235 allele frequencies decreased with age, suggesting that in the Emirati population, T235 alleles are associated with a reduced life span.
Preeclampsia Susceptibility
In a series of Caucasian women with pregnancy-induced hypertension, Ward et al. (1993) observed significant association of preeclampsia (see 189800) with the M235T variant. The finding was corroborated in a sample ascertained in Japan. Arngrimsson et al. (1993) studied involvement of the ATG gene in preeclampsia and eclampsia by linkage studies with a highly informative dinucleotide repeat from the 3-prime flanking region of the ATG gene. They used a nonparametric method, i.e., one in which the mode of inheritance, gene frequency, and penetrance did not have to be specified. Their results supported the findings of Ward et al. (1993).
In a study of 150 'coloured' South African patients, 50 with normal pregnancies, 50 with severe preeclampsia, and 50 with abruptio placentae, Hillermann et al. (2005) found no association between the M235T variant of the AGT gene and preeclampsia or abruptio placentae.
Progression to Renal Failure in IgA Nephropathy
Studying the met235-to-thr polymorphism of the AGT gene in 168 Caucasian patients with IgA nephropathy (161950), Pei et al. (1997) found that patients with the AGT MT (79) and TT (29) genotypes had a faster rate of deterioration of creatinine clearance than those with the MM (60) genotype. Similarly, patients with AGT MT and TT genotypes had higher maximal values of proteinuria than those with the MM genotype. Multivariant analysis detected an interaction between the AGT and ACE gene polymorphisms, with the presence of ACE/DD polymorphism (106180.0001) adversely affecting disease progression only in patients with the AGT/MM genotype. Neither of these gene polymorphisms was associated with systemic hypertension. Thus, Pei et al. (1997) suggested that polymorphisms at the AGT and ACE gene loci are important markers for predicting progression to chronic renal failure in Caucasian patients with IgA nephropathy.
Inoue et al. (1997) found that a common variant in the proximal promoter of the ATG gene, an adenine instead of a guanine 6 bp upstream from the site of transcription initiation (-6G-A), is in very tight linkage disequilibrium with T235 (106150.0001) and marks the original form of the gene. Tests of promoter function in cultured cells and studies of binding between AGT oligonucleotides and nuclear proteins strongly suggested that the substitution at nucleotide -6 affects specific interactions between at least 1 trans-acting nuclear factor and the promoter of AGT, thereby influencing the basal rate of transcription of the gene. These observations suggested a biologic mechanism by which individual differences in the AGT gene may predispose carriers to the development of essential hypertension. They also suggested an evolutionary scenario to account for the emergence of common human disorders, which may fit the 'thrifty genotype' hypothesis advanced by Neel (1962). See Neel et al. (1998) for an update on this hypothesis.
The geographic distribution of the A allele of the -6G-A polymorphism in the AGT gene leads to the hypothesis that the G allele has been selectively advantageous outside Africa. To test this hypothesis, Nakajima et al. (2004) investigated the roles of population history and natural selection in shaping patterns of genetic diversity in AGT by sequencing the entire AGT gene (14,400 bp) in 736 chromosomes from Africa, Asia, and Europe. They found that the A allele was present at higher frequency in African populations than in non-African populations. Neutrality tests found no evidence of a departure from selective neutrality, when whole AGT sequences were compared. However, tests restricted to sites in the vicinity of the -6G-A polymorphism found evidence of a selective sweep. Sliding window analyses showed that evidence of the sweep was restricted to sites in tight linkage disequilibrium with the -6G-A polymorphism. Furthermore, haplotypes carrying the G allele showed elevated levels of linkage disequilibrium, suggesting that they have risen to high frequency relatively recently (the G allele was estimated to have arisen 22,500 to 44,500 years ago). Departures from neutral expectation in some, but not all, regions of AGT indicated that patterns of diversity in the gene cannot be accounted for solely by population history, which would affect all regions equally. Taken together, patterns of genetic diversity in AGT suggested that natural selection has generally favored the G allele over the A allele in non-African populations.
In a study of 2 cohorts of Australian patients with inflammatory bowel disease (see 266600) and age- and sex-matched controls, Hume et al. (2006) found that the AGT -6 A/A genotype was significantly associated with Crohn disease in 1 cohort and in the 2 cohorts combined (p = 0.007 and p = 0.008, respectively). TDT analysis of 148 Crohn families showed moderately significant overtransmission of the variant A allele (p = 0.03).
Jain et al. (2010) presented evidence that the SNP at -6 of the AGT gene is a haplotype marker rather than a functional polymorphism. They identified 3 additional SNPs in the promoter region of the AGT gene at positions -1670, -1562, and -1561. Variants -1670A, -1562C, and -1561T almost always occurred with -6A and were designated the -6A haplotype, and variants -1670G, -1562G, and -1561G almost always occurred with -6G and were designated -6G haplotype. Chromatin immunoprecipitation analysis showed that both HNF1-alpha (HNF1A; 142410) and glucocorticoid receptor (GR, or GCCR; 138040) had higher affinity for the -6A haplotype than the -6G haplotype. Within the -6A haplotype, HNF1-alpha preferentially bound sequence around -1670A, and GR preferentially bound sequence containing -1562C and -1561T. An intact HNF1 site was required for GR-induced promoter activity in vitro. Jain et al. (2010) engineered transgenic mice expressing human BACs covering 116 kb of the 5-prime flanking region of the AGT gene of either haplotype, plus all 5 exons and 4 introns and 54 kb of the 3-prime flanking region. Mice expressing the human AGT gene of the -6A haplotype showed increased plasma AGT levels and increased blood pressure compared with mice expressing the -6G haplotype.
In a consanguineous family of Turkish derivation with renal tubular dysgenesis (RTD; 267430), Gribouval et al. (2005) found an arg375-to-gln (R375Q) mutation in the AGT gene. The nucleotide substitution, 1124G-A, involved the last nucleotide of exon 3. There were 2 affected sisters in this family reported by Kemper et al. (2001). One sister survived after several days of anuria; she had severe and persistent hypotension at birth, requiring fluid infusion, adrenaline, and dopamine treatment. The other sister, who died at 4 days of life, also had very low blood pressure.
In a Japanese female infant with renal tubular dysgenesis (RTD; 267430), Uematsu et al. (2006) identified compound heterozygosity for 2 mutations in the AGT gene: a 604C-T transition in exon 2, resulting in a glu202-to-ter (E202X) substitution, and a 1-bp deletion (1290delT; 106150.0005) in exon 5, resulting in a frameshift and a premature stop codon at position 454. The patient was born at 35 weeks' gestation with Potter syndrome, hypoplastic lungs, and severe hypotension. Treatment with fresh frozen plasma and peritoneal dialysis resulted in clinical improvement and she had spontaneous urination at day 29. At age 18 months, she had no obvious motor or mental retardation. An older brother with similar features had died a few days after birth.
Gribouval et al. (2012) stated that the frameshift and premature stop caused by the 1290delT mutation was Phe430LeufsTer25.
For discussion of the 1-bp deletion (1290delT) in the AGT gene that was found in compound heterozygous state in a Japanese female infant with renal tubular dysgenesis (RTD; 267430) by Uematsu et al. (2006), see 106150.0004.
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