Skip Navigation

European Journal of Heart Failure 2002 4(6):707-712; doi:10.1016/S1388-9842(02)00168-X
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Herrmann, S.-M.
Right arrow Articles by Regitz-Zagrosek, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Herrmann, S.-M.
Right arrow Articles by Regitz-Zagrosek, V.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2002 European Society of Cardiology

Angiotensin II type 2 receptor gene polymorphism and cardiovascular phenotypes: the GLAECO and GLAOLD studies

Stefan-Martin Herrmanna,*, Viviane Nicaudb, Klaus Schmidt-Petersena, Jacqueline Pfeifera, Jeanette Erdmannc, Theresa McDonaghd, Henry J. Dargied, Martin Paula and Vera Regitz-Zagrosekc

a Institute of Clinical Pharmacology and Toxicology, Department of Clinical Pharmacology, Benjamin Franklin Medical Center, Freie Universität Berlin Hindenburgdamm 30, 12200 Berlin, Germany
b Inserm U525, Epidemiologic and Molecular Genetics of Cardiovascular Diseases Paris, France
c German Heart Institute, Humboldt University Berlin Berlin, Germany
d Department of Cardiology and MRC Clinical Research Initiative in Heart Failure, Western Infirmary and University of Glasgow Glasgow, UK

* Corresponding author. Tel.: +49-30-8445-2293; fax: 49-30-8445-4482. E-mail address: herrmann{at}medizin.fu-berlin.de


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The angiotensin II type 2 (AT2) receptor is thought to play a role in cardiovascular disorders such as neointima formation after vascular injury, cardiac hypertrophy and myocardial infarction (MI). Recently, the biallelic polymorphism G+1675A in intron 1 of the AT2 receptor gene has been associated with left ventricular posterior, septal and relative wall thickness, as well as left ventricular mass index in young hypertensive males.

Methods: To investigate its potential role in left ventricular hypertrophy (LVH) and other cardiovascular traits, 1968 individuals from two population samples (the Glasgow Heart Scan, GLAECO and Glasgow Heart Scan Old, GLAOLD studies) with echocardiographically and electrocardiographically assessed phenotypes, were genotyped for G+1675A using allele-specific oligonucleotide hybridization. Both studies had a similar design, only the age-ranges differed, being 25–74 years in the GLAECO study and 55–74 years in the GLAOLD study, so that internal consistency of results could also be assessed. Since the AT2 gene is located on the X chromosome, males and females were analysed separately.

Results: The +1675A allele frequency was 0.49 and 0.51, in the GLAECO and GLAOLD studies, respectively. In both studies, the genotype frequencies were similar in hypertensive and non-hypertensive individuals. In the GLAOLD study, in females with episodes of coronary ischemia and MI, the AT2 +1675A allele was more common than in females with no episode (86.5% vs. 73.5%, respectively; P<0.007). This effect was not observed in males. In the same study, AT2 +1675A allele carriers were more common in males with LVH, than in those without LVH (60.3% vs. 46.0%, respectively; P=0.047). This result was unchanged after exclusion of subjects taking antihypertensive drugs (including ACE inhibitors) (64.4% vs. 47.4%, P=0.038). However, in the GLAECO study, these results could not be replicated, even when subjects >55 years of age were considered separately.

Conclusions: Our study gives rise to a potential implication of the AT2 G+1675A polymorphism in LVH and coronary ischemia subgroups. Since these results were not consistent in both studies, but are partially in agreement with two independent investigations, further efforts should be made to elucidate the specific nature of these genotype/phenotype interactions.

Key Words: Angiotensin II type 2 receptor gene • Genetic polymorphism • Left ventricular hypertrophy • Coronary ischemia

Received September 26, 2001; Revised February 21, 2002; Accepted March 26, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Angiotensin II (Ang II), the potent vasoactive and salt-retaining effector peptide of the renin–angiotensin system, is involved in blood pressure hemostasis and cardiovascular pathophysiology [1,2], its actions being mediated through Ang II receptors type 1 (AT1) and 2 (AT2). The AT2 receptor represents the predominant receptor subtype in the human heart [3,4] and myocardial AT2 receptor expression is increased under pathological conditions such as neointima formation after vascular injury [5], cardiac hypertrophy [6] and myocardial infarction (MI) [3,7]. The AT2 receptor gene which is located on the X chromosome, comprises two non-coding exons, two introns and a third exon which harbors the entire uninterrupted open reading frame of the AT2 receptor gene [8]. Recently, a biallelic polymorphism in intron 1 at position +1675 (G/A) from the transcription start point has been reported [9,10], possibly affecting a lariat branchpoint motif [10]. In a broader context, no significant association between this variant and hypertension, dilated or hypertrophic cardiomyopathy could be demonstrated [9]; however, more specifically, AT2 G+1675A has recently been shown to be associated with left ventricular posterior, septal and relative wall thickness, as well as left ventricular mass index [11]. To investigate further the possible pathogenic implications of this polymorphism, we investigated its associations with left ventricular hypertrophy (LVH), hypertension and CHD in two independent clinical studies.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study populations
The Glasgow Heart Scan (GLAECO) Study has been previously reported [12]. The sample included 629 men and 682 women aged 25–74 years (mean age±S.D.: 51±14) randomly selected from North Glasgow (UK), who had participated in the third Glasgow MONICA risk factor survey in 1992. Each subject gave informed consent. This sample is representative of the original cohort in all relevant criteria [13], except that they were more affluent and there were fewer smokers. The incidence of coronary heart disease and hypertension was the same as in the original cohort.

Standard 12-lead electrocardiographs (ECGs) were coded by two observers, for the presence of pathological Q waves, left bundle–branch block, ST-segment depression, T-wave abnormalities, LVH, or atrial fibrillation/flutter by the Minnesota coding system (codes 1·1, 1·2, 1·3, 3·1, 3·3, 3·4, 4·1–4·4, 5·1–5·3, 7·1, 8·31, 8·32) [14]. Unresolved discrepancies were resolved by a third coder. Signs of coronary ischemia or MI were diagnosed on ECG evidence (Q waves, left bundle–branch block, ST/T wave changes).

Standard two-dimensional echocardiography (Acuson 128) was carried out with the participant reclining at 40°, in the left lateral position. Images were stored on videotape and analysed on-line. The left ventricular ejection fraction was calculated by the biplane disc summation method (Simpson's rule) [15]. Each ejection fraction was calculated as a mean of three cardiac cycles. Echocardiograms were deemed of acceptable quality if 80% or more of the endocardium was visible.

Quantitative echocardiogram analysis was performed by a single observer. A random sample of 10% of data was re-analysed by the same observer, who was blinded to the first results. A separate 5% random sample was analysed by a second observer. The variation between the two readings by the same observer for the left ventricular ejection fraction expressed as a median percentage error was 7%. The variation between observers was 10%.

All participants completed a questionnaire recording their current medication. Blood pressure was measured twice with the MONICA protocol (MONICA Manual Part 3, Section 1: Population survey data component revision, March 1992, Geneva, Switzerland: World Health Organization; 1992).

A similar protocol was used for the Glasgow Heart Scan Old (GLAOLD) study (336 men and 348 women aged 55–74 years, mean age±S.D.: 65±5). However, with respect to the left ventricle, only the presence of hypertrophy, based on ECG evidence, was recorded.

2.2. DNA preparation and amplification of study samples using polymerase chain reaction
Genomic DNA was prepared from white blood cells by phenol extraction. Polymerase chain reaction (PCR) was performed using the following primers according to the published gene sequence with the accession number U20860 [GenBank] ; sense: 5'-ATT-ACG-TCC-CAG-CGT-CTG-AG-3'; antisense: 5'-ATA-AAT-CAG-CTT-GCT-TAG-TGC-C-3'. The PCR was performed using 250 ng of DNA in a total volume of 50 µl containing 10 mM Tris–HCl (pH 9), 50 mM KCl, 1.5 mM MgCl2, 0.1% Triton-X100, 0.2 mg ml–1 BSA, 200 µM dNTPs, 25 pmol of each primer and 0.2 U Taq polymerase.

2.3. Genotyping of study populations
Genotyping was done using hybridization with allele-specific oligonucleotides [16] as previously described [17] using the following oligonucleotides: 5'-AAA-CTC-CTG-AAT-TAT-TT-3' and 5'-AAA-CTC-CTA-AAT-TAT-TT-3' to detect the frequent and the less frequent allele, respectively.

2.4. Statistical analysis
Data were analysed using the SAS statistical software (SAS Institute Inc., Cary, NC). Hardy–Weinberg equilibrium was tested by a {chi}2 test. Allele frequencies were computed in each study by gene counting in males and females combined, taking into account that males provide only one copy of the X chromosome. For testing the deviation from Hardy–Weinberg equilibrium, the distribution of the expected genotype frequencies were compared to the observed ones by a {chi}2 test with 3 degrees of freedom in the whole population [18].

Hypertension was defined as present in patients who took antihypertensive drugs or who had a systolic blood pressure >160 mmHg or diastolic blood pressure >95 mmHg. In the GLAECO study, association of genotype with left ventricular mass indexed on body surface area was tested by a general linear model adjusted for age.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
There was no deviation of genotype frequencies from Hardy–Weinberg expectation in the GLAECO or GLAOLD studies; the frequency of the +1675A allele was 0.49 and 0.51, in both studies, respectively.

Since the AT2 gene is located on the X chromosome, results for males and females were calculated separately. The genotype frequencies were similar in hypertensive and non-hypertensive individuals of both genders, in both studies (Table 1). There were no differences with respect to the type of antihypertensive medication.


View this table:
[in this window]
[in a new window]

  		Table 1 Genotype frequency of AT2 G+1675A in males and females according to hypertension in the GLAECO and GLAOLD studies

 
In the GLAOLD study, the AT2 +1675A allele was more common among females with episodes of coronary ischemia and MI, than in females with no episode (86.5% vs. 73.5% respectively; P<0.007) (Table 2). This effect was not detected in males. This result could not be replicated in subjects in the GLAECO study, even when subjects >55 years of age were studied separately (data not shown).


View this table:
[in this window]
[in a new window]

  		Table 2 Genotype frequency of AT2 G+1675A in males and females according to signs of coronary ischemia in the GLAOLD study

 
In the GLAOLD study, AT2 +1675A allele carriers were more common among males with LVH than in those without LVH (60.3% vs. 46.0%, respectively; P=0.047) (Table 3). This result was unchanged after exclusion of subjects taking antihypertensive drugs (including ACE inhibitors) (64.4% vs. 47.4%, P=0.038). No such difference was observed in females. In the GLAECO study, indexed left ventricular mass showed no significant association with genotype in males or females, even when subjects >55 years of age were studied separately (data not shown). No significant association was found with left ventricular wall thickness, blood pressure or ejection fraction in the GLAECO study, even after adjusting for age, gender, antihypertensive treatment, BMI and smoking. However, when adjusting for the same variables in the GLAOLD study, female AT2 +1675A allele carriers had significantly lower diastolic blood pressure (83.1 mmHg, 79.3 mmHg, 77.5 mmHg, for GG, GA and AA genotypes, respectively; P=0.0057 for codominant effect).


View this table:
[in this window]
[in a new window]

  		Table 3 Genotype frequency of AT2 G+1675A in males and females according to LVH in the GLAOLD study

 
Since angiotensin-converting enzyme (ACE) insertion/deletion (I/D) genotypes were available in both study populations, we tested possible interactions between the latter variant and AT2 G+1675A on available phenotypes. As a result, no significant interaction of ACE I/D with AT2 G+1675A on blood pressure, LVH or other left ventricular phenotypes in either study population was identified. However, in females with ischemia or MI from the GLAOLD Study, AT2 +1675A allele carriers more often bore the ACE DD genotype than AT2 +1675GG carriers (36.8% vs. 11.1%, respectively; P=0.031). The corresponding percentages of DD carrying in non-ischemic women were 29.3% and 22.8%, respectively (P=0.35).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The main results of this study can be summarized as follows:

  1. In females >55 years of age from the GLAOLD Study, the +1675A allele was significantly associated with electrocardiographically assessed ischemic episodes and MI.
  2. In males from the same study population, this allele was related to echocardiographically assessed LVH.
  3. A lack of consistency was observed with respect to the above mentioned genotype/phenotype relationships, since we were unable to detect any association of the polymorphism with cardiac phenotypes in the GLAECO Study, even when individuals >55 years of age were analysed separately.

Association studies provide a powerful tool to investigate the relationship between candidate (functional) variants or markers in linkage disequilibrium with these variants and the disease or disease-related phenotypes [19,20]. However, once a significant genotype/phenotype relationship is suggested, it has to be confirmed in other study populations to meet the criterion of external consistency [21]. The unexpected lack of ‘internal’ consistency in our study is surprising since both study populations (GLAECO and GLAOLD) were recruited in the same geographical area, following an identical study protocol.

There are several possible explanations for this apparent discrepancy. A limiting factor is the assessment of phenotypes. In particular, LVH in both studies was assessed using only the Minnesota Code 3.1 as electrocardiographic criterion and not by the more sensitive echocardiography [22]. The observation that the method of electrocardiographical assessment can influence genotype/phenotype relationships has already been reported by Schunkert et al. [23], in a study describing an association of ACE I/D polymorphism with LVH. Unexpectedly, they demonstrated that the association between the ACE ID gene polymorphism and LVH was only significant when using the Sokolow–Lyon index or the Rautaharju equations for electrocardiographic diagnosis of LVH. There was a lack of association when the Minnesota Code 3.1 was used. From the results of our current study, we cannot conclude whether our inconsistent results are simply due to the method of assessment used or if the nature of the relationship in general was too weak or specific and would thus have also occurred with other methods.

In addition, we have no obvious explanation for the apparent gender-specific significant association of the +1675A allele with LVH in men and coronary ischemia and MI in women. This tends to favor a more specific role of the AT2 gene polymorphism in cardiac pathophysiology, as has also been postulated in a recent genetic study on the AT2 A3123C polymorphism in patients with hypertrophic cardiomyopathy [24]. In fact, the association between the +1675A allele and LVH, which appeared to be confined to men, has also been found in hypertensive males in a large cohort that was systematically and prospectively screened for LVH (MONICA Augsburg), but not in normotensives, or in women (Erdmann et al., submitted for publication). Furthermore, in a study of untreated young hypertensive male students, Schmieder et al. [11] reported an association of the +1675A allele with left ventricular posterior, septal and relative wall thickness, as well as left ventricular mass index. In our studies, the trends did not differ significantly between hypertensives and non-hypertensives. Interestingly, in the GLAOLD study, after adjusting for multiple covariates, female AT2 +1675A allele carriers had significantly lower diastolic blood pressure, an effect, which appeared to be codominant. Since this effect on diastolic blood pressure was only observed in females from the GLAOLD study and after multiple adjustments, we rather think of it as a spurious association. Alternatively, if the AT2 +1675A allele is actually the deleterious one, as it is associated with coronary phenotypes in females from the GLAOLD study, a bias of +1675A allele carriers towards lower diastolic blood pressure could be the consequence of its hypothesized effects on mortality. This, however, remains conjectural until a prospective study clarifies this point.

The hypothesis that the AT2 receptor could be functionally related to cardiovascular phenotypes, was deduced from the fact that the AT2 receptor is up-regulated in different pathological conditions including cardiac hypertrophy and intima proliferation [5,6]. Tsutsumi et al. [25] recently reported a 3.5-fold increase of AT2 receptor protein and a 3.1-fold increase of mRNA expression in hearts from patients with dilated cardiomyopathy or diseased hearts of other pathological origin such as MI. A possible role of the AT2 receptor in blood pressure regulation has been drawn from the AT2 knockout model [26], where the contraction induced by Ang II was increased in AT2 receptor null mice, compared with that in wild-type mice [27]. AT2 receptors might additionally contribute to blood pressure lowering in the presence of the AT1 receptor antagonist losartan [28]. This is also consistent with the findings by Stoll et al. [29], that the AT2 receptor mediates antiproliferative effects of Ang II in coronary endothelial cells. There are at least two convincing arguments why genetic variation, e.g. the G+1675A variant, of the AT2 receptor gene, might exert a functional impact on cardiovascular pathophysiology. First, the possible implication of the AT2 receptor gene in cardiovascular disease has recently been substantiated by results from genome-wide linkage analysis in a Finnish population [30]. They identified a locus on chromosome Xq23–26, actually containing the AT2 receptor gene, as candidate locus for premature coronary heart disease. Second, AT2 G+1675A has been suggested to be a functional variant in that it involves a lariat branchpoint motif in intron 1, leading to a diminished AT2 receptor splice efficiency [10]. Furthermore, this sequence region is adjacent to an intron fragment that has recently been demonstrated to direct AT2 gene transcription in the absence of the 5'-flanking region of the AT2 receptor gene [31].

It is conceivable that the G+1675A polymorphism is transcriptionally functional in such a way that the A allele might be associated with some degree of loss-of-function, giving rise to a decreased AT2 gene transcription and therefore, a decreased number of counteracting AT2 receptors. The other possible situation involves the putative branchpoint in intron 1, so that the presence of the A allele would lead to a different and perhaps less functional AT2 receptor transcript with respect to receptor expression.

In light of these results, future study designs should more accurately account for gene–environment interactions which largely influence genotype/phenotype relationships in a complex way. Individuals are exposed to different growth stimuli for various lengths of time, including hypertension, emotional stress, dietary factors, smoking, and also drug intake. In this respect, it should be possible to adjust for these factors when dissecting specific genotype/phenotype associations in appropriate large study populations.

In conclusion, our study gives rise to a potential implication of the AT2 G+1675A polymorphism in LVH and coronary ischemia in subgroups. Since these results are not consistent in both studies but are partially in agreement with two independent investigations, further efforts should be made to elucidate the specific nature of this genotype/phenotype interactions in future study designs.


   Acknowledgements
 
This study was supported by the MRC Clinical Initiative in Heart Failure. S.M. Herrmann (DFG He 2852 1/1) and V. Regitz-Zagrosek (DFG Re 662/4-2) have been supported by grants from the Deutsche Forschungsgemeinschaft. This work was also supported by grants from the Bundesministerium for Education, Science and Technology (BMBF) to Martin Paul and Vera Regitz-Zagrosek in the context of the Clinical Pharmacology Network Berlin–Brandenburg. Stefan-Martin Herrmann and Martin Paul are participants in the grant of the Deutsche Forschungsgemeinschaft: ‘Graduierten-Kolleg 426/2-00 (supported Jacqueline Pfeifer), Molekularbiologische Grundlagen der Therapie’. Vera Regitz-Zagrosek, Stefan-Martin Herrmann and Martin Paul are participants in the grant of the Deutsche Forschungsgemeinschaft ‘Graduierten-Kolleg 754 (supported Klaus Schmidt-Petersen), Myokardiale Genexpression und Funktion, Myokardhypertrophie’.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Pfeffer J.M., Fischer T.A., Pfeffer M.A. Angiotensin-converting enzyme inhibition and ventricular remodeling after myocardial infarction. Annu Rev Physiol (1995) 57:805–826.[CrossRef][Web of Science][Medline]
  2. Hirsch A.T., Talsness C.E., Schunkert H., Paul M., Dzau V.J. Tissue-specific activation of cardiac angiotensin converting enzyme in experimental heart failure. Circ Res (1991) 69:475–482.[Abstract/Free Full Text]
  3. Wharton J., Morgan K., Rutherford R.A., et al. Differential distribution of angiotensin AT2 receptors in the normal and failing human heart. J Pharmacol Exp Ther (1998) 284:323–336.[Abstract/Free Full Text]
  4. Regitz-Zagrosek V., Friedel N., Heymann A., et al. Regulation, chamber localization, and subtype distribution of angiotensin II receptors in human hearts. Circulation (1995) 91:1461–1471.[Abstract/Free Full Text]
  5. Janiak P., Pillon A., Prost J.F., Vilaine J.P. Role of angiotensin subtype 2 receptor in neointima formation after vascular injury. Hypertension (1992) 20:737–745.[Abstract/Free Full Text]
  6. Ohkubo N., Matsubara H., Nozawa Y., et al. Angiotensin type 2 receptors are reexpressed by cardiac fibroblasts from failing myopathic hamster hearts and inhibit cell growth and fibrillar collagen metabolism. Circulation (1997) 96:3954–3962.[Abstract/Free Full Text]
  7. Nio Y., Matsubara H., Murasawa S., Kanasaki M., Inada M. Regulation of gene transcription of angiotensin II receptor subtypes in myocardial infarction. J Clin Invest (1995) 95:46–54.[Web of Science][Medline]
  8. Martin M.M., Elton T.S. The sequence and genomic organization of the human type 2 angiotensin II receptor. Biochem Biophys Res Commun (1995) 209:554–562.[CrossRef][Web of Science][Medline]
  9. Erdmann J., Guse M., Kallisch H., Fleck E., Regitz-Zagrosek V. Novel intronic polymorphism (+1675G/A) in the human angiotensin II subtype 2 receptor gene. Hum Mutat (online) (2000) 15:487.[Medline]
  10. Nishimura H., Yerkes E., Hohenfellner K., et al. Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT of mice and men. Mol Cell (1999) 3:1–10.[CrossRef][Web of Science][Medline]
  11. Schmieder R.E., Erdmann J., Delles C., et al. Effect of the angiotensin II type 2–receptor gene (+1675 G/A) on left ventricular structure in humans. J Am Coll Cardiol (2001) 37:175–182.[Abstract/Free Full Text]
  12. McDonagh T.A., Morrison C.E., Lawrence A., et al. Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population. Lancet (1997) 350:829–833.[CrossRef][Web of Science][Medline]
  13. Tunstall-Pedoe H., Morrison C., Woodward M., Fitzpatrick B., Watt G. Sex differences in myocardial infarction and coronary deaths in the Scottish MONICA population of Glasgow to 1991. Presentation, diagnosis, treatment, and 28-day case fatality of 3991 events in men and 1551 events in women. Circulation (1996) 93:1981–1992.[Abstract/Free Full Text]
  14. Rose GA, Blackburn H, Gillum RF, Prineas RJ. Cardiovascular survey methods, 2nd ed. Geneva: WHO. Monograph series, no 56.
  15. Schiller N.B., Acquatella H., Ports T.A., et al. Left ventricular volume from paired biplane two-dimensional echocardiography. Circulation (1979) 60:547–555.[Abstract/Free Full Text]
  16. Saiki R.K., Bugawan T.L., Horn G.T., Mullis K.B., Erlich H.A. Analysis of enzymatically amplified beta-globin and HLA-DQ alpha DNA with allele-specific oligonucleotide probes. Nature (1986) 324:163–166.[CrossRef][Medline]
  17. Herrmann S.M., Ricard S., Nicaud V., Mallet C., Evans A. Ruidavets JB, Arveiler D, Luc G, Cambien F. The P-selectin gene is highly polymorphic: reduced frequency of the Pro715 allele carriers in patients with myocardial infarction. Hum Mol Genet (1998) 7:1277–1284.[Abstract/Free Full Text]
  18. Vogel F., Motulsky A.G. Human genetics—problems and approaches (1979) Berlin Heidelberg New York: Springer.
  19. Risch N., Merikangas K. The future of genetic studies of complex human diseases. Science (1996) 273:1516–1517.[Abstract/Free Full Text]
  20. Cambien F., Poirier O., Nicaud V., et al. Sequence diversity in 36 candidate genes for cardiovascular disorders. Am J Hum Genet (1999) 65:183–191.[CrossRef][Web of Science][Medline]
  21. Cambien F., Poirier O., Mallet C., Tiret L. Coronary heart disease and genetics in epidemiologist's view. Mol Med Today (1997) 3:197–203.[CrossRef][Web of Science][Medline]
  22. Levy D., Garrison R.J., Savage D.D., Kannel W.B., Castelli W.P. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med (1990) 322:1561–1566.[Abstract]
  23. Schunkert H., Hense H.W., Holmer S.R., et al. Association between a deletion polymorphism of the angiotensin-converting-enzyme gene and left ventricular hypertrophy. N Engl J Med (1994) 330:1634–1638.[Abstract/Free Full Text]
  24. Deinum J., van Gool J.M., Kofflard M.J., ten Cate F.J., Danser A.H. Angiotensin II type 2 receptors and cardiac hypertrophy in women with hypertrophic cardiomyopathy. Hypertension (2001) 38:1278–1281.[Abstract/Free Full Text]
  25. Tsutsumi Y., Matsubara H., Ohkubo N., et al. Angiotensin II type 2 receptor is upregulated in human heart with interstitial fibrosis, and cardiac fibroblasts are the major cell type for its expression. Circ Res (1998) 83:1035–1046.[Abstract/Free Full Text]
  26. Ichiki T., Labosky P.A., Shiota C., et al. Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor. Nature (1995) 377:748–750.[CrossRef][Medline]
  27. Akishita M., Yamada H., Dzau V.J., Horiuchi M. Increased vasoconstrictor response of the mouse lacking angiotensin II type 2 receptor. Biochem Biophys Res Commun (1999) 261:345–349.[CrossRef][Web of Science][Medline]
  28. Gigante B., Piras O., De Paolis P., Porcellini A., Natale A., Volpe M. Role of the angiotensin II AT2-subtype receptors in the blood pressure-lowering effect of losartan in salt-restricted rats. J Hypertens (1998) 16:2039–2043.[CrossRef][Web of Science][Medline]
  29. Stoll M., Steckelings U.M., Paul M., Bottari S.P., Metzger R., Unger T. The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest (1995) 95:651–657.[Web of Science][Medline]
  30. Pajukanta P., Cargill M., Viitanen L., et al. Two loci on chromosomes 2 and X for premature coronary heart disease identified in early- and late-settlement populations of finland. Am J Hum Genet (2000) 67:1481–1493.[CrossRef][Web of Science][Medline]
  31. Warnecke C., Willich T., Holzmeister J., Bottari S.P., Fleck E., Regitz-Zagrosek V. Efficient transcription of the human angiotensin II type 2 receptor gene requires intronic sequence elements. Biochem J (1999) 340:17–24.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
C. Warnecke, P. Mugrauer, D. Surder, J. Erdmann, C. Schubert, and V. Regitz-Zagrosek
Intronic ANG II type 2 receptor gene polymorphism 1675 G/A modulates receptor protein expression but not mRNA splicing
Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1729 - R1735.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
K. Alfakih, R. A. Lawrance, A. Maqbool, K. Walters, S. G. Ball, A. J. Balmforth, and A. S. Hall
The clinical significance of a common, functional, X-linked angiotensin II type 2-receptor gene polymorphism (-1332 G/A) in a cohort of 509 families with premature coronary artery disease
Eur. Heart J., March 2, 2005; 26(6): 584 - 589.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
T. Kuznetsova, J. A. Staessen, L. Thijs, C. Kunath, A. Olszanecka, A. Ryabikov, V. Tikhonoff, K. Stolarz, G. Bianchi, E. Casiglia, et al.
Left Ventricular Mass in Relation to Genetic Variation in Angiotensin II Receptors, Renin System Genes, and Sodium Excretion
Circulation, October 26, 2004; 110(17): 2644 - 2650.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
K. Alfakih, A. Maqbool, M. Sivananthan, K. Walters, G. Bainbridge, J. Ridgway, A. J. Balmforth, and A. S. Hall
Left Ventricle Mass Index and the Common, Functional, X-Linked Angiotensin II Type-2 Receptor Gene Polymorphism (-1332 G/A) in Patients With Systemic Hypertension
Hypertension, June 1, 2004; 43(6): 1189 - 1194.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Herrmann, S.-M.
Right arrow Articles by Regitz-Zagrosek, V.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Herrmann, S.-M.
Right arrow Articles by Regitz-Zagrosek, V.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?