(Hypertension. 1997;29:165.)
© 1997 American Heart Association, Inc.
Scientific Contributions |
Angiotensin-Converting Enzyme and Angiotensinogen Gene Polymorphisms, Plasma Levels, Cardiac Dimensions A Twin Study
A Twin Study
From the Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Virchow Klinikum, Humboldt University of Berlin; and the Department of Clinical Pharmacology, Klinikum Benjamin Franklin, Free University of Berlin (M.K.), Germany.
Correspondence to Friedrich C. Luft, Franz Volhard Clinic, Wiltberg Strasse 50, 13122 Berlin, Germany. E-mail fcluft{at}mdc.berlin.de
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Abstract |
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We tested the hypotheses that angiotensin-converting enzyme insertion/deletion (I/D) and angiotensinogen 235 methionine/threonine (M/T) substitution gene polymorphisms influence angiotensin-converting enzyme and angiotensinogen serum concentrations and cardiac dimensions in 91 monozygotic and 41 dizygotic twin pairs. Cardiac dimensions were determined echo-cardiographically. Angiotensin-converting enzyme levels were 24±11, 43±18, and 58±24 U/L for the II, ID, and DD genotypes, respectively (P<.01). Posterior wall thickness was 8.1±1.3, 8.6±1.7, and 8.9±1.9 mm for these genotypes (P<.05). Angiotensin-converting enzyme levels were correlated with posterior wall thickness (r=.15, P<.05). The intrapair differences in angiotensin converting enzyme levels for monozygotic, concordant dizygotic, and discordant dizygotic twins were 1.36±1.6, 1.86±1.6, and 17.25±4.3 U/L, respectively. The angiotensinogen M/T genotypes exerted no influence on cardiac dimensions or on angiotensinogen concentrations. The additive genetic effect on angiotensin-converting enzyme levels (0.49), on posterior wall thickness (0.26), and on septum thickness (0.37) was significant (P<.01), although shared and nonshared environmental effects were also identified. Our data confirm the impressive effect that the angiotensin-converting enzyme D allele exerts on angiotensin-converting enzyme plasma levels. Furthermore, our data also suggest that the angiotensin-converting enzyme gene locus is primarily responsible for angiotensin-converting enzyme plasma levels. Our twin study also indicates that the angiotensin-converting enzyme gene locus is genetically linked to posterior wall thickness. The correlation between angiotensin-converting enzyme levels and posterior wall thickness suggests that this effect is exerted by angiotensin-converting enzyme. We were unable to demonstrate genetic linkage between the angiotensinogen gene locus and cardiac dimensions in this study.
Key Words: genetics • twins • ACE polymorphisms • angiotensinogen polymorphisms • cardiac hypertrophy
Abbreviations: ACE = angiotensin-converting enzyme • AGT = angiotensinogen • Ang = angiotensin • D = deletion • I = insertion • M = methionine • T = threonine
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Introduction |
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Adiallelic polymorphism in the ACE gene, characterized by a D or I allele in the 16th intron of the ACE gene, has been associated with differences in plasma ACE levels, as well as risk for myocardial infarction and cardiac hypertrophy.1 Tiret et al2 used evidence from combined segregation and linkage analysis and showed that the I allele was characterized by lower ACE levels. A similar association between the I and D alleles and ACE in monocytes has also been identified.3 Cambien et al4 relied on an association study, in which the DD genotype was associated with myocardial infarction in men with low risk. They found that in that group, ACE levels did not decrease with age and were higher in patients with the DD and ID genotypes than in control subjects. Schunkert et al5 reported an excess homozygosity for the D allele among subjects with cardiac hypertrophy as assessed by electrocardiographic criteria. The D allele has also been associated with the severity of cardiac hypertrophy in patients with hypertrophic cardiomyopathy.6 A second renin-angiotensin system gene associated with heart disease is the AGT gene. A 235 M/T substitution (T for M) has been associated with higher blood pressures7,8 and higher AGT levels, at least in blacks. To our knowledge, no twin study has been done to test the relationship between the ACE D allele, ACE plasma levels, the AGT T allele, and AGT levels and cardiac dimensions. We conducted a study in monozygotic and dizygotic twin pairs to test these hypotheses.
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Methods |
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Subjects and Protocol
We recruited 132 pairs of MZ (91 pairs) and DZ (41 pairs) of twins by print media advertisement to participate in studies involving blood pressure and blood pressure reactivity to physical, and mental stress. The protocol was approved by the University's ethical committee on the protection of human subjects and written informed consent was obtained from all participants. Venous blood was obtained for genomic DNA. Each participant underwent a medical history and physical examination. None had hypertension or any other chronic medical illness. Blood pressure and heart rate were measured in the nondominant arm under standardized conditions by an automated oscillometric method (Dinamap).
Echocardiography
M-mode and two-dimensional echocardiograms were recorded with patients in the left lateral decubitus position. M-mode tracings that were guided two-dimensionally were recorded from the short parasternal axis at the chordal level between the free edges of the mitral leaflets at the tips of the papillary muscles. Only tracings with optimal visualization of left ventricular interfaces were used. In our echocardiographic laboratory, the range of variability of observations by a single reader is 0 mm to 1.5 mm for the left ventricular dimensions and 0 mm to 0.5 mm for the wall thickness. Interventricular septal thickness and posterior wall thickness were measured in all patients according to the guidelines of the American Society of Echocardiography.9
Laboratory Methods
The zygosity was verified with the use of five highly polymorphic short tandem repeat polymerase chain reaction-amplified microsatellite markers, namely THO1, TPOX, FES/FPS, F13A1, and FGA.10 We used fluorescent labeled primers in a multiplex automated genotyping system relying on a 373 DNA sequencer, 672 GENESCAN, and GENOTYPER software (all Applied Biosystems). The I/D polymorphism of the ACE gene was identified with the polymerase chain reaction using a set of oligonucleotide primers flanking the polymorphic site according to the method described by Rigat et al.11 Allele specific oligonucleotide hybridization was used for the genotyping of AGT codons 174 and 235. Genomic DNA was subjected to 30 rounds of amplification using primers described elsewhere.12 The resulting 354 base pair fragment was denatured, dot blotted in duplicate onto nitrocellulose, and then neutralized. The filters were subsequently hybridized to the appropriate 32P-labeled oligonucleotides. ACE activity in plasma was determined by means of a synthetic substrate (FAPGG) as outlined elsewhere,13 and plasma AGT was determined by radioimmunoassay.14 Since oral contraceptives increase AGT concentrations, we included only AGT determinations from men and women not taking oral contraceptives in our calculations.
Analytical Techniques
Statistical analysis was conducted using the SPSS program. To test for differences in the mean level of the cardiovascular measures, t tests for independent groups were used. In addition to univariate methods, analysis of variance was employed as a true multivariate method. Parameters of the quantitative genetic models were estimated by path analysis techniques using the LISREL 8 program developed by Jöreskog and Sörbom.15 Analogous to a regression analysis, the variability of any given phenotype (P) within a population can be decomposed in additive genetic influences (A), nonadditive genetic influences (D), environmental influences shared (common) by the twins within a family (C), and random environment (E):
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2 value. The LISREL 8 output also gives estimates of the Goodness of Fit Index, the Adjusted Goodness of Fit Index, and the Akaike Information Criterion. These estimates concurred with the results of the 2 analysis, so that we have elected not to present these estimates.
Allele frequencies and standard binomial errors were determined by the gene counting method. Genotype distributions of all groups were checked for Hardy-Weinberg equilibrium and were compared to each other by 2 and likelihood ratio methods. Relative risk figures (odds ratio statistics) and their 95% confidence intervals were calculated by using the SPSS statistical program package. Allele-dose (codominant) effects were tested by linear regression.
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Results |
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In Table 1 are shown the demographic data of 139 subjects displayed in terms of ACE genotype. Only one member of each twin pair was included for the association testing. Selecting either twin 1 or twin 2 did not influence the results. No differences in terms of age, gender, body dimensions, systolic blood pressure or heart rate are apparent. Diastolic blood pressure was actually slightly higher (P<.1) in subjects with at least one I allele than in subjects with the DD genotype. Significant differences (P<.01) between the genotypes were observed in ACE levels. Interestingly, the AGT concentrations were significantly lower in persons with the ACE DD genotype than in those with the II or ID genotype. Posterior wall thickness was greater in subjects with the DD genotype than in those with the II genotype. Since gender, age, body size, weight, BMI, systolic and diastolic blood pressure, and physical activity have a considerable effect on heart size, cardiac dimensions were corrected for these variables by stepwise multiple linear regression. For posterior wall thickness age, sex, and weight were the only variables entering the relationship, for septum thickness these were age, weight and systolic blood pressure.
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Serum ACE activity levels and ACE genotypes are shown in Fig 1A. The linear regression of ACE activity over the number of D alleles attests to an significant allele-dose effect with a slope of 17. The variance was progressively greater in subjects with the ID and DD genotype than in subjects with the II genotype, resulting in a significant increase of the intrapair differences among MZ between genotypes. Variance differences were adjusted by log transformation of the difference from the genotype-specific mean. We next examined the twin pair difference in ACE activity. In Fig 1B is shown the difference in MZ twins, DZ twins concordant for the ACE genotype, and DZ twins discordant for the ACE genotype. MZ twins and concordant DZ twins showed the same, narrow within-pair difference in ACE activity. Discordant DZ twins on the other hand showed a 10-fold greater within-pair difference in ACE activity (P<.01). These data attest to the sole influence of ACE genotypes on the serum ACE activity level in these subjects. We performed linear regression analysis to examine correlations between serum ACE activity levels and posterior wall thickness, with or without correction for gender, body size, and physical activity. These correlations were: r=.15, P<.05 uncorrected and r=.22, P<.01 corrected.
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In Fig 2A are shown the corrected posterior wall thickness values in the three ACE genotypes. Posterior wall thickness increases progressively with addition of the D allele (P<.05). In Fig 2B is shown the within-pair difference in MZ twins, concordant DZ twins, and discordant DZ twins. MZ twins showed a small degree of within-pair difference, while the within-pair difference in concordant and discordant DZ twins was significantly greater (P<.05). These data suggest that, in addition to ACE genotypes, other genes influence posterior wall thickness. Table 2 shows the genetic variance on ACE levels and on cardiac size. The additive genetic effects, shared, and non-shared environmental effects were all highly significant. In Table 3 are shown the demographic and clinical data on the subject population broken down in terms of AGT genotypes. No significant differences were found. The AGT levels increased numerically with addition of the T allele; however, the variability of the levels was too great to show significance.
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Discussion |
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We documented the effect of genetic variance on echo-cardiographically determined cardiac dimensions and serum ACE activity levels. We verified that the ACE I/I genotype is associated with low serum ACE activity levels, the I/D genotype with intermediate levels, and the D/D genotype with high serum ACE activity levels. We were able to show a correlation between serum ACE activity levels and posterior wall thickness. We observed a small within-pair difference in serum ACE activity levels in MZ and concordant DZ twins, while in discordant DZ twins the difference was much greater. This observation gives strong support to the notion that the D allele exercises a strong, independent effect on serum ACE activity levels, and that the ACE gene alone is primarily responsible for ACE activity in normal individuals.
McKenzie et al17 used a segregation and linkage analysis and found evidence for two quantitative-trait loci influencing ACE levels. Our findings are at variance with these observations and rather suggest that the ACE gene locus is primarily responsible for ACE levels. Morrison et al18 studied African-Caribbean families from Jamaica, who may have differed genetically from our twin subjects. We tested our assumption with two different approaches. First, we corrected the ACE levels for the influence of the ACE gene by regression analysis and tested the residuals for remaining genetic effects. No significant additive or nonadditive genetic influences were discernible. Second, we compared the intrapair differences between MZ and concordant and discordant DZ twins. Were a second gene locus exerting an effect, the within-pair difference of concordant DZ twins would be expected to lie between those of MZ and DZ discordant twins. However, we observed no significant within-pair difference between MZ and concordant DZ twins. Instead, their values were almost identical. Twin methodology has substantial power for testing such hypotheses, as was shown in other studies.18
We found that the uncorrected posterior wall thickness was greater in subjects with the DD genotype than in subjects with the II or ID genotypes. Correcting the posterior wall thickness for gender, body size, and physical activity accentuated these differences. The within-pair difference was small in MZ twins, but similarly great in concordant and discordant DZ twins, attesting to the fact that posterior wall thickness is not merely a function of ACE genotypes but rather that other (perhaps many) genes are involved. Finally, our data are the first to show a correlation between serum ACE activity and any parameter of cardiac size. We have no immediate explanation on our failure to find a similar effect of the DD genotype on septal thickness. The effects we observed were small and our subjects were all normotensive. Possibly, the distribution of ACE in ventricular tissue is not uniform. ACE has been documented in the endocardium and coronary vasculature.19 Danser et al20 measured ACE activity in human left ventricular wall and found higher cardiac ACE levels in persons with the DD genotype. No comparisons of ACE levels in septum and posterior wall have been made; however, conceivably differing distributions of ACE could be responsible for differences in local growth effects.
Schunkert et al5 studied a large random sample of men and women. With electrocardiographic criteria, they identified 141 women and 149 men with left ventricular hypertrophy. Among these subjects, an excess were homozygous for the D allele of the ACE gene. The association of the DD genotype with left ventricular hypertrophy was stronger in men than women, and was most prominent when blood pressure measurements were normal. They did not measure ACE levels in their subjects. Since their report, the ACE gene DD genotype has been associated with left ventricular hypertrophy by a group of Japanese investigators.21 Furthermore, Marian et al22 reported that the D allele was associated with hypertrophic cardiomyopathy and that the D allele was a risk for sudden cardiac death. They have extended these findings to show that the D allele is associated with the degree of hypertrophy in this disease.6,23 They did not report the result of ACE measurements, and so the conclusion rests on the basis that ACE may be a genetic marker for left ventricular hypertrophy. Lindpaintner1 subsequently commented that the diallelic polymorphism is only modestly informative and, since it resides in an intron, is extremely unlikely to represent a biologically relevant mutation.
Our results confirm the finding that the I/D polymorphism is associated with serum ACE activity.2,18 Cambien et al4 postulate the existence of an ACE Ss polymorphism, which has not yet been characterized at a molecular level. They suggest that the I/D polymorphism is a marker for the postulated functional variant ACE Ss and is associated with 28% to 44% of the interindividual variability of plasma ACE activity.4 Our finding that serum ACE activity levels are correlated with posterior wall thickness, coupled with the relationship between the I/D genotypes and posterior wall thickness is evidence that the D allele is not merely a potential genetic marker but rather that plasma ACE activity is related to the development of left ventricular size, independent of blood pressure. Our findings conflict with the observations of Kupari et al,24 who measured left ventricular size and function but not serum ACE activity levels in relation to ACE polymorphisms in normal subjects. They studied 86 individuals, fewer than the number reported here. Furthermore, they did not apply the power of the twin model to test the hypothesis. Lindpaintner et al25 also recently reported the absence of association or genetic linkage between ACE gene and left ventricular mass. They relied on echocardiographic data from the Framingham study and examined 759 sibling pairs in their linkage analysis. We have no immediate explanation for the discrepancy. The numbers of sibling pairs in their study is impressive. Echocardiography is a sensitive method of determining cardiac dimensions. They did not report on posterior wall thickness, which was the only ACE genotype-related parameter of cardiac size we identified. Echocardiography for the Framingham study was performed by numerous people over a period of years. The method does have errors and observer variability. There may have been a substantial within-pair age difference in the Framingham siblings. The twin model used is an extension of the sib-pair linkage approach. Our twin pairs were identical in age, which renders less variability. All echocardiograms were performed by the same experienced cardiologist in our study.
We cannot conclude for certain that the ACE DD genotype and increased ACE levels were responsible for increased posterior wall thickness in our population. The causative gene could be linked to the ACE gene locus and thereby show allelic association. Since the ACE locus had such a dominant effect on ACE levels, the correlation between ACE levels and posterior wall thickness does not necessarily strengthen the case for ACE. Nevertheless, there are several mechanisms whereby ACE could influence cardiac hypertrophy. For instance, increased ACE expression has been shown in the hearts of rats with pressure-overload-induced cardiac hypertrophy.26 Ang I is converted to Ang II by ACE in the heart and elsewhere.27–30 Ang II is associated with cell growth and can interact with several oncogenes such as c-myc, c-fos, and c-jun, which are known to be growth regulators.31,32
In addition to ACE, we also directed our attention to ATG and the ATG gene. We were only able to analyze ATG plasma concentrations from men and from women not ingesting oral contraceptives. We found lower ATG concentrations in subjects with the ACE DD genotype than in subjects with the ACE I allele. Conceivably, higher ACE levels may have led to an increase in AGT consumption. However, renin is considered to be most important in terms of generating Ang II.33 We have recently been able to show in animal experiments that ACE gene expression and ACE activity in the vessel wall are a rate limiting step in Ang II generation.34 We found no effect of AGT M/T genotypes on blood pressure or heart size. We were not able to document an effect of AGT M/T genotypes on AGT concentrations; however, the number of AGT samples in our study was limited to male twins only and may have been too small to test that hypothesis.
We conclude that the ACE gene locus in primarily responsible for ACE levels in our subjects and that the ACE DD genotype exerts an influence on cardiac posterior wall thickness independent of blood pressure. The correlation between ACE levels and posterior wall thickness suggests that ACE is indeed responsible. The AGT M/T polymorphism, in contrast, had no demonstrable effect on cardiac dimensions. These data support the notion that the ACE gene exerts an influence on cardiac size and development through the actions of ACE.
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Acknowledgments |
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Andreas Busjahn is supported by a grant-in-aid from the Leo-poldina Stiftung. Herbert Schuster is a recipient of a Hess Fellowship from the Deutsche Forschungsgemeinschaft. Friedrich C. Luft is supported by a grant-in-aid from the Bundesministerium für Bildung und Forschung.
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A. Busjahn, G.-H. Li, H.-D. Faulhaber, M. Rosenthal, A. Becker, E. Jeschke, H. Schuster, B. Timmermann, M. R. Hoehe, and F. C. Luft {beta}-2 Adrenergic Receptor Gene Variations, Blood Pressure, and Heart Size in Normal Twins Hypertension, February 1, 2000; 35(2): 555 - 560. [Abstract] [Full Text] [PDF]
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H. Knoblauch, A. Busjahn, B. Muller-Myhsok, H.-D. Faulhaber, H. Schuster, R. Uhlmann, and F. C. Luft Peroxisome Proliferator-Activated Receptor {gamma} Gene Locus Is Related to Body Mass Index and Lipid Values in Healthy Nonobese Subjects Arterioscler. Thromb. Vasc. Biol., December 1, 1999; 19(12): 2940 - 2944. [Abstract] [Full Text] [PDF]
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 K. F. Hilgers, M. R. W. Langenfeld, M. Schlaich, R. Veelken, and R. E. Schmieder 1166 A/C Polymorphism of the Angiotensin II Type 1 Receptor Gene and the Response to Short-Term Infusion of Angiotensin II Circulation, September 28, 1999; 100(13): 1394 - 1399. [Abstract] [Full Text] [PDF]
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J. Karjalainen, U. M. Kujala, A. Stolt, M. Mantysaari, M. Viitasalo, K. Kainulainen, and K. Kontula Angiotensinogen gene M235T polymorphism predicts left ventricular hypertrophy in endurance athletes J. Am. Coll. Cardiol., August 1, 1999; 34(2): 494 - 499. [Abstract] [Full Text] [PDF]
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 Z. NAGY, A. BUSJAHN, S. BÄHRING, H.-D. FAULHABER, H.-R. GOHLKE, H. KNOBLAUCH, M. ROSENTHAL, B. MÜLLER-MYHSOK, H. SCHUSTER, and F. C. LUFT Quantitative Trait Loci for Blood Pressure Exist Near the IGF-1, the Liddle Syndrome, the Angiotensin II-Receptor Gene and the Renin Loci in Man J. Am. Soc. Nephrol., August 1, 1999; 10(8): 1709 - 1716. [Abstract] [Full Text]
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 A. Busjahn, H.-D. Faulhaber, K. Freier, and F. C. Luft Genetic and Environmental Influences on Coping Styles: A Twin Study Psychosom Med, July 1, 1999; 61(4): 469 - 475. [Abstract] [Full Text] [PDF]
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A. Busjahn, H. Knoblauch, H.-D. Faulhaber, T. Boeckel, M. Rosenthal, R. Uhlmann, M. Hoehe, H. Schuster, and F. C. Luft QT Interval Is Linked to 2 Long-QT Syndrome Loci in Normal Subjects Circulation, June 22, 1999; 99(24): 3161 - 3164. [Abstract] [Full Text] [PDF]
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R. J. van SUYLEN, E. F. WOUTERS, H. J. PENNINGS, E. C. CHERIEX, P. E. van POL, A. W. AMBERGEN, A.-M. VERMELIS, and M. J. DAEMEN The DD Genotype of the Angiotensin Converting Enzyme Gene Is Negatively Associated with Right Ventricular Hypertrophy In Male Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., June 1, 1999; 159(6): 1791 - 1795. [Abstract] [Full Text]
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P. Corvol, A. Persu, A.-P. Gimenez-Roqueplo, and X. Jeunemaitre Seven Lessons From Two Candidate Genes in Human Essential Hypertension : Angiotensinogen and Epithelial Sodium Channel Hypertension, June 1, 1999; 33(6): 1324 - 1331. [Abstract] [Full Text] [PDF]
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 G. I. Rice, C. A. Foy, and P. J. Grant Angiotensin converting enzyme and angiotensin II type 1-receptor gene polymorphisms and risk of ischaemic heart disease Cardiovasc Res, March 1, 1999; 41(3): 746 - 753. [Abstract] [Full Text] [PDF]
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C. J. O'Donnell, K. Lindpaintner, M. G. Larson, V. S. Rao, J. M. Ordovas, E. J. Schaefer, R. H. Myers, and D. Levy Evidence for Association and Genetic Linkage of the Angiotensin-Converting Enzyme Locus With Hypertension and Blood Pressure in Men but Not Women in the Framingham Heart Study Circulation, May 19, 1998; 97(18): 1766 - 1772. [Abstract] [Full Text] [PDF]
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 P. Corvol and X. Jeunemaitre Molecular Genetics of Human Hypertension: Role of Angiotensinogen Endocr. Rev., October 1, 1997; 18(5): 662 - 677. [Abstract] [Full Text]
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H. Knoblauch, A. Busjahn, S. Munter, Z. Nagy, H.-D. Faulhaber, H. Schuster, and F. C. Luft Heritability Analysis of Lipids and Three Gene Loci in Twins Link the Macrophage Scavenger Receptor to HDL Cholesterol Concentrations Arterioscler. Thromb. Vasc. Biol., October 1, 1997; 17(10): 2054 - 2060. [Abstract] [Full Text]
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