Published online before print October 25, 2004, doi: 10.1161/01.HYP.0000147824.08621.a6
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(Hypertension. 2004;44:884.)
© 2004 American Heart Association, Inc.
Scientific Contributions |
Endothelin-1 Gene and Progression of Blood Pressure and Left Ventricular Mass
Longitudinal Findings in Youth
From the Georgia Prevention Institute Department of Pediatrics (Y.D., X.W., H.Z., F.A.T., H.S.) and Department of Psychiatry (F.A.T.), Medical College of Georgia, Augusta; and Twin Research and Genetic Epidemiology Unit (H.S.), St. Thomas’ Hospital, London, UK.
Reprint requests to Dr Yanbin Dong Georgia Prevention Institute, Medical College of Georgia, 1120 15th St, Building HS-1640, Augusta, GA 30912-3710. E-mail ydong{at}mcg.edu
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Abstract |
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Endothelin-1 (ET-1) is a powerful vasconstrictor peptide implicated in development of essential hypertension and left ventricular hypertrophy. To evaluate the impact of genetic variability of the ET-1 gene on progression of blood pressure (BP) and left ventricular mass (LVM), we conducted individual growth curve modeling for 537 European American and black youths with 12 assessments during a 15-year period. Four common single-nucleotide polymorphisms (SNPs) including T-1370G, +138/ex1 del/ins, T-37/in2C, and Lys198Asn were included in this study. Single SNP analyses showed that individuals with the +138/ex1 ins allele had a borderline significant lower systolic BP (SBP; P=0.072). Furthermore, the –37/in2C allele showed an SBP-lowering effect in males, accounting for 1.6% between-subject variation of SBP (P=0.016). Haplotype analyses in males confirmed the BP-lowering effect of the –37/in2C allele. SBP in individuals homozygous for the del (+138/ex1) –C (–37/in2) haplotype was 3.3 mm Hg lower than those homozygous for the del (+138/ex1) –T (–37/in2) haplotype (P=0.038). For LVM, we observed a significant gene–environment interaction. LVM levels were 20 g higher in carriers versus noncarriers of the –1370G allele in the low socioeconomic status (SES) group only (P=0.004). In summary, our results uncover a sex-specific protective effect of variation in the ET-1 gene on the progression of hypertension risk, and a SES-specific effect on risk of developing left ventricular hypertrophy in multiethnic youth.
Key Words: endothelin • polymorphisms • haplotypes
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Introduction |
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Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by vascular endothelial cells. Plasma ET-1 levels were found to be elevated in subjects with essential hypertension (EH)1 and are thought to influence the progression of this disease.2 Further evidence for the involvement of ET-1 in blood pressure (BP) regulation comes from mice heterozygous for a knockout of the ET-1 gene.3 Furthermore, ET-1 induced hypertrophy by increasing cell volume and cellular protein synthesis in neonatal rat ventricular cardiomyocytes in vitro.4 In hypertensive rats, cardiac ET-1 was thought to play a critical role in dysfunction of left ventricles.5 A correlation between plasma ET-1 concentration and the severity of left ventricular hypertrophy was found in humans.4 Therefore, the ET-1 gene is a strong candidate for EH and left ventricular hypertrophy.
The ET-1 gene (6p24-23) contains 5 exons spanning 6836 bp. A single-nucleotide polymorphism (SNP) in exon 5, Lys198Asn (G to T tranversion), has been associated with BP levels in a few cross-sectional studies in adult cohorts.6–8 Our research group previously found that the Lys198Asn was associated with BP reactivity in a cohort of young adults (age 18.5±2.7 years).9 Apart from the Lys198Asn, the Etude Cas-Temoins de l’Infarctus du Myocarde study identified several additional SNPs in other exons, introns, and the 5' untranslated region.6 However, the roles of these SNPs on BP and left ventricular mass (LVM) development remain unknown.
Most gene association studies are cross-sectional and do not offer information on the impact of genetic susceptibility on interindividual differences in development of BP and LVM over time. We previously observed effects of a positive family history of EH on systolic BP (SBP) and LVM trajectories in European American (EA) and black youth.10 However, to the best of our knowledge, no longitudinal studies have investigated the influence of specific susceptibility genes on development of SBP and LVM from childhood to adulthood in a multiethnic cohort. Furthermore, recent findings suggest that haplotype use can reduce inconsistencies observed in single-marker analysis and may improve power to detect susceptibility genes for EH.11 In particular, ET-1 haplotypes have not yet been examined in association with EH and cardiovascular diseases. Therefore, the present study explored the roles of ET-1 polymorphisms and haplotypes on development of BP and LVM from childhood into early adulthood in a cohort of EA and black youth.
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Methods |
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Subjects
Subjects are among participants in ongoing longitudinal studies evaluating development of cardiovascular risk factors in youth. Data encompass 12 assessments over a 15-year period (1989 to 2004). This cohort has been described in detail previously.10,12,13 Descriptive characteristics by ethnicity and gender at first visit of subjects with available DNA for the SBP (n=538) and LVM cohort (n=537) are shown in Table 1. The data set is complicated because not all subjects had the same number of visits, with subjects recruited into the study at different ages and different years. However, >80% of subjects had
5 visits with data on LVM and 6 visits on SBP, making this data set very informative for the study of LVM and SBP changes over time.
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Subjects were classified as black or EA according to criteria described previously.12 At baseline evaluation, subjects were normotensive for age and gender and were apparently healthy based on parental reports of childhood medical history. Eleven subjects began to take antihypertensive medication during the study, and the data obtained during this period were excluded from analyses.
Subject recruitment, evaluation, and attrition rate have been described previously.12,14 The Institutional Review Board at the Medical College of Georgia had given approval for the study. The fact that 114 of the total number of subjects for SBP or LVM sample were siblings may have affected the significance of observed effects because they share genes and environment. However, when siblings were excluded from the analyses, results were virtually unchanged, so results for the entire sample are reported here.
Measurements
On each laboratory visit after obtaining informed consent, anthropometric, resting hemodynamic, and cardiac structure evaluations were conducted as described previously.10,12,13 The effect of ET-1 gene polymorphisms on longitudinal development of BP in this study was restricted to SBP because SBP can be measured with greater accuracy in youth,15 and increasing evidence suggests that SBP is a better predictor of coronary heart disease mortality than DBP.16 LVM was calculated using the necropsy-validated formula of Devereux et al.17 Intrarater and inter-rater coefficients of variation for all cardiac structures assessed were <10%. Socioeconomic status (SES) was used as a proxy for environmental stress exposure18 and indexed by father’s education level (low education level [<12 years], medium education level [12 and <16 years], or high education level [16 years]) because it was the most influential SES variable affecting SBP and LVM in previous studies involving this cohort.12,13
Genotyping
Of the 6 ET-1 SNPs reported in the Genecanvas database, we selected the 4 common SNPs (>5% allele frequency) for inclusion in this study (T-1370G, +138/ex1 del/ins, T-37/in2C, and Lys198Asn). Genotyping for T-1370G, +138/ex1 del/ins, and T-37/in2C was performed with an Applied Biosystems allelic discrimination assay using the fluorogenic 5'nuclease assay and Taqman MGB probes by using the Applied Biosystems Prism 7000 Sequence Detection System. The Lys198Asn was genotyped by a polymerase chain reaction–restriction fragment length polymorphism (Cac8 I) method.
Statistical Analyses
The main purpose of our analyses was to test the effect of SNP and haplotype variation in the ET-1 gene on development of SBP and LVM from childhood to adulthood. We further investigated whether the effects of the ET-1 gene on SBP and LVM were moderated by ethnicity, gender, SES, or adiposity.
Growth Curve Modeling and Haplotype Trend Regression
All analyses in this study were conducted by using individual growth curve modeling within a multilevel framework, which is a data analysis technique especially designed for longitudinal data.13 In growth curve modeling, a curve is fitted for each individual subject. These curves (SBP or LVM development with age) are characterized by their intercept (or level) and slope (rate of change). Addition of independent variables to the model, such as SNP and haplotype variation in the ET-1 gene, is aimed at explaining between-subject variation (in level and slope) of the growth curves.
To test the effects of statistically inferred haplotypes on changes in SBP and LVM over time, we incorporated the haplotype trend regression (HTR) method19 into the growth curve modeling framework. Details of using HTR for continuous data have been described previously.20 Assuming additive effects of the haplotypes on the trait, the HTR approach tests for the contribution of individual haplotypes rather than haplotype pairs, with the probabilities of haplotype pairs (divided by 2) estimated by PHASE 2.0 software.21 Subjects with at least genotype data on 2 of the 4 ET-1 SNPs were used for haplotype reconstruction. Haplotypes with estimated frequencies below 5% in all the subjects were pooled together and included in the model as 1 term. The most frequent haplotype was used as the baseline haplotype, with which effects of the other haplotypes were contrasted.22
Analytical Strategy and Software
Analyses were done separately for each of the SNPs and followed up by haplotype analyses. For single SNP analysis, heterozygote and homozygote carriers of the rare alleles were combined into 1 group to increase statistical power. We first modeled the effects of age,2 ethnicity, gender, body mass index (BMI), SES, and interactions on development of SBP and LVM as described in detail previously.12,13 After arriving at the most parsimonious full "environmental" model including only significant terms, SNPs or haplotypes were added to the model to test their main effects on the level of the growth curve. Effects on the slope of SBP and LVM curves were modeled as interactions of SNPs or haplotypes with age. In the next step, interactions of SNPs or haplotypes with ethnicity, gender, BMI, and father’s education level were modeled to examine whether the effect of the ET-1 gene on SBP and LVM was moderated by these factors. For LVM, SBP was also added as a predictor.13 Hierarchical 
2 tests were used to determine the significance of the effects that were added to the model in each of the analysis steps.
All multilevel modeling was performed using MLwiN software.23 Hardy–Weinberg equilibrium was tested separately in blacks and EAs by a 2 test with 1 df. Ethnic differences in allele and genotype frequencies were tested with 2 tests of 1 and 2 df, respectively. To prevent inflated significance, these tests were performed in data including only 1 of the sibs, chosen at random. We used D' to describe the pattern of pairwise linkage disequilibrium (LD) calculated using 2LD software.24 Haplotype frequencies for ET-1 SNPs were estimated using PHASE 2.0 software.21 All subjects were used for estimates of haplotype frequencies and LD.
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Results |
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Table 2 shows genotype and allele frequencies of the 4 ET-1 polymorphisms in EAs and blacks. As can be seen in Table 2, total number of subjects genotyped for each polymorphism varied slightly and was somewhat <538. This was because of unsuccessful amplification of the target sequences for some samples (0.56% for T-1370G, 2.8% for +138/ex1del/ins, 3.2% for T-37/in2C, and 2.0% for Lys198Asn, respectively). None of the loci showed deviation from Hardy–Weinberg equilibrium whether in EAs or in blacks. Significantly different allele and genotype frequencies for the T-1370G polymorphism (P<0.001) and significantly different allele frequencies for +138/ex1 ins/del (P=0.012) were found between blacks and EAs. Compared with EAs, the –1370G allele was more common (41% versus 17%) and the +138/ex1 ins allele less common in blacks (19% versus 28%). Significant LD was observed between all ET-1 loci with similar LD patterns in EAs and blacks (Table 3).
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Table 4 displays the results for the analyses of single SNP effects on SBP and LVM based on the most parsimonious full environmental models shown in the footnote. A significant interaction of T-37/in2C polymorphism and gender on SBP level was observed. Stratification of the sample in males and females showed that this locus effect was only significant in males, with lower SBP levels in the –37/in2C allele carriers. Compared with the full environmental model of SBP in males, this locus explained an additional 1.6% between-subject variation of SBP. We also found a borderline significant main effect of +138/ex1del/ins polymorphism on SBP level, with ins allele carriers having lower SBP levels. For LVM, we observed a significant interaction between the T-1370G SNP and SES (Table 4). Separate analyses in low, medium, and high SES groups showed that this polymorphism only had effect within the low SES group, with LVM levels 20 g higher in -1370G allele carriers compared with noncarriers. No significant main or interaction effects for the Lys198Asn polymorphism on SBP or LVM levels were found. None of the 4 polymorphisms showed significant interactions with age; that is, these polymorphisms did not affect the slope of the SBP or LVM curves.
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The inferred haplotype frequencies of the 4 ET-1 polymorphisms in EAs were significantly different from those in blacks (P=0.01). Only 3 common haplotypes (>5%) comprising 88% of the total in EAs and 4 common haplotypes comprising 92.6% of the total in blacks were observed (Table 5). Haplotype 4 is quite common in blacks (18.1%), but its frequency is <1% in EAs. Because the frequency of this haplotype in all subjects is 8.9%, we kept this haplotype as 1 term in the regression model, with all the other rare haplotypes pooled together as 1 term. After adding the haplotype or haplotype interactions with age, gender, ethnicity, BMI, and SES into the full environmental models of SBP, no significant overall changes of 2 values were observed (data not shown). That is, no significant main effect of ET-1 haplotypes or effects of interactions on SBP were found. Pooling the haplotype 4 with the other rare haplotypes in a rest category did not change the results (data not shown). No significant main effects of ET-1 haplotypes on LVM were found. However, the inclusion of haplotype–SES interactions led to a significant improvement of the overall model for LVM (P=0.008), with haplotype 3 (P=0.05) and 4 (P=0.019; Table 5) responsible for the effect. In accordance with the single SNP analysis, the differentiating characteristic of these 2 haplotypes compared with the most common haplotype is the –1370G allele at position 1.
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We noticed that the SBP-lowering alleles in the polymorphisms for which we identified a borderline significant effect (Ins allele of +138/ex1del/ins) and a significant effect in males (C allele of T-37/in2C) in single SNP analyses showed a trans-LD pattern (D'=–0.57 and –0.89 in EAs and blacks, respectively). That is, they do not usually occur together on the same chromosome, which makes it unlikely that the SBP-lowering effect is attributable to LD between these 2 loci. To clarify the combined effect of these 2 SNPs on SBP, we repeated haplotype estimation and analyses using only these 2 SNPs. Results of these haplotype analyses are shown in Table 6. No significant main effect of these haplotypes on SBP was found. A significant interaction of haplotype Del-C and gender was observed although the overall contribution of haplotype variation to the model is only borderline significant (P=0.053). Separate analyses in males and females showed a main effect of haplotype Del-C on SBP level in males only. The ß-coefficient representing the effect of this haplotype on SBP level was –3.31. This means that the level of the SBP growth curve shows a downward shift of on average 3.3 mm Hg for individuals who are homozygous for the Del-C haplotype compared with individuals who are homozygous for the Del-T haplotype. The differentiating characteristic of this haplotype is the –37/in2C allele compared with the most common haplotype Del-T. Very low frequency of haplotype Ins-C makes it impossible to investigate gene–gene interaction between these 2 polymorphisms. Lake et al22 suggested that haplotype frequencies need to be 5% to avoid biased regression parameters. Thus, we excluded individuals with haplotype 4 (Ins-C) and repeated the analysis. However, the results remained the same.
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Discussion |
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We evaluated the effect of genetic variation in the ET-1 gene on development of BP and LVM during a 15-year period in EA and black youth. Significant LD between all the ET-1 loci genotyped in EAs was observed, which is compatible with the ECTIM study.6 A similar LD pattern was observed in blacks, which has not been reported previously.
There were 2 major findings in this study. The first was the association between lower SBP and some common ET-1 alleles and their haplotypes, specifically in EA and black males. Thus, some genetic polymorphisms of the ET-1 gene may have a protective effect on the progression of BP and EH risk. Single SNP analyses showed a borderline significant SBP-lowering effect of the +138/ex1ins allele and an SBP-lowering effect of the –37/in2C allele for males only, accounting for 1.6% between-subject variation of SBP. Haplotype analyses revealed that SBP growth curve levels in males homozygous for the del (+138/ex1) – C (–37/in2) haplotype was 3.3 mm Hg lower than those homozygous for the del (+138/ex1) – T (–37/in2) haplotype. SBP in males homozygous for the haplotype combining the 2 BP-lowering alleles as based on the single SNP analysis (ins [+138/ex1] – C [–37/in2]) was 11.8 mm Hg lower than those homozygous for the most common haplotype. However, this difference did not reach a statistical significance because of the low frequency of this Ins-C haplotype (2.7% and 0.4% in EAs and blacks, respectively).
The second major finding was a gene by environment (ie, SES) interaction for LVM. LVM levels were 20 g higher in carriers versus noncarriers of the -1370G allele in the low SES group only, and this effect was confirmed by our haplotype analyses. Therefore, we conclude that the T-1370G locus confers an increased risk of developing left ventricular hypertrophy but only in the presence of adverse environmental conditions such as chronic stress.
ET-1 increases stress-induced sympathetic activity and arterial vasoconstriction. Enhanced ET-1 activity impaired endothelium-dependent vasodilator function of hypertensive patients.25 ET-1 also regulates body fluid volume by stimulating aldosterone secretion and decreasing kidney perfusion and function and subsequently causing retention of sodium and water, leading to increased intravascular volume.26 All this evidence indicates that ET-1 is a powerful agent controlling BP, and functional genetic variation of the ET-1 gene is likely to contribute to development and variation of BP. The functional impact of the +138/ex1 del/ins and T-37/in2C loci and their haplotypes need to be verified in vitro (eg, vascular reactivity in human artery rings). The T-37/in2C is located in an intron at the 37th nucleotide before exon 3 of the ET-1 gene, and the +138/ex1 del/ins is at the 5' untranslated region. They may regulate the expression levels of the ET-1 gene or be in LD with other functional variants.
We did not find an association between BP and the most investigated ET-1 polymorphism, the Lys198Asn. Most studies have observed an interaction between the Lys198Asn polymorphism and obesity (ie, this polymorphism was only associated with BP levels in overweight subjects).6–8 The present study did not observe an interaction between BMI and any of the 4 polymorphisms or common haplotypes in association with development of BP. The lack of an interactive impact of the ET-1 gene variation with BMI on BP could be attributable to the young age of our subjects and their relatively normal BMI. In summary, this study was conducted to investigate the roles of genetic variation of the ET-1 gene on progression of BP and LVM from childhood to early adulthood by performing growth curve modeling for multiple SNPs and their haplotypes in a multiethnic cohort. The +138/ex1ins and –37/in2C alleles and the Del-C haplotype appear to have SBP-lowering effects in males, whereas the T-1370G locus confers an increased risk of developing left ventricular hypertrophy in the presence of an adverse and stressful environment.
Perspectives
The –37/in2C allele and Del-C haplotype of the ET-1 gene appear to be protective against high BP in males but not in females. This gender-specific effect provides evidence of interaction between gender and genetic components of BP regulation, an example of which has recently emerged in the literature.27 Studies including our own suggest that human sex hormones may modulate plasma ET-1 levels, with male hormones raising levels and female hormones lowering them.28,29 Furthermore, in an animal model of EH, increased vascular responsiveness to ET-1 was observed in males but not in females.30 These findings may partly explain the higher prevalence of EH in men compared with women. Males with the –37/in2C allele and Del-C haplotype may have lower ET-1 tissue or plasma levels, thus protected from the progression of high BP. The exact mechanism responsible is yet to be determined. The significant gene by environment interaction we observed for LVM indicates that the –1370G allele increases risk of developing left ventricular hypertrophy in youth from low socioeconomic backgrounds. Our data thus support the notion that complex cardiovascular traits such as LVM may result from a genetic predisposition, the effects of which are conditional on exposure to a stress-inducing environment.
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Acknowledgments |
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This study was supported in part by grants PO1 HL69999 and R21 HL076723 from the National Heart, Lung, and Blood Institute. Y.D. (0430078N), X.W. (0425447B), and H.Z. (0435146N) are also funded by the American Heart Association.
Received June 4, 2004; first decision June 23, 2004; accepted October 5, 2004.
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References |
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1. Schiffrin EL, Thibault G. Plasma endothelin in human essential hypertension. Am J Hypertens. 1991; 4: 303–308.[Medline] [Order article via Infotrieve]
2. Shichiri M, Hirata Y, Ando K, Emori T, Ohta K, Kimoto S, Ogura M, Inoue A, Marumo F. Plasma endothelin levels in hypertension and chronic renal failure. Hypertension. 1990; 15: 493–496.
3. Kurihara Y, Kurihara H, Suzuki H, Kodama T, Maemura K, Nagai R, Oda H, Kuwaki T, Cao WH, Kamada N. Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature. 1994; 368: 703–710.[CrossRef][Medline] [Order article via Infotrieve]
4. Cullen JP, Bell D, Kelso EJ, McDermott BJ. Use of A-192621 to provide evidence for involvement of endothelin ET(B)-receptors in endothelin-1-mediated cardiomyocyte hypertrophy. Eur J Pharmacol. 2001; 417: 157–168.[CrossRef][Medline] [Order article via Infotrieve]
5. Iwanaga Y, Kihara Y, Hasegawa K, Inagaki K, Yoneda T, Kaburagi S, Araki M, Sasayama S. Cardiac endothelin-1 plays a critical role in the functional deterioration of left ventricles during the transition from compensatory hypertrophy to congestive heart failure in salt-sensitive hypertensive rats. Circulation. 1998; 98: 2065–2073.
6. Tiret L, Poirier O, Hallet V, McDonagh TA, Morrison C, McMurray JJ, Dargie HJ, Arveiler D, Ruidavets JB, Luc G, Evans A, Cambien F. The Lys198Asn polymorphism in the endothelin-1 gene is associated with blood pressure in overweight people. Hypertension. 1999; 33: 1169–1174.
7. Jin JJ, Nakura J, Wu Z, Yamamoto M, Abe M, Tabara Y, Yamamoto Y, Igase M, Kohara K, Miki T. Association of endothelin-1 gene variant with hypertension. Hypertension. 2003; 41: 163–167.
8. Asai T, Ohkubo T, Katsuya T, Higaki J, Fu Y, Fukuda M, Hozawa A, Matsubara M, Kitaoka H, Tsuji I, Araki T, Satoh H, Hisamichi S, Imai Y, Ogihara T. Endothelin-1 gene variant associates with blood pressure in obese Japanese subjects: the Ohasama Study. Hypertension. 2001; 38: 1321–1324.
9. Treiber FA, Barbeau P, Harshfield G, Kang HS, Pollock DM, Pollock JS, Snieder H. Endothelin-1 gene Lys198Asn polymorphism and blood pressure reactivity. Hypertension. 2003; 42: 494–499.
10. Dekkers JC, Treiber FA, Kapuku G, Snieder H. Differential influence of family history of hypertension and premature myocardial infarction on systolic blood pressure and left ventricular mass trajectories in youth. Pediatrics. 2003; 111: 1387–1393.
11. Zhu X, Chang YP, Yan D, Weder A, Cooper R, Luke A, Kan D, Chakravarti A. Associations between hypertension and genes in the renin-angiotensin system. Hypertension. 2003; 41: 1027–1034.
12. Dekkers JC, Snieder H, Van Den Oord EJ, Treiber FA. Moderators of blood pressure development from childhood to adulthood: a 10-year longitudinal study. J Pediatr. 2002; 141: 770–779.[CrossRef][Medline] [Order article via Infotrieve]
13. Dekkers C, Treiber FA, Kapuku G, Van Den Oord EJ, Snieder H. Growth of left ventricular mass in African American and European American youth. Hypertension. 2002; 39: 943–951.
14. Treiber FA, Davis H, Musante L, Raunikar RA, Strong WB, McCaffrey F, Meeks MC, Vandernoord R. Ethnicity, gender, family history of myocardial infarction, and hemodynamic responses to laboratory stressors in children. Health Psychol. 1993; 12: 6–15.[CrossRef][Medline] [Order article via Infotrieve]
15. Biro FM, Daniels SR, Similo SL, Barton BA, Payne GH, Morrison JA. Differential classification of blood pressure by fourth and fifth Korotkoff phases in school-aged girls. The National Heart, Lung, and Blood Institute Growth and Health Study. Am J Hypertens. 1996; 9: 242–247.[CrossRef][Medline] [Order article via Infotrieve]
16. Miura K, Dyer AR, Greenland P, Daviglus ML, Hill M, Liu K, Garside DB, Stamler J. Pulse pressure compared with other blood pressure indexes in the prediction of 25-year cardiovascular and all-cause mortality rates: the Chicago Heart Association Detection Project in Industry Study. Hypertension. 2001; 38: 232–237.
17. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol. 1986; 57: 450–458.[CrossRef][Medline] [Order article via Infotrieve]
18. Snieder H, Harshfield GA, Barbeau P, Pollock DM, Pollock JS, Treiber FA. Dissecting the genetic architecture of the cardiovascular and renal stress response. Biol Psychol. 2002; 61: 73–95.[CrossRef][Medline] [Order article via Infotrieve]
19. Zaykin DV, Westfall PH, Young SS, Karnoub MA, Wagner MJ, Ehm MG. Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Hum Hered. 2002; 53: 79–91.[Medline] [Order article via Infotrieve]
20. Dong Y, Zhu H, Wang X, Dalageorgou C, Carter N, Spector TD, Snieder H. Obesity reveals an association between blood pressure and the G-protein beta3-subunit gene: a study of female dizygotic twins. Pharmacogenetics. 2004; 14: 419–427.[CrossRef][Medline] [Order article via Infotrieve]
21. Stephens M, Donnelly P. A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet. 2003; 73: 1162–1169.[CrossRef][Medline] [Order article via Infotrieve]
22. Lake SL, Lyon H, Tantisira K, Silverman EK, Weiss ST, Laird NM, Schaid DJ. Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous. Hum Hered. 2003; 55: 56–65.[CrossRef][Medline] [Order article via Infotrieve]
23. Rasbash J, Browne W, Goldstein H, Yang M, Plewis I, Healy M, Woodhouse G, Draper D, Langford I, Lewis T. A User’s Guide to MLwiN. London, UK: University of London, Institute of Education; 2000.
24. Zhao JH. 2LD—Two-locus linkage disequilibrium (LD) calculator. Available at: http://www.iop.kcl.ac.uk/IoP/Departments/PsychMed/GEpiBSt/software.shtml; 2002.
25. Cardillo C, Campia U, Kilcoyne CM, Bryant MB, Panza JA. Improved endothelium-dependent vasodilation after blockade of endothelin receptors in patients with essential hypertension. Circulation. 2002; 105: 452–456.
26. Levin ER. Endothelins. N Engl J Med. 1995; 333: 356–363.
27. Turner ST, Boerwinkle E, Sing CF. Context-dependent associations of the ACE I/D polymorphism with blood pressure. Hypertension. 1999; 34: 773–778.
28. Treiber FA, Kapuku GK, Davis H, Pollock JS, Pollock DM. Plasma endothelin-1 release during acute stress: role of ethnicity and sex. Psychosom Med. 2002; 64: 707–713.
29. Polderman KH, Stehouwer CD, van Kamp GJ, Dekker GA, Verheugt FW, Gooren LJ. Influence of sex hormones on plasma endothelin levels. Ann Intern Med. 1993; 118: 429–432.
30. David FL, Montezano AC, Reboucas NA, Nigro D, Fortes ZB, Carvalho MH, Tostes RC. Gender differences in vascular expression of endothelin and ET(A)/ET(B) receptors, but not in calcium handling mechanisms, in deoxycorticosterone acetate-salt hypertension. Braz J Med Biol Res. 2002; 35: 1061–1068.[Medline] [Order article via Infotrieve]
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