(Hypertension. 1996;28:881-887.)
© 1996 American Heart Association, Inc.
Articles |
Polymorphisms of the Transforming Growth Factor-ß1 Gene in Relation to Myocardial Infarction and Blood Pressure
The Etude Cas-Temoin de l'Infarctus du Myocarde (ECTIM) Study
INSERM SC7, Paris, France (F.C., S.R., C.M., O.P.); UMR 103 CNRS-Biomerieux, ENS, Lyon, France (A.T., L.G.); and the MONItoring of trends and determinants in CArdiovascular disease (MONICA) Projects of Belfast, UK (A.E.), and Strasbourg (D.A.), Lille (G.L.), and Toulouse (J.-B.R.), France.
Correspondence to Francois Cambien, INSERM SC7, 17 rue du Fer a Moulin, 75005 Paris, France. E-mail cambien@infobiogen.fr.
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Abstract |
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Transforming growth factor-ß1 (TGF-ß1) plays an important role in the modulation of cellular growth and differentiation and the production and degradation of the extracellular matrix. A number of experimental results suggest that TGF-ß1 may be involved in cardiovascular physiopathology. In the present study, we assessed whether the TGF-ß1 gene is a candidate gene for coronary heart disease or hypertension. We screened the coding region and 2181 bp upstream of the TGF-ß gene for polymorphisms and identified seven polymorphisms: 3 in the upstream region of the gene at positions -988, -800, and -509 from the first transcribed nucleotide; 1 in a nontranslated region at position +72; 2 in the signal peptide sequence Leu10
Pro, Arg25Pro; and 1 in the region of the gene coding for the precursor part of the protein not present in the active form, Thr263Ile. We analyzed these TGF-ß1 polymorphisms in 563 patients with myocardial infarction and 629 control subjects from four regions in Northern Ireland and France. The Pro25 allele was more frequent in patients than in control subjects in Belfast (P<.01) and Strasbourg (P<.05). The TGF-ß1 polymorphisms were not associated with the degree of angiographically assessed coronary artery disease in patients. The presence of a Pro25 allele was associated with a lower systolic pressure in the four control groups (P<.002), and a history of hypertension was significantly less frequent in homozygotes or heterozygotes for Pro25 than in homozygotes for Arg25 (odds ratio, 0.43; 95% confidence interval, 0.19 to 0.92; P<.03). Since the Pro25 allele was associated with an increased risk of myocardial infarction and a reduced risk of hypertension, we favor a cautious interpretation of these apparently inconsistent results. Other studies will need to verify whether these associations are real.
Key Words: transforming growth factors • myocardial infarction • polymorphism, genetic
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Introduction |
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The multifunctional protein TGF-ß1 plays an important role in the modulation of cellular growth and differentiation in a wide variety of cell types and in the production and degradation of the extracellular matrix. A number of experimental results suggest that TGF-ß1 may be involved in cardiovascular pathophysiology. Through several mechanisms, variable availability of this growth factor could affect endothelial function,1 2 3 4 5 interfere with the development of atherosclerosis,6 7 and influence vascular8 9 10 and cardiac11 remodeling. TGF-ß1 is synthesized as a latent protein composed of 390 amino acids.12 Active TGF-ß1 is formed of two identical disulfide-linked polypeptide chains consisting of the 112 amino acids of the C-terminal part of the precursor protein. The amino acid sequence of the active form of TGF-ß is highly conserved across mammalian species, indicating a strong selection against variant forms of the protein. However, even if qualitatively variable forms of TGF-ß are probably quite rare in humans, variable constitutive or induced expression of the protein as a consequence of variability of the TGF-ß gene is conceivable and could be associated with different effects of TGF-ß on cellular growth and extracellular matrix formation.
In the present study, we assessed whether the TGF-ß gene was a candidate gene for CHD and hypertension. We identified several polymorphisms of the TGF-ß1 gene and investigated their associations with MI, coronary artery disease, blood pressure, hypertension, and other risk factors for CHD in the ECTIM Study.
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Methods |
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Study Population
The study population has been described previously.13 In the ECTIM Study, male patients and control subjects aged 25 to 64 years were recruited between 1989 and 1991 from four MONICA registers—one in Northern Ireland (Belfast) and three in France (Lille, Strasbourg, and Toulouse). Patients with a previous history of CHD (angina pectoris or MI) were not excluded from the study. The subjects had to be residents of the region where they were recruited; their parents had to be born in this same region; and their four grandparents had to be born in Europe. Cases were recruited into the study 3 to 9 months after the event and had to satisfy the World Health Organization criteria for definite acute MI (category I). Control subjects were randomly recruited from the same areas as the cases and were stratified by age so that they approximately matched the age distribution of the cases. In the present analysis, all control subjects with CHD (prevalent cases in the random samples) were excluded, and only those patients and control subjects who were genotyped for all genetic polymorphisms investigated were included in the analysis.
A coronary angiography was available for 93% of the French cases and 18% of the Irish cases. To avoid any selection bias, we report the angiography results only in French cases. Coronary angiograms were read in each recruitment center. As central reading was impossible, the number of major arteries with more than 50% stenosis was the only information recorded for assessment of the degree of coronary artery disease.
Informed consent was obtained from the subjects and their family doctors. The subjects were examined by especially trained staff and completed a set of questionnaires that included details of personal history, drug intake, and parental history of MI. Blood pressure was measured twice with a random-zero sphygmomanometer according to the standardized protocol of the MONICA project.14 Hypertension was defined by a clinical history of hypertension, presence of antihypertensive treatment, or diastolic pressure over 95 mm Hg. The assays used for measurement of plasma lipid variables and plasma levels of PAI-1 and fibrinogen in the ECTIM Study have been described.13 15 16
Identification of Polymorphisms on the TGF-ß1 Gene
For PCR-SSCP analysis17 18 of the TGF-ß1 gene, 20 individuals with MI were selected from the ECTIM Study. From the published sequences of the TGF-ß1 gene,19 20 17 overlapping fragments of approximately 250 bp were enzymatically amplified to cover the entire coding region and 2181 bp upstream of the coding region. Each amplification was performed with 500 ng genomic DNA in a total volume of 50 µL containing 10 mmol/L Tris-HCl (pH 9), 50 mmol/L KCl, 1.5 mmol/L MgCl2, 0.1% Triton X-100, 0.2 g/L bovine serum albumin, 200 µmol/L dNTPs, 25 pmol of each primer, and 0.2 U Taq polymerase (Appligene). For the SSCP analysis, 0.3 µCi of [
-32P]dCTP was added to the mix. The PCR fragments longer than 300 bp were restricted overnight by the addition of 2 or 5 U of the appropriate enzyme to yield fragments between 150 and 300 bp in length.21
Thereafter, products were diluted twofold in a solution containing 95% formamide, 10 mmol/L EDTA, 0.05% bromphenol blue, and 0.05% xylene cyanol. After denaturation at 95°C for 5 minutes, the samples were placed on ice and 4 µL was loaded onto nondenaturing 6% acrylamide gels (acrylamide-to-bisacrylamide ratio of 37.5:1). Two conditions were used for electrophoresis: 0% and 7.5% glycerol with migration performed at 40 W constant power for 5 hours at room temperature with a cooling fan. The gels were dried and exposed and autoradiographed at -80°C for 12 hours with an intensifying screen.
DNA from patients presenting a different SSCP pattern of migration was reamplified by PCR with unlabeled primers. PCR products were purified by centrifugation with Bio-spin 6 columns (Bio-Rad). Sequencing was performed by the method of Sanger et al22 in 20 PCR cycles with [
-32P]dATP end-labeled primer using a direct sequencing kit (Life Technologies).
Genotyping of All Subjects Included in the ECTIM Study
Genotyping of all subjects participating in the ECTIM Study was performed with allele-specific oligonucleotides.23 After enzymatic amplification, one fifth of the PCR product was denatured in 150 µL of 0.5 mol/L NaOH and 1.5 mol/L NaCl and blotted onto nylon membranes (N+, ICN). Each allele was detected after prehybridization by incubation of the membranes for 2 hours with 100 pmol of unlabeled oligonucleotide probe specific for the other allele, followed by incubation for 4 hours with 20 pmol of the labeled probe specific for the allele. The allele-specific oligonucleotides are listed in Table 1
. The melting temperature (Tm) used for hybridization was calculated by addition of 4°C for each G or C and 2°C for each T or A and subtraction of 5°C from the total. The membranes were washed twice at room temperature in 1x SSC for 5 minutes followed by 5 minutes in 0.5x SSC at temperatures of Tm minus 3°C.
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Statistical Analysis
When a putative risk factor is being considered, the MI case versus control difference is the main hypothesis tested in the ECTIM Study. If there is some suggestion of a difference, other end points are examined for investigation of the internal consistency of the result. These secondary end points include parental history of MI, the degree of coronary stenosis evaluated by angiography in cases, and various risk factors for which the investigated gene may be a candidate in control subjects. In the case of TGF-ß, blood pressure and hypertension were considered as secondary end points. Probability values are provided without adjustment for multiple comparisons.24 The hierarchy in the analytic strategy, the strong linkage disequilibrium among the loci, the associations among phenotypes, and above all the internal consistency of the results need to be considered when the results are being interpreted.
Data were analyzed with the SAS statistical software (SAS Institute). Continuous variables were compared between groups by ANOVA (SAS-PROC GLM); when required, adjustment on continuous covariates was performed by ANCOVA. Genotype frequencies were compared between genotypes, after adjustment on population by logistic regression analysis (SAS-PROC LOGISTIC). Odds ratios and their 95% confidence intervals were computed from the logistic regression coefficients and their standard errors. Homogeneity of the results according to population was tested by introduction into the model of the interaction term crossing populations and genotypes.
Hardy-Weinberg equilibrium was tested by a 
2 test with 1 df. Pairwise linkage disequilibrium coefficients were estimated in the control samples; coefficients are reported as the ratio of the unstandardized coefficients to their minimal/maximal values (|D'|)25 ; the sign added in front of the coefficients indicates whether the linkage disequilibrium is positive or negative (Table 3). The global heterozygosity provided by the polymorphisms was computed from the haplotype frequencies estimated with the myriad algorithm.26 Except for one TGF-ß polymorphism (TGF-ß–509), only one genetic model grouping heterozygotes and less-frequent homozygotes was tested because the number of less-frequent homozygotes was small.
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Results |
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The number of subjects genotyped for all TGF-ß1 polymorphisms was 1192 (563 MI cases and 629 control subjects). The mean age of the cases and control subjects was 54.2±8.1(SD) and 52.8±8.4 years, respectively (P<.01). The entire coding region and 2181 bp upstream of the initiation site of transcription were screened for polymorphisms by PCR-SSCP and sequencing. Forty alleles from 20 MI patients participating in the ECTIM Study were analyzed. Seven polymorphisms were identified: 3 in the upstream region of the gene at positions -988, -800, and -509 from the first transcribed nucleotide; 1 in a nontranslated region at position +72; and 3 in the region of the gene coding for the precursor part of the protein not present in the active form: Leu10
Pro, Arg25Pro, and Thr263Ile (Table 2). The TGF-ß1–988 variant was present in only 2 individuals (1 case and 1 control subject), and as a consequence it is not reported in the tables.
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The polymorphisms were strongly associated with each other, as shown in Table 3
, which gives the coefficients of linkage disequilibrium between pairs of polymorphisms. A negative sign in front of the coefficient indicates that the less-frequent allele at one site is associated with the most-frequent allele at the other site; conversely, a positive sign indicates that the less-frequent alleles at both sites are preferentially associated. The similar allele frequencies and strong positive linkage disequilibrium existing between the +72 and codon 25 polymorphisms reflect the almost complete association between these two polymorphisms. The overall heterozygosity provided by the seven polymorphisms was 0.65.
The distributions of genotypes and alleles for the different polymorphisms in cases and control subjects are shown in Table 4. No significant deviation of genotype frequencies from Hardy-Weinberg expectation was noted. Genotype and allele frequencies in cases and control subjects did not vary significantly across the four ECTIM populations (not shown), except for TGF-ß1–509. The frequencies of the less-frequent allele at this locus in Belfast, Lille, Strasbourg, and Toulouse were 0.326, 0.313, 0.326, and 0.402, respectively, in control subjects (P<.06, 3 df) and 0.291, 0.376, 0.336, and 0.399 in cases (P<.05, 3 df), indicating a higher frequency of the less-frequent allele in Toulouse than in the other populations.
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The genotype distribution of the codon 25 polymorphism was significantly (P<.05) different between cases and control subjects. As a consequence of their strong mutual association, the +72 and codon 25 genotypes were very similarly distributed in cases and control subjects. The distributions of codon 25 genotypes and alleles in cases and control subjects in the different populations are shown in Table 5. There was a significant excess of the Pro25 allele in cases in Belfast (P<.01) and Strasbourg (P<.05) but no significant excess in the two other populations. As it has been shown that Lp(a) inhibits the activation of TGF-ß127 28 and that this could be an important mechanism in the initiation and progression of atherosclerosis, we tested a possible interaction between plasma levels of Lp(a) and the TGF-ß1 codon 25 polymorphism on the risk of MI. In carriers of the Pro25 allele, the mean plasma levels of Lp(a) in patients and control subjects were 0.205 (SD, 0.235) and 0.101 (0.149) g/L, respectively (P<.001), whereas in Arg25 homozygotes, the means were 0.180 (0.228) and 0.099 (0.166) g/L, respectively (P<.0001); there was no significant heterogeneity across populations. We can conclude from this analysis that the codon 25 polymorphism does not influence the case-control difference of plasma Lp(a) level.
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In MI patients, a parental history of fatal or premature MI, presence of a previous MI, and history of hypertension were not associated with the codon 25 polymorphism (Table 6) or any other TGF-ß1 polymorphism. Furthermore, among the 374 French MI patients who underwent coronary angiography, no association between any TGF-ß polymorphism and degree of stenosis could be detected (Table 6).
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In control subjects, there was no association between TGF-ß1 genotypes and a number of quantitative traits investigated in the ECTIM Study, including age, body mass index, plasma lipids, lipoproteins and apolipoproteins, Lp(a), and plasma levels of fibrinogen and PAI-1. Conversely, a significant association between the codon 25 polymorphism and systolic pressure was observed (Table 7). After adjustment for age, body mass index, and alcohol consumption, the presence of a Pro25 allele was associated with a lower systolic pressure in the four control groups (global P value adjusted on populations and covariates <.002). A similar trend was observed for diastolic pressure, but the association was not significant. In control subjects, a parental history of fatal or premature MI was not associated with the codon 25 polymorphism (Table 8), but a history of hypertension was significantly less frequent in homozygotes and heterozygotes for Pro25 than in homozygotes for Arg25 (odds ratio, 0.43; 95% confidence interval, 0.19 to 0.92; P<.03).
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Discussion |
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Polymorphisms of the TGF-ß Gene
The aim of this association study was to identify common polymorphisms of the TGF-ß gene that might be associated with a predisposition to MI or hypertension. If such polymorphisms existed, they might be functional or they might be markers for functional polymorphisms. There are several reasons why the screening strategy we used could have missed a relevant functional polymorphism of the TGF-ß1 gene. (1) The polymorphism may be located outside the region analyzed by PCR-SSCP: in an intron, in the 3' flanking region of the gene, or more than 2181 bp upstream of the start of transcription. (2) The polymorphism may have not been found in the 40 alleles that we analyzed from the MI patients. Such variants may exist, but their low frequency would signify that their putative effect on CHD or hypertension in the population would be quite low. (3) The PCR-SSCP technique for identification of polymorphisms is not 100% sensitive. The conditions used in the present study probably provide a sensitivity of more than 90%.21 The set of polymorphisms of the TGF-ß1 gene that we have analyzed provides a heterozygosity of 0.65. Given the strong linkage disequilibrium existing on the TGF-ß1 gene, it is possible that even if the SSCP analysis had missed a functionally important polymorphism of the gene, one of the identified polymorphisms would be a good marker for this variant.
Among the seven common polymorphisms of the TGF-ß1 gene identified by PCR-SSCP and sequencing in the present study, those affecting codons 10 and 25 had already been observed by screening of two genomic DNA libraries, but they were thought to be artifactual.19 We are not aware of any former study investigating putative associations between polymorphisms of the TGF-ß gene and cardiovascular disorders.
The Leu10Pro and Arg25Pro polymorphisms of the TGF-ß1 gene are located in the signal peptide sequence that is cleaved from the TGF-ß1 precursor at the level of codon 29. The signal sequence allows export of the newly synthesized protein across the membranes of the endoplasmic reticulum. Signal peptides exhibit a unity of function despite having highly diverse sequences; however, they all comprise three regions: a positively charged N-terminal region, a central hydrophobic core, and a polar C-terminal region.29 The amino acid 10 polymorphism is located in the hydrophobic core; both Leu and Pro are apolar, and the polymorphism probably should not affect the function of the signal peptide. Conversely, the Arg25Pro polymorphism corresponds to a change of a big polar amino acid for a small apolar one and is located close to the 3' end of the hydrophobic core. Different classes of signal sequence mutations changing one amino acid to another and affecting export efficiency have been described,30 and the importance of a change in charge in the hydrophobic core has been stressed. Whether the amino acid 25 polymorphism affects the export of the preproTGF-ß protein is thus possible and needs to be assessed experimentally.
The Thr263Ile polymorphism is located in the part of the TGF-ß proprotein that is cleaved from the active part at the level of amino acid 278. It has been proposed that in addition to the transcriptional regulation, activation of latent TGF-ß is a component in the sequence of events leading to growth regulation by this growth factor.31 As a consequence, it is conceivable that the codon 263 polymorphism is involved in the activation process of TGF-ß.
The other four polymorphisms identified at positions -988, -800, -509, and +72 were all located in the 5' region of the gene. Their location does not correspond to any known consensus sequence; however, this does not formally exclude the possibility that they modulate the expression of the TGF-ß gene.
TGF-ß Gene Polymorphisms and MI
The Pro25 allele was more frequent in MI patients than in control subjects in Belfast and Strasbourg; the overall difference in the four populations was also significant, and there was no significant heterogeneity of the association across populations. An association with MI was observed for the +72 polymorphism, but this association was almost identical to that observed between the codon 25 polymorphism and MI. No associations between the polymorphisms and plasma lipids, lipoproteins, apolipoproteins, and coagulation factors were found in the control groups of the ECTIM Study.
It has been suggested that TGF-ß may interfere with the development of atherosclerosis, principally through its action on endothelial function.1 2 3 4 5 TGF-ß modulates the endothelial expression of several molecules involved in cell adhesion and spreading4 6 32 or in the regulation of vasomotor tone and cell proliferation.33 34 TGF-ß1 also preserves endothelial function35 and protects against reperfusion injury in several animal models of reperfusion after ischemia.36 Another mechanism linking TGF-ß and atherogenesis could involve an interaction with the fibrinolytic system. Human vascular smooth muscle cells (VSMCs) produce latent TGF-ß that is activated by the serine protease plasmin.31 Plasmin is produced from plasminogen by tissue plasminogen activator. Lp(a) and PAI-1 block the activation of latent TGF-ß by inhibiting tissue plasminogen activator. As a consequence, PAI-1 and Lp(a) promote VSMC proliferation in culture by relieving the autocrine inhibition caused by active TGF-ß.37 In the ECTIM Study, the association between plasma levels of Lp(a) and MI was similar in the different TGF-ß genotypes. We also performed a similar analysis with plasma PAI-1 instead of Lp(a) and found no interaction between plasma PAI-1 and TGF-ß genotypes.
TGF-ß Gene Polymorphisms and Blood Pressure
Through its effect on endothelial and VSMC function, TGF-ß1 could play a role in blood pressure regulation. TGF-ß1 potentiates the proliferative effect of several growth factors on VSMCs in spontaneously hypertensive rats but inhibits this effect in Wistar-Kyoto rats.8 Fluid shear stress induces endothelial TGF-ß1 transcription and production.9 It is thus possible that TGF-ß1 is involved in flow-induced vascular remodeling. TGF-ß induces fibrosis and angiogenesis in vivo and stimulates collagen formation in vitro.10 In the ECTIM Study, we found a significant association between the Arg25Pro polymorphism and blood pressure that was consistent across the four populations. Carriers of the Pro25 allele had a systolic pressure 5 to 10 mm Hg lower than Arg25 homozygotes, depending on the population. As a consequence of this association, a history of hypertension was less frequent in Pro25 carriers than in Arg25 homozygotes: 9.3% versus 21.2% in Belfast and 11.3% versus 22.2% in France (global P<.03).
The lower frequency of allele Pro25 in hypertensive than in normotensive individuals appears to be inconsistent with the higher frequency of this allele in MI patients than in control subjects. Furthermore, in patients there was no association between the codon 25 polymorphism and parental history of MI, presence of a previous MI, and degree of angiographically assessed coronary artery disease. Given the partial inconsistency of the results, we favor a cautious interpretation of the associations found between the TGF-ß codon 25 polymorphism, MI, and blood pressure or hypertension in the present study. Other studies will have to verify whether these associations are real. However, the highly pleiotropic effect of TGF-ß according to cell types and pathophysiological circumstances and its likely implication in endothelial dysfunction, atherosclerosis, and vascular or cardiac remodeling1 2 3 4 5 6 7 8 9 10 11 might explain the apparently inconsistent effects of the TGF-ß1 polymorphism on MI and hypertension.
Quantitative phenotypes and disease end points other than those studied in the ECTIM Study ought to be investigated in relation to TGF-ß gene polymorphisms. TGF-ß1 may be involved in the arterial and cardiac remodeling induced by hypertrophic stimuli,11 suggesting that these remodeling processes might be associated with functional polymorphisms of the TGF-ß gene. Noncardiovascular phenotypes and diseases such as tissue repair after injury or fibrotic disorders of the kidney, liver, lung, skin, or central nervous system38 might also be associated with TGF-ß gene polymorphisms.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The recruitment in the ECTIM Study was supported by grants from the Squibb Laboratory, the British Heart Foundation, INSERM, and the "Institut Pasteur–Lille." The genetic study of the TGF-ß gene was supported by an agreement between INSERM and the Merck Sharpe & Dohme Chibret Co. We thank Francoise Defranoux for technical assistance and Christiane Souriau for extracting DNA of the ECTIM Study.
Received January 2, 1996;
first decision March 5, 1996; first decision June 3, 1996;
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References |
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1. Dickson K, Philip A, Warshawsky H, O'Connor-McCourt M, Bergeron JJM. Specific binding of endocrine transforming growth factor-ß1 to vascular endothelium. J Clin Invest. 1995;95:2539-2554.
2.
Gamble JR, Vadas MA. Endothelial adhesiveness for blood neutrophils is inhibited by transforming growth factor-ß1. Science. 1988;242:97-99.
3. Gamble JR, Vadas MA. Endothelial adhesiveness for human T-lymphocytes is inhibited by transforming growth factor-ß1. J Immunol. 1991;148:1149-1154.[Abstract]
4. Gamble JR, Khew-Goodall Y, Vadas MA. Transforming growth factor-beta inhibits E-selectin expression on human endothelial cells. J Immunol. 1993;150:4494-4503.[Abstract]
5.
Zeiher AM, Drexler H, Wollschlager H, Just H. Modulation of coronary vasomotor tone in humans: progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation. 1991;83:391-401.
6.
Brown SL, Lundgren CH, Nordt T, Fujii S. Stimulation of migration of human aortic smooth muscle cells by vitronectin: implications for atherosclerosis. Cardiovasc Res. 1994;28:1815-1820.
7. Grainger D, Kemp PR, Metcalfe JC, Liu AC, Lawn RM, Williams NR, Grace AA, Schofield PM, Chauhan A. The serum concentration of active transforming growth factor-beta is severely depressed in advanced atherosclerosis. Nature Medicine. 1995;1:74-79.[Medline] [Order article via Infotrieve]
8.
Agrotis A, Saltis J, Bobik A. Transforming growth factor-ß1 gene activation and growth of smooth muscle from hypertensive rats. Hypertension. 1994;23:593-599.
9. Ohno M, Cooke JP, Dzau VJ, Gibbons GH. Fluid shear stress induces endothelial TGF ß1 transcription and production: modulation by potassium channel blockade. J Clin Invest. 1995;95:1363-1369.
10.
Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta A, Falanga V, Kehrl JH, Fauci AS. Transforming growth factor ß: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci U S A. 1986;83:4167-4171.
11. Takahashi N, Calderone A, Izzo NJ, Maki TM, Marsh JD, Colucci WS. Hypertrophic stimuli induce transforming growth factor-ß1 expression in rat ventricular myocytes. J Clin Invest. 1994;94:1470-1476.
12. Derinck R, Jarrett JA, Chen EY, Eaton DH, Bell JR, Assoian RK, Roberts AB, Sporn MB, Goeddel DV. Human transforming growth factor ß complementary DNA sequence and expression in normal and transformed cells. Nature. 1985;316:701-705.[Medline] [Order article via Infotrieve]
13.
Parra HJ, Arveiler D, Evans AE, Cambou JP, Amouyel P, Bingham A, McMaster D, Schaffer P, Douste-Blazy P, Luc G, Richard JL, Ducimetiere P, Fruchart JC, Cambien F. A case-control study of lipoprotein particles in two populations at contrasting risk for CHD, the Ectim Study. Arterioscler Thromb. 1992;12:701-707.
14. Tiret L, Ricard S, Poirier O, Arveiler D, Cambou JP, Luc G, Evans AE, Nicaud V, Cambien F. Genetic variation at the angiotensinogen locus in relation to high blood pressure and myocardial infarction, The ECTIM Study. J Hypertens. 1995;13:311-317.[Medline] [Order article via Infotrieve]
15.
Scarabin PY, Barra L, Ricard S, Poirier O, Cambou JP, Arveiler D, Luc G, Evans AE, Samama MM, Cambien F. Genetic variation at the ß fibrinogen gene in relation to plasma fibrinogen concentrations and risk of myocardial infarction. Arterioscler Thromb. 1993;13:886-891.
16. Ye S, Green FR, Henney AM, Dawson SJ, Humphries SE, Scarabin PY, Evans A, Cambou JP, Arveiler D, Bara L, Cambien F. Genetic variation in the promoter of the plasminogen activator inhibitor type-1 (PAI-1) gene in relation to plasma PAI-1 activity and risk of myocardial infarction: The ECTIM Study. Thromb Haemost. 1995;74:837-841.[Medline] [Order article via Infotrieve]
17.
Saiki RK, Gefland DH, Stoffel S, Scahrf SJ, Higuchi R, Horn GT, Mullis KB, Herlich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988;239:487-491.
18. Orita M, Suzuki Y, Sekiya T, Hayashi K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics. 1989;5:874-879.[Medline] [Order article via Infotrieve]
19.
Derynck R, Rhee L, Chen EY, Van Tilburg A. Intron-exon structure of the transforming growth factor ß precursor gene. Nucleic Acids Res. 1987;15:3188-3189.
20.
Kim SJ, Glick A, Sporn MB, Roberts AB. Characterization of the promoter region of the human transforming growth factor-ß1 gene. J Biol Chem. 1989;264:402-408.
21. Hayashi K. PCR-SSCP: a single sensitive method for detection of mutations in the genomic DNA. PCR. 1991;1:34-38.
22.
Sanger F, Nicklen S, Coulson R. DNA sequencing with chain terminating inhibitors. Proc Natl Acad Sci U S A. 1977;74:5463-5467.
23. Saiki RK. Genetic analysis of enzymatically amplified ß globin and HLA-DQa genomic DNA with allele specific oligonucleotide probes. Nature. 1987;324:163-166.
24. Rothman KJ. No adjustments are needed for multiple comparisons. Epidemiology. 1990;1:43-46.[Medline] [Order article via Infotrieve]
25. Nei M. Molecular Evolutionary Genetics. New York, NY: Columbia University Press; 1987.
26. MacLean CJ, Morton NE. Estimation of myriad haplotype frequencies. Genet Epidemiol. 1985;2:263-272.[Medline] [Order article via Infotrieve]
27.
Kojima S, Harpel PC, Rifkin DB. Lipoprotein(a) inhibits the generation of transforming growth factor-beta: an endogenous inhibitor of smooth muscle cell migration. J Cell Biol. 1991;113:1439-1445.
28. Grainger DJ, Kemp PR, Liu AC, Lawn RM, Metcalfe JC. Activation of transforming growth factor-beta is inhibited in transgenic apolipoprotein(a) mice. Nature. 1994;370:460-462.[Medline] [Order article via Infotrieve]
29.
Randall LL, Hardy SJS. Unity in function in the absence of consensus in sequence: role of leader peptides in export. Science. 1989;243:1156-1159.
30. Benson SA, Hall MN, Silhavy TJ. Genetic analysis of protein export in Escherichia coli K12. Annu Rev Biochem. 1985;54:101-134.[Medline] [Order article via Infotrieve]
31.
Lyons RM, Gentry LE, Purchio AF, Moses HL. Mechanisms of activation of transforming growth factor ß1 by plasmin. J Cell Biol. 1990;110:1361-1367.
32.
Gamble JR, Bradley S, Noack L, Vadas MA. TGF-ß and endothelial cells inhibit VCAM-1 expression on human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1995;15:949-955.
33. Matsumura Y, Murata S, Takada K, Takaoka M, Morimoto S. Involvement of transforming growth factor-ß1 for platelet-induced stimulation of endothelin-1 production. Clin Exp Pharmacol Physiol. 1994;21:991-996.[Medline] [Order article via Infotrieve]
34. Cristiani C, Volpi D, Landonio A, Bertolero F. Endothelin-1-selective binding sites are downregulated by transforming growth factor-beta and upregulated by basic fibroblast growth factor in a vascular smooth muscle-derived cell line. J Cardiovasc Pharmacol. 1994;23:988-994.[Medline] [Order article via Infotrieve]
35. Kenny D, Coughlan MG, Pagel PS, Kampine JP, Warltier DC. Transforming growth factor beta 1 preserves endothelial function after multiple brief coronary artery occlusions and reperfusion. Am Heart J. 1994;127:1456-1461.[Medline] [Order article via Infotrieve]
36.
Lefer AM, Tsao P, Aoki N, Palladiro MA. Mediation of cardioprotection by transforming growth factor ß. Science. 1990;249:61-64.
37.
Grainger DJ, Kirschenlohr HL, Metcalfe JC, Weissberg PL, Wade DP, Lawn RM. Proliferation of human smooth muscle cells promoted by Lp(a). Science. 1993;260:1655-1657.
38.
Border WA, Noble NA. Transforming growth factor ß and tissue fibrosis. N Engl J Med. 1994;331:1286-1292.
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 V. F. Panoulas, K. M. J. Douglas, J. P. Smith, A. Stavropoulos-Kalinoglou, G. S. Metsios, P. Nightingale, and G. D. Kitas Transforming growth factor-{beta}1 869T/C, but not interleukin-6 -174G/C, polymorphism associates with hypertension in rheumatoid arthritis Rheumatology, February 1, 2009; 48(2): 113 - 118. [Abstract] [Full Text] [PDF]
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S.-J. Chang, C.-J. Chen, F.-C. Tsai, H.-M. Lai, P.-C. Tsai, M.-H. Tsai, and Y.-C. Ko Associations between gout tophus and polymorphisms 869T/C and -509C/T in transforming growth factor {beta}1 gene Rheumatology, May 1, 2008; 47(5): 617 - 621. [Abstract] [Full Text] [PDF]
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 B. S. Saltzman, J. F. Yamamoto, R. Decker, L. Yokochi, A. G. Theriault, T. M. Vogt, and L. Le Marchand Association of Genetic Variation in the Transforming Growth Factor {beta}-1 Gene with Serum Levels and Risk of Colorectal Neoplasia Cancer Res., February 15, 2008; 68(4): 1236 - 1244. [Abstract] [Full Text] [PDF]
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 K. Hatta, A. Morimoto, E. Ishii, H. Kimura, I. Ueda, S. Hibi, S. Todo, T. Sugimoto, and S. Imashuku Association of transforming growth factor-{beta}1 gene polymorphism in the development of Epstein-Barr virus-related hematologic diseases Haematologica, November 1, 2007; 92(11): 1470 - 1474. [Abstract] [Full Text] [PDF]
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 A. C. Jonth, L. Silveira, T. E. Fingerlin, H. Sato, J. C. Luby, K. I. Welsh, C. S. Rose, L. S. Newman, R. M. du Bois, L. A. Maier, et al. TGF-beta1 Variants in Chronic Beryllium Disease and Sarcoidosis J. Immunol., September 15, 2007; 179(6): 4255 - 4262. [Abstract] [Full Text] [PDF]
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 M. Thys, I. Schrauwen, K. Vanderstraeten, K. Janssens, N. Dieltjens, K. Van Den Bogaert, E. Fransen, W. Chen, M. Ealy, M. Claustres, et al. The coding polymorphism T263I in TGF-{beta}1 is associated with otosclerosis in two independent populations Hum. Mol. Genet., September 1, 2007; 16(17): 2021 - 2030. [Abstract] [Full Text] [PDF]
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 S. I. Berndt, W.-Y. Huang, N. Chatterjee, M. Yeager, R. Welch, S. J. Chanock, J. L. Weissfeld, R. E. Schoen, and R. B. Hayes Transforming growth factor beta 1 (TGFB1) gene polymorphisms and risk of advanced colorectal adenoma Carcinogenesis, September 1, 2007; 28(9): 1965 - 1970. [Abstract] [Full Text] [PDF]
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 D. Kang, K.-M. Lee, S. K. Park, S. I. Berndt, D. Reding, N. Chatterjee, R. Welch, S. Chanock, W.-Y. Huang, and R. B. Hayes Lack of Association of Transforming Growth Factor-{beta}1 Polymorphisms and Haplotypes with Prostate Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Trial Cancer Epidemiol. Biomarkers Prev., June 1, 2007; 16(6): 1303 - 1305. [Full Text] [PDF]
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 D. J. Grainger TGF-{beta} and atherosclerosis in man Cardiovasc Res, May 1, 2007; 74(2): 213 - 222. [Abstract] [Full Text] [PDF]
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 Y. Kim and C. Lee The Gene Encoding Transforming Growth Factor {beta}1 Confers Risk of Ischemic Stroke and Vascular Dementia Stroke, November 1, 2006; 37(11): 2843 - 2845. [Full Text] [PDF]
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M. P.S. Sie, A. G. Uitterlinden, M. J. Bos, P. P. Arp, M. M.B Breteler, P. J. Koudstaal, H. A.P. Pols, A. Hofman, C. M. van Duijn, and J. C.M. Witteman TGF-{beta}1 Polymorphisms and Risk of Myocardial Infarction and Stroke: The Rotterdam Study Stroke, November 1, 2006; 37(11): 2667 - 2671. [Abstract] [Full Text] [PDF]
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 P. August and M. Suthanthiran Transforming growth factor beta signaling, vascular remodeling, and hypertension. N. Engl. J. Med., June 22, 2006; 354(25): 2721 - 2723. [Full Text] [PDF]
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 J.-H. Mao, E. F. Saunier, J. P. de Koning, M. M. McKinnon, M. N. Higgins, K. Nicklas, H.-T. Yang, A. Balmain, and R. J. Akhurst Genetic variants of Tgfb1 act as context-dependent modifiers of mouse skin tumor susceptibility PNAS, May 23, 2006; 103(21): 8125 - 8130. [Abstract] [Full Text] [PDF]
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 W. Koch, P. Hoppmann, J. C. Mueller, A. Schomig, and A. Kastrati Association of Transforming Growth Factor-{beta}1 Gene Polymorphisms With Myocardial Infarction in Patients With Angiographically Proven Coronary Heart Disease Arterioscler Thromb Vasc Biol, May 1, 2006; 26(5): 1114 - 1119. [Abstract] [Full Text] [PDF]
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A. M. Summers, B. M. Coupes, M. F. Brennan, S. A. Ralph, C. D. Short, and P. E. C. Brenchley VEGF -460 genotype plays an important role in progression to chronic kidney disease stage 5 Nephrol. Dial. Transplant., November 1, 2005; 20(11): 2427 - 2432. [Abstract] [Full Text] [PDF]
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 T Hamaguchi, S Okino, N Sodeyama, Y Itoh, A Takahashi, E Otomo, M Matsushita, H Mizusawa, and M Yamada Association of a polymorphism of the transforming growth factor-{beta}1 gene with cerebral amyloid angiopathy J. Neurol. Neurosurg. Psychiatry, May 1, 2005; 76(5): 696 - 699. [Abstract] [Full Text] [PDF]
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V. G. Kaklamani, L. Baddi, J. Liu, D. Rosman, S. Phukan, C. Bradley, C. Hegarty, B. McDaniel, A. Rademaker, C. Oddoux, et al. Combined Genetic Assessment of Transforming Growth Factor-{beta} Signaling Pathway Variants May Predict Breast Cancer Risk Cancer Res., April 15, 2005; 65(8): 3454 - 3461. [Abstract] [Full Text] [PDF]
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 M van der Paardt, J B A Crusius, M A Garcia-Gonzalez, B A C Dijkmans, A S Pena, and I E van der Horst-Bruinsma Susceptibility to ankylosing spondylitis: no evidence for the involvement of transforming growth factor {beta}1 (TGFB1) gene polymorphisms Ann Rheum Dis, April 1, 2005; 64(4): 616 - 619. [Abstract] [Full Text] [PDF]
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 R. Sparks, J. Bigler, J. G Sibert, J. D Potter, Y. Yasui, and C. M Ulrich TGF{beta}1 polymorphism (L10P) and risk of colorectal adenomatous and hyperplastic polyps Int. J. Epidemiol., October 1, 2004; 33(5): 955 - 961. [Abstract] [Full Text] [PDF]
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A. Ewart-Toland, J. M. Chan, J. Yuan, A. Balmain, and J. Ma A Gain of Function TGFB1 Polymorphism May Be Associated With Late Stage Prostate Cancer Cancer Epidemiol. Biomarkers Prev., May 1, 2004; 13(5): 759 - 764. [Abstract] [Full Text] [PDF]
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D. J. Grainger Transforming Growth Factor {beta} and Atherosclerosis: So Far, So Good for the Protective Cytokine Hypothesis Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 399 - 404. [Abstract] [Full Text]
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 L Wu, J Chau, R P Young, V Pokorny, G D Mills, R Hopkins, L McLean, and P N Black Transforming growth factor-{beta}1 genotype and susceptibility to chronic obstructive pulmonary disease Thorax, February 1, 2004; 59(2): 126 - 129. [Abstract] [Full Text] [PDF]
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Z. Li, T. Habuchi, N. Tsuchiya, K. Mitsumori, L. Wang, C. Ohyama, K. Sato, T. Kamoto, O. Ogawa, and T. Kato Increased risk of prostate cancer and benign prostatic hyperplasia associated with transforming growth factor-beta 1 gene polymorphism at codon10 Carcinogenesis, February 1, 2004; 25(2): 237 - 240. [Abstract] [Full Text] [PDF]
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E. Jaakkola, A. M. Crane, K. Laiho, I. Herzberg, A.-M. Sims, L. Bradbury, A. Calin, S. Brophy, M. Kauppi, K. Kaarela, et al. The effect of transforming growth factor {beta}1 gene polymorphisms in ankylosing spondylitis Rheumatology, January 1, 2004; 43(1): 32 - 38. [Abstract] [Full Text] [PDF]
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 S. Levesque, J.-M. Moutquin, C. Lindsay, M.-C. Roy, and F. Rousseau Implication of an AGT Haplotype in a Multigene Association Study With Pregnancy Hypertension Hypertension, January 1, 2004; 43(1): 71 - 78. [Abstract] [Full Text] [PDF]
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 A. Xaubet, A. Marin-Arguedas, S. Lario, J. Ancochea, F. Morell, J. Ruiz-Manzano, E. Rodriguez-Becerra, J. M. Rodriguez-Arias, P. Inigo, S. Sanz, et al. Transforming Growth Factor-{beta}1 Gene Polymorphisms Are Associated with Disease Progression in Idiopathic Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., August 15, 2003; 168(4): 431 - 435. [Abstract] [Full Text] [PDF]
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Y. Tang, M. L. McKinnon, L. M. Leong, S. A. B. Rusholme, S. Wang, and R. J. Akhurst Genetic modifiers interact with maternal determinants in vascular development of Tgfb1-/- mice Hum. Mol. Genet., July 1, 2003; 12(13): 1579 - 1589. [Abstract] [Full Text] [PDF]
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A. M. Dunning, P. D. Ellis, S. McBride, H. L Kirschenlohr, C. S. Healey, P. R. Kemp, R. N. Luben, J. Chang-Claude, A. Mannermaa, V. Kataja, et al. A Transforming Growth Factor{beta}1 Signal Peptide Variant Increases Secretion in Vitro and Is Associated with Increased Incidence of Invasive Breast Cancer Cancer Res., May 15, 2003; 63(10): 2610 - 2615. [Abstract] [Full Text] [PDF]
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 H Schotte, P Willeke, S Rust, G Assmann, W Domschke, M Gaubitz, and B Schluter The transforming growth factor-{beta}1 gene polymorphism (G915C) is not associated with systemic lupus erythematosus Lupus, February 1, 2003; 12(2): 86 - 92. [Abstract] [PDF]
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 R. A. Lynch, L. Wagoner, S. Li, L. Sparks, J. Molkentin, and G. W. Dorn II Novel and nondetected human signaling protein polymorphisms Physiol Genomics, September 3, 2002; 10(3): 159 - 168. [Abstract] [Full Text] [PDF]
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J P Pandey and E C LeRoy A profibrotic polymorphism (of TGF{beta}1) in systemic sclerosis Ann Rheum Dis, August 1, 2002; 61(8): 671 - 672. [Full Text] [PDF]
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A Crilly, J Hamilton, C J Clark, A Jardine, and R Madhok Analysis of transforming growth factor {beta}1 gene polymorphisms in patients with systemic sclerosis Ann Rheum Dis, August 1, 2002; 61(8): 678 - 681. [Abstract] [Full Text] [PDF]
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L Araria-Goumidi, J C Lambert, D M A Mann, C Lendon, B Frigard, T Iwatsubo, D Cottel, P Amouyel, and M C Chartier-Harlin Association study of three polymorphisms of TGF-{beta}1 gene with Alzheimer's disease J. Neurol. Neurosurg. Psychiatry, July 1, 2002; 73(1): 62 - 64. [Abstract] [Full Text] [PDF]
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C.-J. Chiu, M.-L. Chang, C.-P. Chiang, L.-J. Hahn, L.-L. Hsieh, and C.-J. Chen Interaction of Collagen-related Genes and Susceptibility to Betel Quid-induced Oral Submucous Fibrosis Cancer Epidemiol. Biomarkers Prev., July 1, 2002; 11(7): 646 - 653. [Abstract] [Full Text] [PDF]
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 A. BAYAT, A. ALANSAR, A. H. HAJEER, M. SHAH, J. S. WATSON, J. K. STANLEY, M. W. J. FERGUSON, and W. E. R. OLLIER Genetic Susceptibility in Dupuytren's Disease: Lack of Association of a Novel Transforming Growth Factor {beta}2 Polymorphism in Dupuytren's Disease J Hand Surg Eur Vol., February 1, 2002; 27(1): 47 - 49. [Abstract] [PDF]
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 F Andreotti, I Porto, F Crea, and A Maseri Inflammatory gene polymorphisms and ischaemic heart disease: review of population association studies Heart, February 1, 2002; 87(2): 107 - 112. [Abstract] [Full Text] [PDF]
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 M. A. Rivera, M. Echegaray, T. Rankinen, L. Perusse, T. Rice, J. Gagnon, A. S. Leon, J. S. Skinner, J. H. Wilmore, D. C. Rao, et al. TGF-{beta}1 gene-race interactions for resting and exercise blood pressure in the HERITAGE Family Study J Appl Physiol, October 1, 2001; 91(4): 1808 - 1813. [Abstract] [Full Text] [PDF]
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 E. Ziv, J. Cauley, P. A. Morin, R. Saiz, and W. S. Browner Association Between the T29->C Polymorphism in the Transforming Growth Factor {beta}1 Gene and Breast Cancer Among Elderly White Women: The Study of Osteoporotic Fractures JAMA, June 13, 2001; 285(22): 2859 - 2863. [Abstract] [Full Text] [PDF]
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R. W. Keen, H. Snieder, H. Molloy, J. Daniels, M. Chiano, F. Gibson, L. Fairbairn, P. Smith, A. J. MacGregor, D. Gewert, et al. Evidence of association and linkage disequilibrium between a novel polymorphism in the transforming growth factor {beta}1 gene and hip bone mineral density: a study of female twins Rheumatology, January 1, 2001; 40(1): 48 - 54. [Abstract] [Full Text] [PDF]
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 M. Yokota, S. Ichihara, T.-L. Lin, N. Nakashima, and Y. Yamada Association of a T29->C Polymorphism of the Transforming Growth Factor-{beta}1 Gene With Genetic Susceptibility to Myocardial Infarction in Japanese Circulation, June 20, 2000; 101(24): 2783 - 2787. [Abstract] [Full Text] [PDF]
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 L. Tiret, C. Mallet, O. Poirier, V. Nicaud, A. Millaire, J.-B. Bouhour, G.e. Roizes, M. Desnos, R. Dorent, K. Schwartz, et al. Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: The CARDIGENE study J. Am. Coll. Cardiol., January 1, 2000; 35(1): 29 - 35. [Abstract] [Full Text] [PDF]
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 S. Lario, P. Inigo, J. M. Campistol, E. Poch, F. Rivera, and F. Oppenheimer Restriction Enzyme-based Method for Transforming Growth Factor-{beta}1 Genotyping: Nonisotopic Detection of Polymorphisms in Codons 10 and 25 and the 5'-Flanking Region Clin. Chem., August 1, 1999; 45(8): 1290 - 1292. [Full Text] [PDF]
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 M. Pahor, M. B. Elam, R. J. Garrison, S. B. Kritchevsky, and W. B. Applegate Emerging Noninvasive Biochemical Measures to Predict Cardiovascular Risk Arch Intern Med, February 8, 1999; 159(3): 237 - 245. [Abstract] [Full Text] [PDF]
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B. Li, A. Khanna, V. Sharma, T. Singh, M. Suthanthiran, and P. August TGF-ß1 DNA Polymorphisms, Protein Levels, and Blood Pressure Hypertension, January 1, 1999; 33(1): 271 - 275. [Abstract] [Full Text] [PDF]
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R. N. Re and E. D. Frohlich Controversies in the Genetic Analysis of Hypertensive Diseases Hypertension, November 1, 1996; 28(5): 880 - 880. [Full Text]
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M. Suthanthiran, B. Li, J. O. Song, R. Ding, V. K. Sharma, J. E. Schwartz, and P. August Transforming growth factor-beta 1 hyperexpression in African-American hypertensives: A novel mediator of hypertension and/or target organ damage PNAS, March 28, 2000; 97(7): 3479 - 3484. [Abstract] [Full Text] [PDF]
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