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(Circulation. 2000;101:2783.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Association of a T29C Polymorphism of the Transforming Growth Factor-ß1 Gene With Genetic Susceptibility to Myocardial Infarction in Japanese

Mitsuhiro Yokota, MD, PhD; Sahoko Ichihara, MD; Tong-Lang Lin, MD; Nobuo Nakashima, MD, PhD; Yoshiji Yamada, MD, PhD

From the Department of Clinical Laboratory Medicine (M.Y., T.-L.L., N.N.) and First Department of Internal Medicine (S.I.), Nagoya University School of Medicine, Nagoya, Japan, and Department of Geriatric Research (Y.Y.), National Institute for Longevity Sciences, Obu, Japan.

Correspondence to Mitsuhiro Yokota, MD, PhD, Department of Clinical Laboratory Medicine, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan. E-mail myokota{at}tsuru.med.nagoya-u.ac.jp

	Abstract

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Background—Transforming growth factor-ß (TGF-ß) is an important regulator of vascular remodeling and is involved in the pathogenesis of atherosclerosis. A TC transition at nucleotide 29 of the TGF-ß1 gene results in a LeuPro substitution at amino acid 10 of the signal peptide. We have now examined a possible association of TGF-ß1 genotype with myocardial infarction (MI) in a Japanese population.

Methods and Results—TGF-ß1 genotype was determined in 315 Japanese patients (234 men and 81 women) with MI and 591 control subjects (289 men and 302 women). We found that age, body mass index, and incidence of habitual smoking, hypertension, diabetes mellitus, and hypercholesterolemia did not differ between the 2 groups for either men or women. Multivariable logistic regression analysis, however, demonstrated the frequency of the T allele to be significantly higher in male subjects with MI than in controls (TT + TC versus CC; P<0.0001, odds ratio 3.5, 95% CI 2.0 to 6.3). In contrast, the T allele was not associated with the prevalence of MI in women. In both male MI patients and controls, the serum concentration of TGF-ß1 was significantly higher in individuals with the CC genotype than in subjects with the TT or TC genotype.

Conclusions—Findings suggest that the T allele at nucleotide 29 in the TGF-ß1 gene is a risk factor for genetic susceptibility to MI, at least in middle-aged Japanese men.

Key Words: growth substances • genes • myocardial infarction • coronary disease

	Introduction

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Coronary artery disease (CAD) is a complex multifactorial and polygenic disorder that is thought to result from an interaction between the individual’s genetic background and various environmental factors.^{1 2} Recent advances in genetic epidemiology have revealed that some genetic variants increase the risk for CAD, including polymorphisms in ACE,³ apolipoprotein E,⁴ and platelet glycoprotein IIb/IIIa.⁵

Transforming growth factor-ß (TGF-ß) is a prototype of a large family of cytokines.⁶ In mammals, TGF-ß has been shown to have 3 isoforms (TGF-ß1, -2, and -3) with very similar biological properties. TGF-ß has been observed to inhibit the proliferation and migration of vascular smooth muscle cells (VSMCs) in culture.^{7 8} In addition, TGF-ß has been found to induce the expression of collagen genes and to stimulate the production of plasminogen activator inhibitor.⁹ Increased TGF-ß mRNA expression has been observed in human restenotic lesions after angioplasty, which is likely to account for the accumulation of collagen within such fibromuscular lesions.¹⁰

In patients with severe CAD, the serum concentration of active TGF-ß was found to be approximately one fifth that in individuals with normal coronary arteries.¹¹ Administration of tamoxifen to mice that were fed a high-fat diet led to an increase in TGF-ß expression, which suggests that the cardiovascular protective effects of this drug may be due to its ability to elevate TGF-ß levels in the artery wall, thus preventing VSMC activation and the consequent accumulation of lipid in vessel wall.¹² In contrast to these findings, which suggest an antiatherogenic role for TGF-ß, Wang et al¹³ found that the serum concentration of active TGF-ß1 was significantly higher in patients with CAD than in controls and that the concentration of this cytokine was proportional to the severity of CAD. However, the serum concentration of TGF-ß may be influenced by various factors associated with disease status or process, including its severity, phase (acute or chronic), treatment, or the presence of such concomitant disorders as diabetes mellitus and hypercholesterolemia.¹⁴ It is therefore difficult to determine whether a change in serum TGF-ß1 concentration is a causal factor in CAD or a compensatory response to myocardial ischemia and the subsequent impairment of left ventricular function.

To clarify the role of TGF-ß1 in the development of CAD, it is important to examine genetic variations that affect the production, secretion, or activity of this cytokine. Several polymorphisms in the TGF-ß1 gene have been detected (Table 1),^{15 16 17 18 19} including a TC transition at nucleotide 29 in the region encoding the signal sequence, which results in a LeuPro substitution at amino acid 10. To determine whether the T29C polymorphism is associated with the development of myocardial infarction (MI), we assayed the TGF-ß1 genotype and serum concentrations in Japanese subjects with MI and in controls.

View this table: [in this window] [in a new window]   Table 1. Known Polymorphisms in the TGF-ß1 Gene

	Methods

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Study Population
The study population comprised 906 unrelated Japanese individuals (523 men 60 years old and 383 women 70 years old) who either visited outpatient clinics of or were admitted to 1 of the 14 participating hospitals (see Appendix) between July 1994 and July 1996. Informed consent was obtained from each subject. The 315 patients with MI (234 men and 81 women) all underwent coronary angiography and left ventriculography. The diagnosis of MI was based on typical ECG changes and increased serum activities of enzymes such as creatinine kinase, aspartate aminotransferase, and lactate dehydrogenase. The diagnosis was confirmed by the presence of a wall motion abnormality on left ventriculography and responsible stenosis in any of the major coronary arteries or in the left main trunk as documented by coronary angiography.

The 591 control subjects (289 men and 302 women) were recruited from individuals who were attending the participating hospitals and were found to have at least 1 of the conventional risk factors for CAD, including habitual cigarette smoking, hypertension (systolic blood pressure 160 mm Hg and/or diastolic blood pressure 95 mm Hg), diabetes mellitus (fasting blood glucose 140 mg/dL), or hypercholesterolemia (serum total cholesterol 220 mg/dL), but who had no history of CAD. These subjects had normal resting ECGs and showed no signs of myocardial ischemia in exercise stress testing.

Genotyping of the TGF-ß1 Gene
Venous blood (7 mL) was collected from each subject into tubes containing 50 mmol/L disodium EDTA, and genomic DNA was isolated with a DNA extraction kit (Biologica).

TGF-ß1 genotype was determined by allele-specific polymerase chain reaction (PCR), as previously described,²⁰ with 2 sense primers (S1, 5'-CTCCGGGCTGCGGCTGCTGCT-3'; S2, 5'-CTCCGGGCTGCGGCTGCTGCC-3') and 1 antisense primer (AS, 5'-GTTGTGGGTTTCCACCATTAG-3'). Amplification reactions were performed in a total volume of 50 µL containing 0.5 µg of genomic DNA; 20 pmol of each primer; 0.2 mmol/L each of dCTP, dTTP, dGTP, and dATP; 1 U of Taq DNA polymerase (Amplitaq Gold; Perkin Elmer); 50 mmol/L KCl; 1.5 mmol/L MgCl₂; 1.5% dimethyl sulfoxide; 0.01% gelatin; and 10 mmol/L Tris-HCl (pH 8.3). The thermocycling procedure consisted of an initial denaturation at 94°C for 5 minutes; 35 cycles of denaturation (94°C for 30 seconds), annealing (60°C for 30 seconds), and extension (72°C for 30 seconds); and a final extension at 72°C for 5 minutes. PCR products were analyzed by 1% agarose gel electrophoresis and visualized by ethidium bromide staining. The expected size of the specific amplification product was 346 bp.

To avoid incorrect assessment of genotype, we performed genotyping twice for each subject. The genotypes differed between the 2 determinations for 14 individuals; for each of these subjects, the first exon of the TGF-ß1 gene was amplified and sequenced with a fluorescence-based automated DNA sequencer (Prism 310; Applied Biosystems) as described previously.²⁰

Measurement of Serum TGF-ß1 Concentration
Venous blood was collected into a plain tube and centrifuged at 1600g for 15 minutes at 4°C, and the sera were stored at -30°C until assayed. Seventy-nine and 70 serum samples were selected from male control and patient groups, respectively. The serum concentration of TGF-ß1 was determined with an ELISA kit (Amersham). The detection limit of this assay was 4 pg/mL, and the intra-assay and interassay coefficients of variance were 3.9% and 13.4%, respectively. The assay showed essentially no cross-reactivity (<1%) with TGF-ß2, TGF-ß3, and other cytokines.

Statistical Analysis
Data are shown as mean±SD. Clinical data were compared between MI subjects and controls by the unpaired Student’s t test or the Mann-Whitney U test. Data among TGF-ß1 genotypes were compared by 1-way ANOVA and Scheffé’s multiple range test. Qualitative data were compared by the ² test. Allele frequencies were estimated by the gene-counting method, and the ² test was used to identify significant departures from Hardy-Weinberg equilibrium. We also performed multivariable logistic regression analysis to adjust risk factors. MI was a dependent variable, whereas independent variables included age, body mass index, smoking status (0=nonsmoker, 1=smoker), metabolic variables (0=no history of hypertension, diabetes mellitus, or hypercholesterolemia; 1=positive history), and TGF-ß1 genotype. TGF-ß1 genotype was calculated according to a dominant (CC=0, TC=TT=1) or additive [CC=(0, 0), TC=(1,0), TT=(0, 1)] genetic model. The OR and 95% CI were also calculated. A value of P<0.05 was considered statistically significant.

	Results

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The characteristics of the total study population are shown in Table 2. There were no significant differences in age or body mass index between MI patients and controls for either men or women. We also found that the incidence of several conventional risk factors for CAD, including habitual smoking, hypertension, diabetes mellitus, and hypercholesterolemia, did not differ significantly between MI patients and controls.

View this table: [in this window] [in a new window]   Table 2. Characteristics of the Total Study Population (n=906)

When we assayed TGF-ß1 genotype in the study population to determine the distribution of the T29C polymorphism, we found that the frequencies of the TT, TC, and CC genotypes among control subjects were 27.0%, 45.7%, and 27.3%, respectively, in men and 23.5%, 54.0%, and 22.5%, respectively, in women; the genotype distribution was in Hardy-Weinberg equilibrium (Table 3). Among the male MI patients, the frequencies of the TT, TC, and CC genotypes were 29.9%, 59.8%, and 10.3%, respectively (Table 3). Multivariable logistic regression analysis revealed that the frequency of the T allele was significantly higher in MI patients than in controls for men. Analysis assuming both dominant (TT + TC versus CC: P<0.0001, OR 3.5, 95% CI 2.0 to 6.3) and additive (TC versus CC: P=0.0002, OR 3.2, 95% CI 1.8 to 6.1; TT versus CC: P<0.0001, OR 3.7, 95% CI 2.1 to 6.7) effects of the T allele showed significant association (Table 3). In contrast, the T allele was not associated with the prevalence of MI in women (Table 3).

View this table: [in this window] [in a new window]   Table 3. Distribution of TGF-ß1 Genotypes in MI Patients and Controls

The serum concentrations of TGF-ß1 in 79 male controls and 70 male MI patients selected from each group were measured to determine whether they were affected as a function of genotype (Figure 1). We found that the serum concentration of this cytokine was significantly higher in control subjects with the CC genotype than in those with the TC or TT genotype. Similarly, in patients with MI, the serum TGF-ß1 concentration in individuals with the CC genotype significantly exceeded that in individuals with the TC or TT genotype. The serum concentration of TGF-ß1 did not differ significantly between MI patients and controls of the same genotype.

View larger version (44K): [in this window] [in a new window]   Figure 1. Serum concentrations of TGF-ß1 as a function of genotype. Serum TGF-ß1 concentrations were determined by ELISA in male control subjects and in patients with MI. In both patients and controls, there was no significant difference in age among the 3 genotypes. Data are expressed as mean±SD. a, P=0.0238 vs TC, P=0.0006 vs TT; b, P=0.0017 vs TC, P<0.0001 vs TT.

	Discussion

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The origin of CAD is multifactorial, with complex interactions existing between genetic and environmental components.^{1 2} In general, the incidence of CAD increases additively as a function of the number of conventional risk factors.² However, some individuals with CAD do not exhibit any conventional risk factors, which suggests the contribution of genetic factors. The present study demonstrated that at least in Japanese men, the T allele of the T29C polymorphism in the TGF-ß1 gene is a risk factor for genetic susceptibility to MI.

We failed to detect an association of the T allele with the prevalence of MI in women. The reason for this lack of association in women is not clear. In Japan, the morbidity rate for CAD is low in women, especially in those who are premenopausal, probably because they are protected by their high serum concentrations of estrogen.²¹ In the present study, most female MI patients were postmenopausal. The TGF-ß1 genotype distribution for female MI patients was similar to that for controls, which suggests that the lack of association of the T allele with MI was not the result of inadequate statistical power due to the small sample size for MI patients. This gender-dependent difference in the association of the TGF-ß1 genotype with MI may contribute, at least in Japan, to the difference in the incidence of MI between men and women.

Because selection bias can influence the results of association studies, it is important that the study population be genetically and ethnically homogenous and that the control group be appropriate. Our study population resided in Nagoya and adjacent cities in central Japan where individuals are thought to share the same ethnic ancestry and to possess a homogeneous genetic background. We also found that the distribution of TGF-ß1 genotypes in our control group was in Hardy-Weinberg equilibrium, which strongly suggests that our study population was genetically homogeneous and that we had avoided selection bias. In addition, our control group consisted of individuals with an incidence of conventional risk factors similar to that in the MI group, thus allowing us to identify the genetic component of risk in the absence of the influence of conventional risk factors.

In a study of the association of MI with common polymorphisms of the TGF-ß1 gene, Cambien et al¹⁶ showed that the G74C (Arg25Pro) polymorphism of this gene was significantly associated with the prevalence of MI among populations in both France and Northern Ireland. We were unable to detect this genetic alteration in 102 Japanese subjects (data not shown). It is therefore unlikely that the T29C and G74C polymorphisms are in linkage disequilibrium in our population. In contrast to our results, Cambien et al¹⁶ did not detect an association of the T29C polymorphism with the risk of MI in their European populations. Syrris et al¹⁸ failed to detect an association of the prevalence of CAD with either the T29C or the G74C polymorphism of the TGF-ß1 gene in white populations within the United Kingdom. The distribution of the T29C polymorphism in European male control subjects (TT, 35.8%; TC, 47.2%; CC, 17.0%)¹⁶ differs significantly (P=0.0005, ² test) from that in our male controls (TT, 27.0%; TC, 45.7%; CC, 27.3%). Such differences in the prevalence of TGF-ß1 polymorphisms may be attributable to the differences in genetic background between races.

TGF-ß1 is synthesized in a latent form composed of 390 amino acids, with the active protein consisting of 2 identical disulfide-linked polypeptide chains corresponding to the 112 carboxyl-terminal residues of the precursor.²² The Leu10Pro polymorphism of this protein is located in the 29-residue signal peptide sequence, which is thought to target newly synthesized protein to the endoplasmic reticulum.²³ Leucine, which possesses a hydrophobic aliphatic side chain, favors the formation of -helices, whereas the cyclic structure of proline results in the introduction of breaks and kinks into the -helical portion of the peptide backbone.²⁴ The association of TGF-ß1 genotype with the serum concentration of this protein suggests that the Leu/Pro polymorphism at residue 10 may affect the function of the signal peptide, perhaps influencing intracellular trafficking or export efficiency of the preproprotein.

We have now shown that the serum concentration of TGF-ß1 was significantly lower in individuals with the T allele than in those with the CC genotype. However, the serum concentrations of TGF-ß1 did not differ between controls and subjects with MI of the same genotype, consistent with the results of Grainger et al¹¹ showing that the serum concentrations of active plus latent TGF-ß did not differ significantly between controls and individuals with CAD. The concentration and activity of TGF-ß are affected by many factors. Most TGF-ß in serum appears to be derived from platelets, which contain 2 pools of latent TGF-ß1.²⁵ During clotting, 1 pool containing the latent TGF-ß binding protein, latency-associated peptide (LAP), and the mature TGF-ß1 dimer is released into the serum. The second pool containing LAP and TGF-ß1 dimers is retained in the clot; subsequent dissolution of the clot by plasmin results in the release and activation of TGF-ß1.²⁵ However, it is not clear whether the differences in the circulating concentration of TGF-ß1 among individuals with different TGF-ß1 genotypes are correlated with the concentration of TGF-ß1 in platelets, clots, or the vascular wall.

Recently, the C-1348T polymorphism in the promoter region of the TGF-ß1 gene has been shown to be associated with the serum concentration of TGF-ß1.¹⁹ Given that the T29C and C-1348T polymorphisms are in linkage disequilibrium,^{16 18} the association of the T29C polymorphism with the serum concentration of TGF-ß1 may be due to an effect of the C-1348T polymorphism. It is possible that the T29C polymorphism of the TGF-ß1 gene is linked to some other gene that is actually responsible for the development of CAD. It is also possible that the low frequency of the CC genotype in male MI patients was attributable to a higher mortality rate in MI patients with the CC genotype than in those with the T allele. Our results, however, suggest that the T29C polymorphism of the TGF-ß1 gene may be an important indicator of genetic susceptibility to MI in middle-aged Japanese men.

	Appendix 1

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The following physicians and institutions participated in this study: M. Maeda, T. Fujimura, and Y. Nishinaka (Chita City Hospital); S. Yabe and C. Takanaka (Hamamatsu Medical Center); A. Tsunekawa and R. Ishiki (Okazaki City Hospital); T. Fukumitsu (Hekinan City Hospital); M. Watarai, K. Takemoto, and F. Takatsu (Kosei Hospital); H. Kanda (Nagoya East City Hospital); Y. Yoshida and H. Hirayama (Nagoya Daini Red Cross Hospital); T. Watanabe (Nagoya National Hospital); T. Sobue (Nagoya University Hospital); S. Ishikawa and F. Saito (Showa Hospital); S. Kamihara, M. Kimura, and H. Inagaki (Toyota Memorial Hospital); S. Ogawa (Tokai Central Hospital); S. Kato (Marine Clinic); and J. Goto (National Chubu Hospital).

Received October 28, 1999; revision received December 21, 1999; accepted January 25, 2000.

	References

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
1. Marenberg ME, Risch N, Berkman LF, et al. Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med. 1994;330:1041–1046.[Abstract/Free Full Text]

2. Nora JJ, Lortscher RH, Spangler RD, et al. Genetic-epidemiologic study of early-onset ischemic heart disease. Circulation. 1980;61:503–508.[Abstract/Free Full Text]

3. Cambien F, Poirier O, Lecerf L, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature. 1992;359:641–644.[Medline] [Order article via Infotrieve]

4. van Bockxmeer FM, Mamotte CDS. Apolipoprotein 4 homozygosity in young men with coronary heart disease. Lancet. 1992;340:879–880.[Medline] [Order article via Infotrieve]

5. Weiss EJ, Bray PF, Tayback M, et al. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med. 1996;334:1090–1094.[Abstract/Free Full Text]

6. Heldin C-H, Miyazono K, ten Dijke P. TGF-ß signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997;390:465–471.[Medline] [Order article via Infotrieve]

7. Kojima S, Harpel PC, Rifkin DB. Lipoprotein(a) inhibits the generation of transforming growth factor-ß: an endogenous inhibitor of smooth muscle cell migration. J Cell Biol. 1991;113:1439–1445.[Abstract/Free Full Text]

8. Grainger DJ, Kirschenlohr HL, Metcalfe JC, et al. Proliferation of human smooth muscle cells promoted by lipoprotein(a). Science. 1993;260:1655–1658.[Abstract/Free Full Text]

9. Agrotis A, Bobik A. Vascular remodelling and molecular biology: new concepts and therapeutic possibilities. Clin Exp Pharmacol Physiol. 1996;23:363–368.[Medline] [Order article via Infotrieve]

10. Nikol S, Isner JM, Pickering JG, et al. Expression of transforming growth factor-ß1 is increased in human vascular restenosis lesions. J Clin Invest. 1992;90:1582–1592.

11. Grainger DJ, Kemp PR, Metcalfe JC, et al. The serum concentration of active transforming growth factor-ß is severely depressed in advanced atherosclerosis. Nat Med. 1995;1:74–79.[Medline] [Order article via Infotrieve]

12. Grainger DJ, Witchell CM, Metcalfe JC. Tamoxifen elevates transforming growth factor-ß and suppresses diet-induced formation of lipid lesions in mouse aorta. Nat Med. 1995;1:1067–1073.[Medline] [Order article via Infotrieve]

13. Wang XL, Liu SX, Wilcken DEL. Circulating transforming growth factor ß1 and coronary artery disease. Cardiovasc Res. 1997;34:404–410.[Abstract/Free Full Text]

14. Grainger DJ, Byrne CD, Witchell CM, et al. Transforming growth factor ß is sequestered into an inactive pool by lipoproteins. J Lipid Res. 1997;38:2344–2352.[Abstract]

15. Derynck R, Rhee L, Chen EY, et al. Intron-exon structure of the human transforming growth factor-ß precursor gene. Nucleic Acids Res. 1987;15:3188–3189.[Free Full Text]

16. Cambien F, Ricard S, Troesch A, et al. Polymorphisms of the transforming growth factor-ß1 gene in relation to myocardial infarction and blood pressure. Hypertension. 1996;28:881–887.[Abstract/Free Full Text]

17. Langdahl BL, Knudsen JY, Jensen HK, et al. A sequence variation: 713–8delC in the transforming growth factor-beta 1 gene has higher prevalence in osteoporotic women than in normal women and is associated with very low bone mass in osteoporotic women and increased bone turnover in both osteoporotic and normal women. Bone. 1997;20:289–294.[Medline] [Order article via Infotrieve]

18. Syrris P, Carter ND, Metcalfe JC, et al. Transforming growth factor-ß1 gene polymorphisms and coronary artery disease. Clin Sci. 1998;95:659–667.[Medline] [Order article via Infotrieve]

19. Grainger DJ, Heathcote K, Chiano M, et al. Genetic control of the circulating concentration of transforming growth factor type ß1. Hum Mol Genet. 1999;8:93–97.[Abstract/Free Full Text]

20. Yamada Y, Miyauchi A, Goto J, et al. Association of a polymorphism of the transforming growth factor-ß1 gene with genetic susceptibility to osteoporosis in Japanese women. J Bone Miner Res. 1998;13:1569–1576.[Medline] [Order article via Infotrieve]

21. Guetta V, Cannon RO III. Cardiovascular effects of estrogen and lipid-lowering therapies in postmenopausal women. Circulation. 1996;93:1928–1937.[Free Full Text]

22. Derynck R, Jarrett JA, Chen EY, et al. 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]

23. Verner K, Schatz G. Protein translocation across membranes. Science. 1988;241:1307–1313.[Abstract/Free Full Text]

24. Karvonen MK, Pesonen U, Koulu M, et al. Association of a leucine(7)-to-proline(7) polymorphism in the signal peptide of neuropeptide Y with high serum cholesterol and LDL cholesterol levels. Nat Med. 1998;4:1434–1437.[Medline] [Order article via Infotrieve]

25. Grainger DJ, Wakefield L, Bethell HW, et al. Release and activation of platelet latent TGF-ß in blood clots during dissolution with plasmin. Nat Med. 1995;1:932–937.[Medline] [Order article via Infotrieve]

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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]

				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]

				C. M. Ulrich, J. Whitton, J.-H. Yu, J. Sibert, R. Sparks, J. D. Potter, and J. Bigler PTGS2 (COX-2) -765G > C Promoter Variant Reduces Risk of Colorectal Adenoma among Nonusers of Nonsteroidal Anti-inflammatory Drugs Cancer Epidemiol. Biomarkers Prev., March 1, 2005; 14(3): 616 - 619. [Abstract] [Full Text] [PDF]

				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]

				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]

				L. L. Marchand, C. A. Haiman, D. van den Berg, L. R. Wilkens, L. N. Kolonel, and B. E. Henderson T29C Polymorphism in the Transforming Growth Factor {beta}1 Gene and Postmenopausal Breast Cancer Risk: The Multiethnic Cohort Study Cancer Epidemiol. Biomarkers Prev., March 1, 2004; 13(3): 412 - 415. [Abstract] [Full Text]

				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]

				X.-O. Shu, Y.-T. Gao, Q. Cai, L. Pierce, H. Cai, Z.-X. Ruan, G. Yang, F. Jin, and W. Zheng Genetic Polymorphisms in the TGF-{beta}1 Gene and Breast Cancer Survival: A Report from the Shanghai Breast Cancer Study Cancer Res., February 1, 2004; 64(3): 836 - 839. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				H. Chen, D. Li, T. Saldeen, and J. L. Mehta TGF-beta 1 attenuates myocardial ischemia-reperfusion injury via inhibition of upregulation of MMP-1 Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1612 - H1617. [Abstract] [Full Text] [PDF]

				Y Sugiura, T Niimi, S Sato, T Yoshinouchi, S Banno, T Naniwa, H Maeda, S Shimizu, and R Ueda Transforming growth factor {beta}1 gene polymorphism in rheumatoid arthritis Ann Rheum Dis, September 1, 2002; 61(9): 826 - 828. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				K. Armstrong Genetic Susceptibility to Breast Cancer: From the Roll of the Dice to the Hand Women Were Dealt JAMA, June 13, 2001; 285(22): 2907 - 2909. [Full Text] [PDF]

				Z. Mallat, A. Gojova, C. Marchiol-Fournigault, B. Esposito, C. Kamate, R. Merval, D. Fradelizi, and A. Tedgui Inhibition of Transforming Growth Factor-{beta} Signaling Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Mice Circ. Res., November 9, 2001; 89(10): 930 - 934. [Abstract] [Full Text] [PDF]

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