TGFB1 promoter polymorphism C-509T and pathophysiology of asthma

doi:10.1016/j.jaci.2007.10.005

Journal of Allergy and Clinical Immunology

Volume 121, Issue 3, March 2008, Pages 659-664

https://doi.org/10.1016/j.jaci.2007.10.005 Get rights and content

Background

TGF-β1 can modulate airway inflammation and exaggerate airway remodeling. A polymorphism of a promoter region of TGFB1, C-509T, might be associated with the development of asthma, but its pathophysiologic relevance remains poorly understood.

Objective

We investigated relations of the C-509T polymorphism to airflow obstruction, sputum eosinophilia, and airway wall thickening, as assessed by means of computed tomography, in 85 patients with stable asthma.

Methods

The CC, CT, and TT genotypes were examined by means of PCR and restriction enzyme fragment length polymorphism. At a selected bronchus, 3 indices of airway wall thickness were measured with an automatic method.

Results

The CC, CT, and TT genotypes were found in 22, 46, and 17 patients, respectively. Serum TGF-β1 levels were significantly associated with the polymorphism and were increased in the CT/TT genotypes. FEV₁ and sputum eosinophil percentages were also significantly associated with the polymorphism and were both decreased in the CT/TT genotypes. The polymorphism was unrelated to airway wall thickness.

Conclusion

In addition to increased serum TGF-β1 levels, the T allele of the C-509T polymorphism is related to increased airflow obstruction but attenuated eosinophilic inflammation. The former relation is not attributed to thickening of the central airway walls. The latter relation might reflect the anti-inflammatory effect of TGF-β1. The C-509T polymorphism has a complex role in asthma pathophysiology, presumably because of the diverse functions of TGF-β1 and its various interactions with cells and humoral factors in vivo.

Section snippets

Subjects

We studied 85 nonsmoking patients with stable asthma. Asthma was diagnosed according to American Thoracic Society criteria.²³ Atopy was determined on the basis of the presence of specific serum IgE antibodies to at least 1 common inhalant allergen. Patients were classified into 4 groups according to asthma severity (intermittent, mild persistent, moderate persistent, and severe persistent), as defined by the step classification of the Global Initiative for Asthma guidelines.²⁴ No patient had

Characteristics of patients

The characteristics of the patients are presented in Table I. Seventy patients had been treated with inhaled corticosteroids at a dose equivalent to 866 ± 343 μg/d (range, 400-1600 μg/d) of chlorofluorocarbon–beclomethasone dipropionate.

Frequency of TGFB1 C-509T genotype

Table II summarizes the allele frequencies and genotype distributions. The results were in accordance with those of a healthy Japanese cohort.²⁹

Relations of TGFB1 C-509T genotype to clinical indices

Age, sex, asthma duration, and the use and dosage of inhaled corticosteroids were similar among the 3 genotypes of

Discussion

In our Japanese patients with stable asthma, the T allele of the C-509T polymorphism of the TGFB1 gene was associated positively with serum TGF-β1 levels and airflow obstruction and negatively with eosinophilic airway inflammation. The polymorphism was not associated with airway wall thickening. To our knowledge, this is the first study of asthmatic patients to examine the relations of a genetic polymorphism associated with asthma to the degree of airway inflammation and airway wall thickening,

References (47)

C. Duvernelle et al.
Transforming growth factor-beta and its role in asthma
Pulm Pharmacol Ther
(2003)
R.A. Ignotz et al.
Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix
J Biol Chem
(1986)
K. Nagpal et al.
TGFbeta1 haplotypes and asthma in Indian populations
J Allergy Clin Immunol
(2005)
A. Niimi et al.
Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma
Am J Med
(2004)
M. Takemura et al.
Bronchial dilatation in asthma: relation to clinical and sputum indices
Chest
(2004)
J.C. Mak et al.
Analysis of TGF-beta(1) gene polymorphisms in Hong Kong Chinese patients with asthma
J Allergy Clin Immunol
(2006)
L. Rosa-Rosa et al.
The R576 IL-4 receptor alpha allele correlates with asthma severity
J Allergy Clin Immunol
(1999)
A.J. Sandford et al.
Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity
J Allergy Clin Immunol
(2000)
C. Sillaber et al.
Type beta transforming growth factors promote interleukin-3 (IL-3)-dependent differentiation of human basophils but inhibit IL-3-dependent differentiation of human eosinophils
Blood
(1992)
J. de Blic et al.
High-resolution computed tomography scan and airway remodeling in children with severe asthma
J Allergy Clin Immunol
(2005)

T. Ueda et al.

Role of small airways in asthma: investigation using high-resolution computed tomography

J Allergy Clin Immunol

(2006)

C. Bergeron et al.

Evidence of remodeling in peripheral airways of patients with mild to moderate asthma: effect of hydrofluoroalkane-flunisolide

J Allergy Clin Immunol

(2005)

J. Bousquet et al.

Asthma. From bronchoconstriction to airways inflammation and remodeling

Am J Respir Crit Care Med

(2000)

C. Boxall et al.

The contribution of transforming growth factor-beta and epidermal growth factor signalling to airway remodelling in chronic asthma

Eur Respir J

(2006)

B.E. McParland et al.

Airway wall remodeling: friend or foe?

J Appl Physiol

(2003)

I. Ohno et al.

Transforming growth factor beta 1 (TGF beta 1) gene expression by eosinophils in asthmatic airway inflammation

Am J Respir Cell Mol Biol

(1996)

A.M. Vignola et al.

Transforming growth factor-beta expression in mucosal biopsies in asthma and chronic bronchitis

Am J Respir Crit Care Med

(1997)

E.M. Minshall et al.

Eosinophil-associated TGF-beta1 mRNA expression and airways fibrosis in bronchial asthma

Am J Respir Cell Mol Biol

(1997)

G. Hansen et al.

CD4(+) T helper cells engineered to produce latent TGF-beta1 reverse allergen-induced airway hyperreactivity and inflammation

J Clin Invest

(2000)

K. Haneda et al.

TGF-beta induced by oral tolerance ameliorates experimental tracheal eosinophilia

J Immunol

(1997)

K. Hobbs et al.

Interleukin-10 and transforming growth factor-beta promoter polymorphisms in allergies and asthma

Am J Respir Crit Care Med

(1998)

L.J. Pulleyn et al.

TGFbeta1 allele association with asthma severity

Hum Genet

(2001)

D. Buckova et al.

TGF-beta1 gene polymorphisms

Allergy

(2001)

Cited by (39)

The TGFB1 -509C/T polymorphism and elevated TGF-β1 levels are associated with chronic hepatitis C and cirrhosis
2020, Immunobiology
Citation Excerpt :
Several polymorphisms have been described in the TGFB1 gene, and some are associated with functional implications and susceptibility to diseases (Cebinelli et al., 2016). Among these polymorphisms, TGFB1 -509C/T (rs1800469) is associated with high plasma concentrations of TGF-β1 (Grainger et al., 1999; Silverman et al., 2004; Ueda et al., 2008). The present study investigated the influence of IFNG +874A/T and TGFB1 -509C/T polymorphisms on the plasma levels of these cytokines and the association of these variants with the clinical progression of chronic hepatitis C.
The IFN-γ and TGF-β1 cytokines perform antagonistic activities in the immune response, and polymorphisms in these genes may induce changes in their plasma levels and influence the course of chronic Hepacivirus C (HCV) infection. The present study evaluated the IFNG +874A/T and TGFB1 -509 C/T polymorphisms in 99 samples from patients with chronic hepatitis C and in 300 samples from healthy donors, and the present study also investigated the association of cytokine plasma level with disease stage. Polymorphisms were identified by real-time PCR, and cytokine levels were measured by enzyme-linked immunosorbent assay. The frequency of the IFNG +874A/T polymorphic allele was not associated with susceptibility to HCV infection, but it was associated with lower inflammatory activity (p = 0.0432). The frequency of the TGFB1 -509C/T polymorphic (TT) genotype was associated with HCV infection (p = 0.0062) and a higher risk of infection (OR = 2.0465; p = 0.0091). Plasma levels of IFN-γ were higher in TT genotype carriers among the control (p = 0.0012) and HCV groups (p = 0.0064) as well as in patients with fibrosis (p = 0.0346) and patients with a high degree of inflammatory activity (p = 0.0381). The highest TGF-β1 levels were found in HCV-infected (p = 0.0329) individuals and in TT genotype carriers. Patients with cirrhosis had higher TGF-β1 (p = 0.0400). IFN-γ and TGF-β1 levels showed a negative correlation (p = 0.0001). In conclusion, the TGFB1 -509C > T polymorphism is associated with a risk of developing chronic hepatitis C, leading to increased TGF-β1, which inhibits IFN-γ production, contributing to the progression to cirrhosis.
Polymorphisms of TGFB1, TLE4 and MUC22 are associated with childhood asthma in Chinese population
2017, Allergologia et Immunopathologia
Citation Excerpt :
It may modulate the development of allergic inflammation and airway remodelling in asthma. As a widely investigated asthma candidate gene, variants of TGFB1 have been associated with asthma in different populations, including Mexicans, Costa Ricans, Japanese and Caucasian French Canadians.26–28 The SNP rs2241715 that was found significantly associated with asthma in the present analysis was in moderate to high LD with the asthma-associated SNPs rs1800469 and rs1982073 reported in previous paper.26
To investigate whether the genetic variants of TGFB1, TLE4, MUC22 and IKZF3 are associated with the development of asthma in Chinese children.
572 adolescent asthma patients and 590 age-matched healthy controls were included in this study. A total of four SNPs were genotyped, including rs2241715 of TGFB1, rs2378383 of TLE4, rs2523924 of MUC22, and rs907092 of IKZF3. Allele frequencies of the patients and the control group were compared by the Chi-square test. The Student t test was used to analyse the relationship between genotypes and clinical feature of the patients.
Patients were found to have significantly different frequencies of allele A of rs2241715, allele G of rs2378383 and allele A of rs2523924 as compared with the controls (40.4% vs. 45.9%, p = 0.01 for rs2241715; 17.2% vs. 13.4%, p = 0.01 for rs2378383; 15.3% vs. 11.9%, p = 0.02 for rs2523924). For patients with severe asthma, those with genotype AA/AG of rs2241715 had remarkably higher FEV1% as compared with those with genotype GG (59.1 ± 4.3% vs. 55.4 ± 3.7%, p < 0.001). Moreover, those with genotype GG/GA of rs2378383 had remarkably lower FEV1% as compared with those with genotype AA (54.6 ± 2.9% vs. 58.6 ± 4.1%, p < 0.001).
Genes TGFB1, TLE4 and MUC22 are associated with the risk of childhood asthma in Chinese population. Our results associating TGFB1 and TLE4 with clinical features of asthma suggest potential application of these parameters in the management of asthma children.
Phenotypic and genetic aspects of epithelial barrier function in asthmatic patients
2017, Journal of Allergy and Clinical Immunology
The bronchial epithelium is continuously exposed to a multitude of noxious challenges in inhaled air. Cellular contact with most damaging agents is reduced by the action of the mucociliary apparatus and by formation of a physical barrier that controls passage of ions and macromolecules. In conjunction with these defensive barrier functions, immunomodulatory cross-talk between the bronchial epithelium and tissue-resident immune cells controls the tissue microenvironment and barrier homeostasis. This is achieved by expression of an array of sensors that detect a wide variety of viral, bacterial, and nonmicrobial (toxins and irritants) agents, resulting in production of many different soluble and cell-surface molecules that signal to cells of the immune system. The ability of the bronchial epithelium to control the balance of inhibitory and activating signals is essential for orchestrating appropriate inflammatory and immune responses and for temporally modulating these responses to limit tissue injury and control the resolution of inflammation during tissue repair. In asthmatic patients abnormalities in many aspects of epithelial barrier function have been identified. We postulate that such abnormalities play a causal role in immune dysregulation in the airways by translating gene-environment interactions that underpin disease pathogenesis and exacerbation.
An updated meta-analysis of transforming growth factor-β1 gene: Three well-characterized polymorphisms with asthma
2016, Human Immunology
The association between TGF-β1 polymorphisms and asthma risk has been widely reported, but results were controversial. We performed this meta-analysis based on the Preferred Reporting Items for Systematic Reviews and meta-analyses statement (PRISMA). Electronic database of Pub Med, Web of Science, CBM, and CNKI were searched for eligible articles published up to September, 2013. The effect summary odds ratio (OR) and 95% confidence intervals were obtained. Finally, a total of 20 articles were identified, 17 studies with 3694 cases and 5613 controls for C-509T polymorphism, 7 studies with 1109 cases and 1098 controls for T869C polymorphism and 5 studies with 849 cases and 829 controls for G915C polymorphism. For C-509T, significant associations with asthma were found in Asians (TT + TC vs. CC: P = 0.004, OR = 1.43, 95%CI = 1.12–1.81, P_{heterogeneity} = 0.001) and in Caucasians (P = 0.05, OR = 1.16, 95%CI = 1.00–1.34, P_{heterogeneity} = 0.36). With respect to T869C, a small significant association was observed in overall analysis of allele contrasts(C vs. T: OR = 1.14, 95%CI: 1.01–1.29, P = 0.03) and homozygote comparison (CC vs. TT: OR = 1.29, 95%CI: 1.00–1.65, P = 0.05), but no significant risks were found among Caucasian population and Asian population. For G915C polymorphism, no significant association with asthma risk was demonstrated in overall analysis and subgroup analyses according to ethnicity for all genetic models. This meta-analysis suggested that TGF-β1 C-509T and T869C polymorphisms may be risk factors for asthma.
Genetics in Asthma and COPD
2015, Murray and Nadel's Textbook of Respiratory Medicine: Volume 1,2, Sixth Edition
TGF-β1 polymorphisms and asthma severity, airway inflammation, and remodeling
2013, Journal of Allergy and Clinical Immunology

View all citing articles on Scopus

: Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

View full text

Asthma and lower airway diseaseTGFB1 promoter polymorphism C-509T and pathophysiology of asthma

Background

Objective

Methods

Results

Conclusion

Section snippets

Subjects

Characteristics of patients

Frequency of TGFB1 C-509T genotype

Relations of TGFB1 C-509T genotype to clinical indices

Discussion

Pulm Pharmacol Ther

J Biol Chem

J Allergy Clin Immunol

Am J Med

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Blood

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Asthma. From bronchoconstriction to airways inflammation and remodeling

Am J Respir Crit Care Med

The contribution of transforming growth factor-beta and epidermal growth factor signalling to airway remodelling in chronic asthma

Eur Respir J

Airway wall remodeling: friend or foe?

J Appl Physiol

Transforming growth factor beta 1 (TGF beta 1) gene expression by eosinophils in asthmatic airway inflammation

Am J Respir Cell Mol Biol

Transforming growth factor-beta expression in mucosal biopsies in asthma and chronic bronchitis

Am J Respir Crit Care Med

Eosinophil-associated TGF-beta1 mRNA expression and airways fibrosis in bronchial asthma

Am J Respir Cell Mol Biol

CD4(+) T helper cells engineered to produce latent TGF-beta1 reverse allergen-induced airway hyperreactivity and inflammation

J Clin Invest

TGF-beta induced by oral tolerance ameliorates experimental tracheal eosinophilia

J Immunol

Interleukin-10 and transforming growth factor-beta promoter polymorphisms in allergies and asthma

Am J Respir Crit Care Med

TGFbeta1 allele association with asthma severity

Hum Genet

TGF-beta1 gene polymorphisms

Allergy

Asthma and lower airway disease
TGFB1 promoter polymorphism C-509T and pathophysiology of asthma