Polymorphisms On TGF-Beta And Asthma - Any Probable Association?
Attention has been given to polymorphisms on TGF-beta and asthma, with TGF-beta-1 being an important replicated asthma candidate gene. Few studies have evaluated its direct association and risk to asthma.
Author:Suleman ShahReviewer:Han JuAug 18, 202433 Shares32.9K Views
The aim of this article was to critically review the main polymorphisms on TGF-beta and asthmaand depict the role of such polymorphisms on asthma development.
Asthma is an inflammatory disease, leading to airway obstruction, hyper-response, and heightened mucus production. It can also affect remodeling of the airway wall.
Almost 300 million people in the world are estimated to be affected by asthma.
Several studies have shown that regulatory T cells (Treg cells) have a key role in controlling allergic diseases and chronic inflammationin asthma.
Thus, recently, more focus has been given to Treg cells producing interleukin-10 (IL-10) and transforming growth factor beta (TGF-β).
Asthma And Its Pathophysiology
Asthma is the most common chronic disease that affects childhood and is the main cause of morbidity in adults.
Epidemiological data show that this illness affects 4% to 17% children and 7.7% adults in the United States.
Furthermore, almost 300 million people worldwide could be affected by asthma.
In Brazil, the municipality of Salvador has extremely high rates of up to 24.6% among school-age children (13 to 14 years).
Studies have shown that asthma develops during the intrauterine fetal programming.
Atopic asthma is most frequent in children because there is a predominant immunological Th2 (T helper 2) response at this stage of life.
The increasing number of studies about this pathology allowed a paradigm shift in immunologyand molecular biology that led to an extensive analysis of inflammatory cells and mediators involved in the pathophysiology of asthma.
The pathophysiological characteristics of asthma are not limited to the Th2 response.
Studies have shown that the immune response also involves T helper cells (Th)-17, Th9, as well as the Th1 and Th33 profile.
The Th2 response is characterized by the production of Th2 cytokines.
Interleukin-4 (IL-4) and IL-13 are main cytokines responsible for the stimulation of plasma cells to secrete immunoglobulin E (IgE) and continue the inflammatory process.
IL-4 also stimulates increased expression of IgE receptors on:
- mast cells
- eosinophils
- basophils
Other mediators are also involved in the inflammatory process, such as Tumor Necrosis Factor (TNF) and nitric oxide released by macrophages, which produce neutrophil elastase.
Rather than Th2-type cytokines, it has been well documented that IL-2, IL-12, interferon-γ (IFN-γ), TNF-α and transforming growth factor-β (TGF-β) produced by CD4+ T helper 1 cells (Th1) are implicated in the pathogenesis of asthma.
Epithelial cells in repair phase produce TGF-β, fibroblast growth factor and endothelin, which regulate fibroblasts and myofibroblasts to release:
- collagen
- elastic fiber
- proteoglycan
- glycoprotein
These substances induce airway wall thickening.
Antigen-presenting cells, especially dendritic cells, play a critical role in initiating and regulating early inflammatory events at epithelial surfaces and control the recruitment and activation of Th2 cells.
A cooperation of airway epithelium and dendritic cells controls asthma development, and Th2 activation requires dendritic cell-mediated antigen presentation. Thus, cytokines such as IL-33 are induced.
IL-33 is a member of the IL-1 family that can induce activation of dendritic cells, mast cells, eosinophils, and basophils, ultimately leading to increased expression of Th2-associated cytokines and IgE.
In addition, IL-33 administration provokes hypertrophy of bronchial epithelial cells, as well as mucus secretion.
Studies have shown that IL-33 is an attractive candidate for therapeutic intervention, either by its soluble receptor, ST2, targeting the lung or by its small molecule inhibitors that could act systemically as a central regulator of the inflammatory response characteristic of asthma.
Based on the central role of TGF-β, especially on its ability to modulate various immunological profiles, the aim of this review was to discuss whether TGF-β gene polymorphisms are associated with asthma risk.
TGF-Beta
Transforming growth factor beta (TGF-beta or TGF-β) is a pleiotropic and multifunctional growth factor released by several immunologic cells showing key roles in immune response on homeostasis, infections, and inflammatory diseases through its immune modulatory and fibrogenic activity.
Some of these immunologic cells include:
- epithelial cells
- eosinophils
- Th2 lymphocytes
- macrophages
- fibroblast
The TGF-β superfamily consists of more than 33 members, all holding a similar prodomain fold, including:
- bone morphogenetic proteins (BMPs)
- growth and differentiation factors (GDFs)
- activins
- inhibins
The TGF-β family has three different TGF-β isoforms in mammals:
- TGF-β1 - the most prevalent isoform
- TGF-β2
- TGF-β3
TGF-β2 and TGF-β3 have similar properties in vitro.
TGF-β is the main regulator of the immune response and exerts potent anti-inflammatory activity by:
a. inhibiting the differentiation of immune cells:
- Th1 (T helper cell 1)
- Th2 (T helper cell 2)
- cytotoxic T cells
- B cells
b. inhibiting cytokine production:
- IFN-γ (interferon‐gamma)
- IL-2 (interleukin-2)
Furthermore, it acts as an important differentiating factor for some cells that exert powerful immunosuppressive effects, such as regulatory T cells (Treg cells) FOXP3+.
Additionally, TGF-β1 plays an important role in extracellular matrix remodeling and fibrosis through the induction of target genes, such as:
- connective tissue growth factor (CTGF)
- α-smooth muscle actin (α-SMA)
- collagen 1a2 (col1a2)
It also induces proliferation and chemo attraction of fibroblasts and their differentiation into myofibroblasts, which finally will induce fibrosis and contraction of the extracellular matrix.
TGF-Βeta And Asthma Immune Response
Allergic diseases are caused by inappropriate immunological responses to allergens.
Several studies have shown that regulatory T cells (Treg cells) have a key role in controlling allergic diseases and chronic inflammation in asthma.
A defect in immune regulation leads to an exacerbation of Th2 response.
Treg cells are essential in the maintenance of immunological tolerance to self-antigens and in the regulation of the immune response to infectious organisms. They represent a major pathway proposed to keep immune homeostasis in the airways.
Thus, recently, attention has been given to Treg cells producing IL-10 and TGF-β. These immunomodulatory cytokines can down regulate the production of both Th1 and Th2 cytokines and suppress the inflammatory response to asthma.
Accordingly, TGF-β is crucial in the development and function of CD4[+] CD25[+] Treg and induces expression of the master regulatory transcription factor Foxp3, a critical gene regulator for Treg cells development.
TGF-β inhibits IgE, the main antibody associated with allergic diseases and asthma and has been shown to induce IL-10 expression in T cells.
In a study published in 2000 by the Journal of Clinical Investigation, the authors, with Gesine Hansen as lead author, have demonstrated that T cells producing TGF-β are able to reduce inflammation and airway hyperreactivity in a mouse model.
It was also demonstrated that blocking the TGF-β signaling pathway in T lymphocytes, an increasing inflammation and airway hyperreactivity is observed, suggesting that TGF-β-induced immune regulation reduces the pulmonary inflammatory response in vivo.
In contrast, several studies have shown that TGF-β is associated with an increased airway remodeling by inducing apoptosis of airway epithelial cells and is potentially involved in the regulation of epithelial cells adhesion leading to tissue damage.
The neutralization of TGF-β in two different models of chronic allergen challenge-reduced airway remodeling.
Asthmatic patients showed increased TGF-β expression in both bronchial biopsy sections and bronchoalveolar lavage in comparison with normal subjects and expression correlated with the lung fibrosis degree.
These data reinforce the idea that TGF-β acts to regulate immune response in the lungs and that perturbations in the level of expression of that cytokine or even in one of the TGF-β signaling pathway molecules may have severe consequences for maintenance of pulmonary homeostasis.
However, many studies have investigated the rationale that increased TGF-β expression may be associated with asthma severity by increasing airway remodeling.
TGF-Βeta Gene Polymorphisms And Allergic Disease Risk
Polymorphisms in gene sequences can affect the expression of proteins in various ways:
- levels of gene transcription
- splicing
- stability
- levels of messenger RNA (mRNA) translation
Polymorphisms in genes that participate in immunity may influence the development of several diseases.
Susceptibility to many diseases is associated with a particular “pro-inflammatory” profile, which can be explained by individual genetic determinants.
TGF-β1 is an important replicated asthma candidate gene, and few studies have evaluated the direct association of TGF-β polymorphisms and risk to allergic diseases, in particular, asthma.
The TGF-β gene is located on chromosome 19q13.1 to 13.3, and some polymorphisms were shown in this gene and can be found in:
- exons
- introns
- promoter gene sequences
Below are some of the most studied polymorphisms on TGF-β gene and a discussion on their role on cytokine levels as well as on asthma development:
Rs1800469 (-509 C > T)
The -509 C > T polymorphism is located in the promoter region of TGFB1 and can modulate TGF-β1 function and circulating TGF-β1 levels.
The T allele has been associated with higher TGF-β1 plasma levels.
An interesting Genome-wide association study (GWAS) previously reported that -509 C > T was associated with asthma in a Mexican population.
These results were consistent with several authors.
In contrast, other authors found no association between -509 polymorphisms and risk to clinically manifested atopic asthma or other allergies.
Although these data seem controversial, this single-nucleotide polymorphism (SNP) can be an interesting marker for allergic diseases.
However, more studies are needed to better understand the results obtained so far.
Lack of associations can be achieved when sample size is small and therefore may have lacked power to detect statistically significant associations.
Moreover, this polymorphism was associated with IgE levels.
One study described phenotypic association between total IgE levels in serum and -509 C > T(39) and also association with persistent IgE-mediated cow’s milk allergy in children.
Rs2241712 (-10807 G > A)
The rs2241712 (-10807) is located in the promoter region of the TGF-β1 gene and has been associated with some respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD).
Studies have analyzed associations between rs2241712 and asthma.
In one of these studies, the authors have shown an association between rs2241712 and asthma in atopic subjects.
The G/A genotype was associated with decreasing asthma risk; however, this association was not statistically significant.
Furthermore, a study conducted in Costa Rica revealed an association of the A allele with increased airway responsiveness.
However, another study showed an association between the G allele with asthma risk, but this difference was not statistically significant.
It seems that this SNP (single nucleotide polymorphism) may have an important role in the development of respiratory disease.
Therefore, more studies are needed to elicit this association.
Although the relationship between rs2241712 and TGF-β1 serum levels has not been evaluated, this polymorphism presents score 2b in the RegulomeDB database being likely to affect binding to transcription factor and, potentially, change the TGF-β1 production.
Rs1800468 (-800 G > A)
We found only one study that analyzed the SNP-800 in association with asthma and serum IgE levels.
Moreover, the authors found no association between the SNP-800 and clinical manifestationof atopic diseases and serum IgE levels.
Rs1800470 (869 T > C)
The rs1800470 is located in codon 10 of exon 1 and is related to change the amino acid sequence, leucine to proline in the signal peptide.
Codon 10 polymorphism has been studied in several diseases as nephropathy in:
The 869 polymorphism was found to be associated with an:
- increased circulating TGF-β1 concentration
- increased production of TGF-β1 in vitro
- increased risk of asthma
Rs1800471 (Codon 25)
The 915 G > C polymorphism results in an amino acid change (arginine to proline) at codon 25; however, the functional impact of this polymorphism is unknown.
In allergic diseases, no association was found for this SNP (single nucleotide polymorphism).
Although, the haplotype analysis including rs1800471 (codon 10) was associated with a historyof parental asthma.
Conclusion
Several single nucleotide polymorphisms (SNPs) on transforming growth factor beta1 (TGF-β1) have been studied in asthma diseases.
Some SNPs were positively associated with asthma but not always replicated by all authors.
Although these data seem controversial, polymorphisms on TGF-β1 may be an interesting marker for asthma since it is related to an increase in TGF-β1 levels, and it may be related to tissue remodeling.
However, more studies are required to better understand the results observed so far.
It is important to point out that in some studies, lack of associations can be related to small sample size and consequently no power to detect statistically significant associations.
Moreover, the prevalence of these polymorphisms may vary from population to population, which can also interfere with these controversial results.
Greater sample size and studies using a considerable number of informative ancestry markers are required to confirm these findings as well as to identify populations, where TGF-β1 variants are mediating the causal pathway of allergic diseases, particularly in asthma.
So, the relationship with polymorphisms on TGF-beta and asthma needs more research.
Suleman Shah
Author
Suleman Shah is a researcher and freelance writer. As a researcher, he has worked with MNS University of Agriculture, Multan (Pakistan) and Texas A & M University (USA). He regularly writes science articles and blogs for science news website immersse.com and open access publishers OA Publishing London and Scientific Times. He loves to keep himself updated on scientific developments and convert these developments into everyday language to update the readers about the developments in the scientific era. His primary research focus is Plant sciences, and he contributed to this field by publishing his research in scientific journals and presenting his work at many Conferences.
Shah graduated from the University of Agriculture Faisalabad (Pakistan) and started his professional carrier with Jaffer Agro Services and later with the Agriculture Department of the Government of Pakistan. His research interest compelled and attracted him to proceed with his carrier in Plant sciences research. So, he started his Ph.D. in Soil Science at MNS University of Agriculture Multan (Pakistan). Later, he started working as a visiting scholar with Texas A&M University (USA).
Shah’s experience with big Open Excess publishers like Springers, Frontiers, MDPI, etc., testified to his belief in Open Access as a barrier-removing mechanism between researchers and the readers of their research. Shah believes that Open Access is revolutionizing the publication process and benefitting research in all fields.
Han Ju
Reviewer
Hello! I'm Han Ju, the heart behind World Wide Journals. My life is a unique tapestry woven from the threads of news, spirituality, and science, enriched by melodies from my guitar. Raised amidst tales of the ancient and the arcane, I developed a keen eye for the stories that truly matter. Through my work, I seek to bridge the seen with the unseen, marrying the rigor of science with the depth of spirituality.
Each article at World Wide Journals is a piece of this ongoing quest, blending analysis with personal reflection. Whether exploring quantum frontiers or strumming chords under the stars, my aim is to inspire and provoke thought, inviting you into a world where every discovery is a note in the grand symphony of existence.
Welcome aboard this journey of insight and exploration, where curiosity leads and music guides.
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