Association of transforming growth factor beta1 gene polymorphisms and asbestos-induced fibrosis and tumors

Our plain-English summary of Association of transforming growth factor beta1 gene polymorphisms and asbestos-induced fibrosis and tumors, by S. Helmig, A. Belwe, J. Schneider (Journal of Investigative Medicine, 2009).

The study

• Authors: S. Helmig, A. Belwe, J. Schneider
• Journal: Journal of Investigative Medicine
• Published: 2009;57(5):655-61
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Aim: Inhaled asbestos fibers are known to cause progressive lung or pleural fibrosis and malignancies such as lung cancer or diffuse malignant mesothelioma. Transforming growth factor beta1 (TGF-beta1), a multifunctional cytokine, regulates the proliferation and differentiation of cells. Transforming growth factor beta1 is known to promote the pathogenesis of lung fibrosis and acts as a tumor suppressor in normal cells. Two genetic polymorphisms in codons 10 (Leu10Pro) and 25 (Arg25Pro) of the TGF-beta1 gene are suggested to be associated with a different TGF-beta1 protein production. Therefore, we examined an association between the 2 TGF-beta1 gene polymorphisms and asbestos-induced lung fibrosis and lung cancer.

Methods: Detection of the 2 polymorphisms was performed by rapid capillary polymerase chain reaction, with melting curve analysis, using fluorescence-labeled hybridization probes. To investigate the association between TGF-beta1 gene polymorphisms in codons 10 and 25 and the susceptibility to asbestos-induced diseases, association studies were performed with healthy control subjects (n = 83), patients with pulmonary fibrosis (n = 591), and patients with bronchial carcinoma (n = 147).

Results: Compared with a healthy control group, odds ratio (OR) analysis revealed an inverse relationship for the proline allele at codon 10 or 25 with pulmonary fibrosis (higher risk) and lung cancer (lower risk). The proline allele at codon 10 or 25 is significantly associated with a higher risk for fibrotic lung diseases (ORcrude, 1.46; 95% confidence interval [CI], 1.01-2.11; P = 0.045 and ORadjusted, 1.76; 95% CI, 1.14-2.72; P = 0.011, respectively, for codon 10; OR, 2.13; 95% CI, 1.33-3.99; P = 0.019 and ORadjusted, 2.27; 95% CI, 1.14-4.52; P = 0.02, respectively, for codon 25) when compared with patients with lung cancer. A significant association for the proline allele is also revealed when comparing patients with asbestosis (ORcrude, 3.01; 95% CI, 1.44-6.29; P = 0.003 and ORadjusted, 3.72; 95% CI, 1.56-8.85; P = 0.011) with patients with asbestos-induced lung cancer.

Conclusions: In summary, the results confirm the hypothesis that TGF-beta1 polymorphisms are associated with asbestos-induced fibrotic or malignant lung diseases in whites.

In plain English

This genetic association study examined whether two variants of the TGF-beta1 gene, at codons 10 and 25 (where the amino acid proline can replace leucine or arginine), were linked to asbestos-related and other lung diseases. It included male whites: 83 healthy controls without workplace exposure to carcinogenic agents, 591 patients with lung fibrosis (401 asbestosis, 156 silicosis, 34 other fibrosis) and 176 with tumors (32 asbestos-related lung cancers, 29 asbestos-caused diffuse malignant mesotheliomas, 115 lung cancers without relevant asbestos exposure). Controls averaged 44.8 years old and patients 67.3. Compared with controls, most odds ratios were not statistically significant. When fibrosis patients were compared with lung cancer patients, carrying at least one proline allele was associated with fibrosis at codon 10 (adjusted odds ratio 1.76; 95% CI 1.14 to 2.72) and at codon 25 (adjusted 2.27; 1.14 to 4.52). Comparing asbestosis with asbestos-induced lung cancer at codon 10 gave a crude odds ratio of 3.01 (1.44 to 6.29). The authors concluded that the gene variants are associated with asbestos-induced lung diseases and lung cancer. They said larger groups, especially of mesothelioma patients, would be desirable.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Genetic association (case-control) study. Blood DNA was genotyped by real-time PCR, and odds ratios were calculated by unconditional logistic regression, crude and adjusted for smoking (pack-years) and age.
• Who was studied: 821 male whites in Giessen, Germany. Groups: 83 unrelated healthy controls (mean age 44.8) with no known diseases and no workplace exposure to carcinogenic or fibrogenic agents; 591 lung fibrosis patients (401 asbestosis, 156 silicosis, 34 interstitial fibrosis without relevant asbestos exposure); 176 tumor patients (32 asbestos-related lung cancer, 29 diffuse malignant mesothelioma caused by asbestos dust, 115 lung cancer without relevant asbestos or other occupational lung carcinogen exposure). Patients' mean age was 67.3. Women were excluded.
• Exposure: Occupational asbestos dust exposure, with diseases recognized under the German occupational disease regulation (BKV). Fiber types were not specified. Silica exposure (silicosis) and non-occupational groups served as comparisons. Smoking was recorded as pack-years. The genetic factor studied was carrying at least one proline allele at TGF-beta1 codon 10 or codon 25.
• Main results:
  • All fibrosis patients compared with healthy controls, codon 10: carrying at least one proline allele gave an odds ratio of 1.26 (95% CI 0.78 to 2.02). This was not statistically significant (P = 0.348 per Table 3).
  • Patients with asbestos-induced hyaline pleural plaques compared with controls, codon 10: crude odds ratio 2.57 (95% CI 1.16 to 5.67; P = 0.02). After adjustment for pack-years, Table 3 gives 2.53 (0.97 to 6.59; P = 0.058).
  • Patients with asbestos-induced lung cancer compared with controls, codon 10: crude odds ratio 0.43 (95% CI 0.19 to 0.99; P = 0.047), a lower likelihood of carrying a proline allele. After adjustment, Table 3 gives 0.72 (0.19 to 2.79; P = 0.635).
  • Mesothelioma patients compared with controls: codon 10 crude odds ratio 1.65 (95% CI 0.65 to 4.16). Table 4 gives codon 25 crude odds ratio 0.54 (0.11 to 2.63). Neither was statistically significant.
  • Fibrosis patients compared with lung cancer patients, codon 10: crude odds ratio 1.46 (95% CI 1.01 to 2.11; P = 0.045); adjusted 1.76 (1.14 to 2.72; P = 0.011).
  • Fibrosis patients compared with lung cancer patients, codon 25: odds ratio 2.13 (text gives 95% CI 1.33 to 3.99; Table 5 gives 1.133 to 3.996; P = 0.019); adjusted 2.27 (1.14 to 4.52; P = 0.02).
  • Asbestosis patients compared with asbestos-induced lung cancer patients, codon 10: crude odds ratio 3.01 (95% CI 1.44 to 6.29; P = 0.003); adjusted 3.72 (1.56 to 8.85). The adjusted P value is 0.011 in the text and 0.003 in Table 5.
  • Asbestosis patients compared with asbestos-induced lung cancer patients, codon 25: crude odds ratio 5.887 (95% CI 0.789 to 43.902; P = 0.084). This was not statistically significant.
  • Patients with asbestos-induced hyaline pleural plaques of extent 1 compared with controls, codon 25: crude odds ratio 3.04 (95% CI 0.89 to 10.46; P = 0.077). After adjusting for smoking it was 5.16 (1.26 to 21.2; P = 0.023).
• The authors' conclusion: The authors concluded that the study shows a genetic impact of TGF-beta1 gene polymorphisms on asbestos-induced lung diseases and lung cancer. In their view, the proline allele was associated with higher risk of fibrotic lung disease and lower risk of lung cancer.
• Limitations the authors state:
  • Some groups were small; a larger mesothelioma group in particular would be desirable.
  • Statistical power is limited for a low-frequency variant such as the codon 25 polymorphism.
  • TGF-beta1 production measured in blood cells in vitro may not reflect production in lung tissue. It is unknown whether these variants affect lung-specific expression.
  • Lung fibrosis may be shaped by many genes rather than one, and other independent risk factors exist.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Asbestosis, Lung cancer.

Medical terms in this study, explained in our Lexicon: Fibrosis, Lung Cancer, Malignant Mesothelioma, Cytokine, Pulmonary Fibrosis, Carcinoma, Odds Ratio, confidence interval.

Related studies

• Tumour necrosis factor-alpha gene polymorphisms in asbestos-induced diseases — S. Helmig, N. Aliahmadi, et al. (2010)
• Distribution of transforming growth factor-beta 1, fibronectin, and smooth muscle actin in asbestos-induced pulmonary fibrosis in rats — T.D. Perdue, A.R. Brody (1994)
• Role of transforming growth factor-beta(1) in down-regulating TNF production by alveolar macrophages during asbestos-induced pulmonary fibrosis — I. Lemaire, S. Ouellet (1996)
• Susceptibility to asbestos-induced and transforming growth factor-beta1-induced fibroproliferative lung disease in two strains of mice — G.S. Warshamana, D.A. Pociask, et al. (2002)
• Small interfering RNAs (siRNAs) targeting TGF-beta1 mRNA suppress asbestos-induced expression of TGF-beta1 and CTGF in fibroblasts — T.C. Lai, D.A. Pociask, et al. (2009)
• Polymorphisms in DNA repair genes as risk factors for asbestos-related malignant mesothelioma in a general population study — I. Dianzani, L. Gibello, et al. (2006)

Browse return to medical research.