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Published ahead of print on May 13, 2003, doi:10.1164/rccm.200210-1165OC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 431-435, (2003)
© 2003 American Thoracic Society

Original Article

Transforming Growth Factor-ß1 Gene Polymorphisms Are Associated with Disease Progression in Idiopathic Pulmonary Fibrosis

Antoni Xaubet, Alejandra Marin-Arguedas, Sergio Lario, Julio Ancochea, Ferran Morell, Juan Ruiz-Manzano, Eulogio Rodriguez-Becerra, Jose M. Rodriguez-Arias, Pablo Iñigo, Sergi Sanz, Josep M. Campistol, Joaquim Mullol and Cesar Picado

Servei de Pneumologia, Institut Clínic de Pneumología i Cirurgía Toràcica, Servei de Trasplantament Renal and Servei d'Otorinolaringologia, Hospital Clinic, Unitat d'Epidemiologia i Bioestadística, Fundació Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona; Servicio de Neumología, Hospital Universitario de la Princesa, Madrid; Servei de Pneumologia, Hospital Vall d'Hebrón, Barcelona; Servei de Pneumologia, Hospital Germans Trias i Pujol, Badalona; Servicio de Neumologia, Hospital Universitario Virgen del Rocío, Seville; and Departament de Neumologia, Hospital de Sant Pau, Barcelona, Spain

Correspondence and requests for reprints should be addressed to Antoni Xaubet, M.D., Servei de Pneumologia, Hospital Clinic, Villarroel 170, Barcelona 08036, Spain. E-mail: axaubet{at}clinic.ub.es


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Transforming growth factor-ß1 (TGF-ß1) is a cytokine that plays a key role in the development of idiopathic pulmonary fibrosis. There have been reports on the presence of two genetic polymorphisms in the DNA sequence encoding the leader sequence of the TGF-ß1 protein, located in codons 10 and 25. The objective of this study was to investigate the association between TGF-ß1 gene polymorphisms in codons 10 and 25 and the susceptibility to idiopathic pulmonary fibrosis and the progression of the disease. Compared with healthy control subjects (n = 140), patients with idiopathic pulmonary fibrosis (n = 128) showed no significant deviations in genotype or allele frequencies. One hundred and ten patients with idiopathic pulmonary fibrosis were followed up for 30.3 ± 25 months. The presence of a proline allele at codon 10 was independently associated with a significant increase in alveolar arterial oxygen tension difference during follow-up, after controlling for the effect of treatment (coefficient = 0.59; 95% confidence intervals, 0.23 to 0.96; p = 0.002). These findings suggest that (1) TGF-ß1 gene polymorphisms in codons 10 and 25 do not predispose to the development of idiopathic pulmonary fibrosis; and (2) TGF-ß1 gene polymorphisms may affect disease progression in patients with idiopathic pulmonary fibrosis.

Key Words: genetic predisposition • interstitial lung diseases • pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic interstitial lung disease associated with the histologic appearance of usual interstitial pneumonia (1). IPF is characterized by abnormal wound healing in the lung, resulting from multiple microscopic sites of alveolar epithelial injury and activation. Some initiating factor or factors activate epithelial cells and induce the secretion of profibrotic molecules, which may produce a continuous fibrotic response (2).

Although the etiology of IPF is largely unknown, it probably involves an interaction between environmental and genetic factors. The genetic predisposition to develop pulmonary fibrosis is suggested by the existence of familial forms of IPF, and the failure of exposure to fibrogenic agents such as asbestos and bleomycin to lead to lung fibrosis in all individuals (3, 4). Although the nature of the genetic component in IPF is unknown, good pathogenetic candidates may include polymorphisms in the genes of mediators that influence the processes of inflammation, wound healing, and repair.

Transforming growth factor-ß1 (TGF-ß1) is a growth factor that may be produced by several cell types and is one of the critical mediators in the development of IPF. TGF-ß1 is chemotactic for fibroblasts, induces the synthesis of matrix proteins and glycoproteins, and inhibits collagen degradation by induction of protease inhibitors and reduction of metalloproteases (4). In light of the relevance of TGF-ß1 to the development of fibrosis, it is feasible that alterations in the TGF-ß1 gene would influence the pathogenesis of IPF.

The human gene encoding TGF-ß1 is located on chromosome 10q13 and seven polymorphisms in this gene have been identified. Three of the seven allelic variations are located in the 5' flanking region of the TGF-ß1 gene (at positions –988, –800, and –509), three are located in the coding region (codons 10 and 25 of exon 1, and codon 263 of exon 5), and a C insertion is located in the 5' untranslated region at position +72 (5). It has been demonstrated that the production of TGF-ß1 varies between individuals and partly depends on polymorphisms in TGF-ß1 gene codons 10 and 25 (6). Single base substitutions are found in codon 10 (T->C) and in codon 25 (G->C). These changes in nucleotide base affect the amino acid-coding sequence and, therefore, have potential functional importance, as they could modulate TGF-ß1 production. Polymorphism in codon 10 represents a change from the amino acid Leu to Pro, whereas polymorphism in codon 25 causes an Arg-to-Pro substitution (5).

In this study we have investigated whether TGF-ß1 gene polymorphisms in codons 10 and 25 are associated with the development and disease progression of IPF. Some of the results of this study have been previously reported in the form of abstracts (7, 8).


   METHODS
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 ABSTRACT
 METHODS
RESULTS
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Subjects
A control group composed of 67 unrelated healthy subjects (age, 33 ± 12 years; 29 men and 38 women) was added to a previously reported control group (9) composed of 73 unrelated cadaveric renal allograft donors (age, 35 ± 18 years; 46 men and 27 women). Together they composed a control group of 140 unrelated healthy subjects with no associated medical disease. Any subject with diseases related to potential tissue fibrosis (diabetes, chronic hepatic disease, etc.) was not included in the study. The IPF group was composed of 128 unrelated patients (age, 66 ± 10 years; 76 men and 52 women). The diagnosis of IPF was established according to the American Thoracic Society/European Respiratory Society Consensus Statement (1). Histologic diagnosis was obtained in 60 of the 128 patients. The findings of pulmonary function tests are represented in Table 1 . Pulmonary function tests were performed as previously described. Reference values from our own laboratory were used (10, 11). The alveolar–arterial oxygen tension difference [P(A–a)O2] was calculated according to the standard formula, using the actual respiratory exchange ratio (R) (12). White subjects from Spain were selected for the study. The representative nature of the control group for the Spanish population has been previously demonstrated in HLA genotyping studies (13, 14). The study was approved by the ethics committees of the hospitals participating in the study.


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  		TABLE 1. Pulmonary function test findings at diagnosis in patients with idiopathic pulmonary fibrosis

 
Identification of Polymorphisms in the TGF-ß1 Gene
Polymorphisms in codons 10 and 25 of the TGF-ß1 gene were determined according to the method of Lario and coworkers (9). Genomic DNA was purified from peripheral leucocytes by salting out (15). A fragment of the coding region of the TGF-ß1 gene was amplified by polymerase chain reaction (PCR), using the following primers: sense, 5'-TTC AAG ACC ACC CAC CTT CT; antisense, 5'-TCG CGG GTG CTG TTG TAC A. The reaction mixture comprised 1x PCR buffer (10 mM Tris-HCl [pH 8.3], 50 mM KCl), 1.5 mM MgCl2, primers (1.0 µM each), dNTPs (0.2 mM each), 25 ng of genomic DNA, 2.0 U of Taq DNA polymerase (Roche Molecular Biochemicals, Indianapolis, IN), and formamide (50 ml/L) in a 30-µl reaction mixture. PCR contamination was checked by the inclusion of negative control subjects. PCRs were initially denatured at 94°C for 5 minutes and subjected to 35 cycles of amplification in a PTC-100 thermal cycler (MJ Research, Waltham, MA) with 30 seconds of denaturing at 94°C, 30 seconds of annealing at 60°C, and 30 seconds of extension at 72°C. Amplified DNA (5–10 µl) was digested with the restriction enzyme MspA1I or FseI (New England BioLabs, Beverly, MA) to detect the allelic variants located in codon 10 or codon 25, respectively. Digested products were fractioned in 7% polyacrylamide gels and visualized by ultraviolet fluorescence after ethidium bromide staining. The Pro allele in codon 10 is defined by the presence of a 273-bp fragment, and the Leu allele in codon 10 is identified by a 285-bp fragment. The Pro allele in codon 25 is detected by an undigested product of 500 bp, whereas the Arg allele produces two bands of 318 and 182 bp.

Statistical Analysis
Hardy–Weinberg equilibrium was assessed by a {chi}2 test with 2 degrees of freedom, or by Fisher exact test. Differences between genotype and allele frequencies were analyzed with the {chi}2 test, or the Fisher test if one cell had n < 5. Differences in the mean values of quantitative variables were tested with the Student's t test or the Wilcoxon rank sum test. The relationship between the progression of IPF (changes in pulmonary function tests), the treatment, and the type of genotype and allele was tested by univariate linear regression analysis. Multivariate analyses were performed by the forward-stepwise method. The criterion for inclusion was p = 0.01 and the criterion for exclusion was p = 0.05. Data were analyzed with STATA statistical software, release 7.0 (Stata, College Station, TX). Data are expressed as means ± SD. p < 0.05 was considered statistically significant.


   RESULTS
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Genotype and Allele Frequencies of TGF-ß1 Gene Polymorphisms in Control Subjects and Patients with IPF
There was agreement between genotypes observed and those predicted by the Hardy–Weinberg equilibrium in the control group (codon 10, x2 = 0.777, degrees of freedom = 2, p = 0.87; codon 25, Fisher exact test, p = 0.83; n = 140). The genotype and allelic frequencies of TGF-ß1 gene polymorphisms in the control group did not differ from those reported in the ECTIM study, which covered subjects from various parts of Europe (data not shown) (5). There were no differences between the genotype and allele frequencies of codons 25 and 10 TGF-ß1 gene polymorphisms in the IPF and control populations (Tables 2 and 3) .


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  		TABLE 2. Transforming growth factor-ß1 genotype frequencies

 

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  		TABLE 3. Transforming growth factor-ß1 allelic frequencies

 
Relationship between Genotype and Allele Frequencies of TGF-ß1 Gene Polymorphisms and Disease Progression in Patients with IPF
One hundred and ten patients with IPF were monitored for 30.3 ± 25 months (range, 3–104 months). Contact with the remaining 18 patients was lost. Overall, patients showed a deterioration in pulmonary functional parameters. To fully determine the changes in pulmonary function tests during the follow-up, we have expressed the changes over time. We divided the changes in pulmonary function tests by the follow-up duration in months (Table 4) . Seventy-one of the monitored patients were treated with glucocorticoids, associated or unassociated with azathioprine or cyclophosphamide, and the remaining 39 patients were untreated. There were no differences in the changes in pulmonary function test results during the follow-up between treated and untreated patients (Table 5) .


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  		TABLE 4. Changes in pulmonary function tests in follow-up study

 

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  		TABLE 5. Changes in pulmonary function test results in treated and untreated patients with idiopathic pulmonary fibrosis during follow-up study

 
A significant difference was found between changes in P(A–a) O2 during the follow-up of patients with the Pro allele in codon 10 (0.42 ± 0.68 mm Hg/month), compared with those without the Pro allele (–0.17 ± 0.8 mm Hg/month) (p = 0.002, Wilcoxon rank sum test) (Figure 1) . There was also a borderline significant difference between changes in FVC in patients with the Pro allele in codon 10 (–0.60 ± 1.36%/month) and those without the Pro allele (–0.11 ± 1.43%/month) (p = 0.053, Wilcoxon rank sum test) (Table 6) . There were no differences between the duration of follow-up in Pro+ and Pro– groups (29.9 ± 3 versus 31.7 ± 3.7 months, respectively). There were no differences between the number of treated patients in Pro+ and Pro– groups (44/70 [62%] versus 28/40 [70%], respectively). In the univariate analysis, the presence of genotypes Leu/Pro and Pro/Pro in codon 10 was significantly associated with an increase in P(A–a)O2 during the follow-up (coefficient, 0.57; 95% confidence interval [95% CI], 0.16–0.98; p = 0.006; and coefficient, 0.63; 95% CI, 0.13–1.13; p = 0.01, respectively). Moreover, the univariate analysis also showed that the presence of the Pro allele in codon 10 was significantly correlated with the increase in P(A–a)O2 (coefficient, 0.59; 95% CI, 0.23–0.96; p = 0.002). Multivariate analysis showed that the presence of Leu/Pro and Pro/Pro genotypes in codon 10 was significantly associated with the increase in P(A–a)O2 (coefficient, 0.58; 95% CI, 0.17–0.98; p = 0.006; and coefficient, 0.71; 95% CI, 0.14–1.28; p = 0.01, respectively).



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  		Figure 1. Changes in P(A–a)O2 over time in carriers and noncarriers of the Pro allele in codon 10. D = at diagnosis; F = at the end of follow-up.

 

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  		TABLE 6. Changes in pulmonary function tests between carriers and noncarriers of pro allele in codon 10 during follow-up study

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The main findings of our study are as follows: (1) There are no differences in the distribution of genotypes and allele frequencies of codons 25 and 10 in the TGF-ß1 gene between patients with IPF and healthy subjects, and (2) the presence of the Pro allele in codon 10 of the TGF-ß1 gene is associated with an increased deterioration in gas exchange in patients with IPF.

IPF may be a genetically complex disease and its pathogenesis is likely to involve an interaction between multiple alleles located on different genes (16). Nevertheless, the identification of genetic factors that predispose to IPF will improve our understanding of the pathogenesis of the disease and may lead to the development of new therapeutic strategies. It has been suggested that there is a potential association between variations in genes located on chromosome 14 and major histocompatibility genes and IPF (17, 18). Thomas and coworkers have reported a mutation in the surfactant protein C gene in a family whose members were affected by IPF or cellular nonspecific interstitial pneumonia (19).

In vitro studies and animal models of pulmonary fibrosis have shown that proinflammatory mediators and growth factors are critical in the processes of inflammation, wound healing, and repair in pulmonary fibrosis (2). There are descriptions of the presence of genetic variants in genes encoding these mediators and their receptors, making these genes candidates for the pathogenesis of IPF (16). Interleukin (IL)-1 receptor antagonist and tumor necrosis factor-{alpha} (TNF-{alpha}) gene polymorphisms have been associated with an increased risk of IPF (20). In contrast, other authors have not found any association between these polymorphisms and IPF (21, 22). Other polymorphisms studied are those of IL-8 and IL-8 receptors, IL-6, lymphotoxin-{alpha}, TNF receptor II, IL-1{alpha}, and IL-1ß, although no association with the development of IPF was found (21, 23). However, the presence of IL-6 gene polymorphisms, particularly when combined with TNF receptor II polymorphisms, has been linked with the decline of diffusion capacity of the lung for carbon monoxide (DLCO) over time (21).

TGF-ß1 has been shown to play a key role in the development of IPF and increased expression of TGF-ß1 has been found in lung tissue from patients with this disease and in animal models of pulmonary fibrosis (24, 25). The potential role of TGF-ß1 genetic variants in the pathogenesis of IPF has been suggested by Mori and coworkers (26), who demonstrated the presence of microsatellite instability in the TGF-ß1 receptor type II gene in the hyperplastic lesions of alveolar lining epithelial cells in lung tissue from patients with the disease. There are two genetic polymorphisms in the DNA sequence encoding the leader sequence of TGF-ß1, located at codon 10 (either Leu or Pro) and at codon 25 (either Arg or Pro). The Arg/Arg homozygous genotype in the TGF-ß1 gene polymorphism at codon 25 and the presence of the Leu allele at codon 10 have been associated with increased TGF-ß1 production (27).

There have been no descriptions to date of associations between TGF-ß1 polymorphisms and either the susceptibility to IPF or the progression of the disease. We found no differences in this study between patients with IPF and healthy subjects regarding the genotype and allele frequencies of codons 25 and 10 TGF-ß1 polymorphisms. Thus, our results indicate that these polymorphisms do not appear to predispose to the development of IPF. The significance of TGF-ß1 polymorphisms in the susceptibility to fibrotic damage in lung diseases other than IPF has previously been investigated. Muraközy and coworkers (28) reported the lack of association between codon 25 polymorphism and the development and clinical evolution of sarcoidosis. Similarly, it has been demonstrated that TGF-ß1 polymorphisms do not predispose to cystic fibrosis (29). In contrast, it has been shown that homozygosity for Arg at codon 25 is associated with the development of fibrosis in the allograft after lung transplantation in patients with various diseases such as cystic fibrosis, IPF, bronchiectasis, and emphysema (27, 30, 31). The different results obtained in these studies can partly be explained by the different pathogeneses of the diseases investigated, and by the fact that the lung fibrotic response is probably modulated by a complex gene interplay rather than by single alleles.

The main finding of our study is that the presence of the Pro allele in codon 10 of the TGF-ß1 gene was independently associated with increased deterioration in gas exchange in patients with IPF, after controlling for the effect of treatment. This finding has not been previously reported and it suggests that TGF-ß1 polymorphisms may be linked with the progression of IPF. However, our results should be interpreted with caution because of the small number of patients with IPF studied. The presence of the Pro allele in codon 10 correlated significantly with changes in P(A–a)O2 during the follow-up, but it did not correlate with changes in other functional parameters. P(A–a)O2 at rest and at exercise are used in the standard assessment of the clinical course of IPF (1). Furthermore, our group has reported that the increase in P(A–a)O2 throughout the follow-up has a significant relationship with the deterioration of gas-exchange parameters at diagnosis (12).

Homozygosity for the Pro allele at codon 10 has been associated with increased TGF-ß1 production and susceptibility to osteoporosis in postmenopausal women (32, 33). Unfortunately, we do not have any data on the plasma levels of TGF-ß1 in our patients. Nevertheless, it has been reported that plasma levels of TGF-ß1 are increased in IPF and it has been suggested that serial determinations of circulating TGF-ß1 may be a useful parameter in assessing the activity of the disease and monitoring the response to therapy (34).

The role of TGF-ß1 polymorphisms in the progression of other lung diseases has also been investigated. It has been reported that carriage of the Leu allele in codon 10 is associated with rapid deterioration in lung function in patients with cystic fibrosis (29). Furthermore, homozygosity for the codon 25 Arg allele in combination with the codon 10 Leu allele has been shown to be a marker for poor posttransplantation prognosis and recipient survival (31). The results of these studies suggest, along with our own findings, that TGF-ß1 polymorphisms may influence the development of excessive lung damage and fibrosis.

The relationship of TGF-ß1 gene polymorphisms to disease progression highlights the significance of the inhibition of TGF-ß1 activity as a potential therapeutic strategy in IPF. Gene transfer of Smad7 to inhibit TGF-ß1–mediated cell signaling has been found to prevent bleomycin-induced lung fibrosis in mice (35). Furthermore, the potential efficacy of interferon-{gamma}–1b in the treatment of IPF has been related to a decrease in TGF-ß1 mRNA levels in lung tissue (36).

In conclusion, the present study is the first to link genetic variations in TGF-ß1 with disease progression in patients with IPF. Further evaluation is needed to be able to assess the biological significance of these findings.


   FOOTNOTES
 
Supported by grants from SEPAR: Fundación Respira 2000, FIS 00/371, CIRIT 2000, 5GR/120.

Received in original form October 11, 2002; accepted in final form May 3, 2003


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 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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