Transforming Growth Factor-β<sub>1</sub> Gene Polymorphisms Are Associated with Disease Progression in Idiopathic Pulmonary Fibrosis

Xaubet, Antoni; Marín-Arguedas, Alejandra; Lario, Sergio; Ancochea, Julio; Morell, Ferrán; Ruiz-Manzano, Juan; Rodríguez-Becerra, Eulogio; Rodríguez-Arias, J.M.; Íñigo, Pablo; Sanz, Sergi; Campistol, Josep M.; Mullol, Joaquim; Picado, César

doi:10.1164/rccm.200210-1165oc

Cited by 163 publications

(96 citation statements)

References 30 publications

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“…The authors found no association of either polymorphism with susceptibility to IPF. Interestingly, however, the +869C allele (codon 10 proline) was associated with increased deterioration of the disease, as measured by gas exchange [39]. Although this allele was not associated with other functional parameters of IPF, and the levels of TGF-b in both case and control subjects were not determined, the study provides the first evidence for TGFB1 as a potential determinant of disease progression in IPF.…”

Section: Fibroblast-related Pathwaysmentioning

confidence: 68%

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Genetics of fibrosing lung diseases

Grutters

Bois²

2005

Eur Respir J

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Genetic studies in familial lung fibrosis have demonstrated an association with surfactant protein C genes: two mutations have been found resulting in protein misfolding and causing type-II epithelial cell injury. Remarkably, different histological patterns were observed in the affected subjects, suggesting the influence of modifier genes and/or environmental factors. Surfactant protein C gene variations have not, however, been associated with sporadic cases,i.e.idiopathic pulmonary fibrosis (IPF).Susceptibility to IPF probably involves a combination of polymorphisms related to epithelial cell injury and abnormal wound healing. To date, the genetic associations with IPF that have been reported in different cohorts include the genes encoding tumour necrosis factor (TNF; −308 adenine), interleukin-1 receptor antagonist (+2018 thymidine) and association with severity and progression (interleukin-6/TNF receptor II and transforming growth factor-β1 (TGFB1; +869 cytosine)), but none of these associations have been replicated by others.Unlike in IPF, immunological inflammation seems to be more prominent in the pathogenesis of scleroderma lung fibrosis, being an autoimmune disease with specific autoantibodies, such as antitopoisomerase antibodies, in patients with diffuse lung disease, and anticentromere antibodies, in patients with pulmonary vascular disease. Antitopoisomerase antibody positivity is associated with the carriage of human leukocyte antigen DRB1*11 and DPB1*1301 alleles, suggesting the recognition of a specific amino-acid motif. Extended haplotype analysis also supports the conclusion that TNF may be the primary association with anticentromere positivity. Intriguingly, associations with TGFB1 and genes involved in extracellular matrix homeostasis have been reported in this disease.In conclusion, significant steps forward have been taken in the understanding of the genetic contribution to fibrosing lung diseases, but major challenges lay ahead. It is the present authors' opinion that only a combined approach studying large numbers of familial and sporadic cases, all clinically well phenotyped, using multiple distinct cohorts, and genotyped according to relevant gene ontologies will be successful. It will be necessary to be particularly vigilant with regard to phenotype; the absence of very strong reproducible associations may be because of the rigidity of phenotype definition, coupled with the possibility that idiopathic pulmonary fibrosis may still be a heterogeneous group of diseases, despite the more rigid definition set out by the European Respiratory Society/American Thoracic Society statement.

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Section: Fibroblast-related Pathwaysmentioning

confidence: 68%

“…Against this background, XAUBET et al [39] have assessed polymorphisms in TGFB1 in White IPF patients from Spain. They studied two exon 1 polymorphisms, at positions +869 (T.C) and +915 (G.C), both resulting in amino acid substitutions.…”

Section: Fibroblast-related Pathwaysmentioning

confidence: 99%

Genetics of fibrosing lung diseases

Grutters

Bois²

2005

Eur Respir J

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“…The TGF-␤1 locus, and specifically the Ϫ509 and codon 10 polymorphisms, has been associated with other forms of more severe lung disease, including cystic fibrosis (28) and idiopathic pulmonary fibrosis (IPF; Ref. 29), but not with the susceptibility of these diseases, as in the case of CBD and sarcoidosis. Interestingly, both of these studies used physiologic markers of disease severity or progression over time; FEV 1 in the case of the cystic fibrosis study and alveolar arterial oxygen gradient, at rest in the case of IPF.…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 Variants in Chronic Beryllium Disease and Sarcoidosis

Jonth

Silveira

Fingerlin³

et al. 2007

The Journal of Immunology

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Evidence suggests a genetic predisposition to chronic beryllium disease (CBD) and sarcoidosis, which are clinically and pathologically similar granulomatous lung diseases. TGF-β1, a cytokine involved in mediating the fibrotic/Th1 response, has several genetic variants which might predispose individuals to these lung diseases. We examined whether certain TGF-β1 variants and haplotypes are found at higher rates in CBD and sarcoidosis cases compared with controls and are associated with disease severity indicators for both diseases. Using DNA from sarcoidosis cases/controls from A Case Control Etiologic Study of Sarcoidosis Group (ACCESS) and CBD cases/controls, TGF-β1 variants were analyzed by sequence-specific primer PCR. No significant differences were found between cases and controls for either disease in the TGF-β1 variants or haplotypes. The −509C and codon 10T were significantly associated with disease severity indicators in both CBD and sarcoidosis. Haplotypes that included the −509C and codon 10T were also associated with more severe disease, whereas one or more copies of the haplotype containing the −509T and codon 10C was protective against severe disease for both sarcoidosis and CBD. These studies suggest that the −509C and codon 10T, implicated in lower levels of TGF-β1 protein production, are shared susceptibility factors associated with more severe granulomatous disease in sarcoidosis and CBD. This association may be due to lack of down-regulation by TGF-β1, although future studies will be needed to correlate TGF-β1 protein levels with known TGF-β1 genotypes and assess whether there is a shared mechanisms for TGF-β1 in these two granulomatous diseases.

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“…An assumption that is often made is that the presence of profibrotic mediators, such as transforming growth factor ␤ and other cytokines known to be associated with fibrosis, relates to the pathogenesis of this disorder (10)(11)(12). Although these observations may be consistent with ongoing fibrosis in the lung, they really do not demonstrate, with any certainty, that they are necessarily important and unique features to this lung disease.…”

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confidence: 97%

State of the Art. Does Current Knowledge Explain the Pathogenesis of Idiopathic Pulmonary Fibrosis?: A Perspective

Hunninghake

Schwarz²

2007

Proceedings of the American Thoracic Society

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The cause of idiopathic pulmonary fibrosis (IPF) remains unknown. Although the observed biologic and biochemical processes associated with the disease are consistent with a fibrotic process, they are not necessarily unique to IPF. Furthermore, the importance of these observations will not be apparent until a directed therapy alters the natural history of the disease. There are essentially no studies that explain the unique histologic features of this disease. As mechanistic data accumulates, it is our opinion that these data should pass the test of explaining the clinical histologic features of the disease before it can be assumed that these features are unique for IPF.

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Transforming Growth Factor-β₁ Gene Polymorphisms Are Associated with Disease Progression in Idiopathic Pulmonary Fibrosis

Cited by 163 publications

References 30 publications

Genetics of fibrosing lung diseases

Genetics of fibrosing lung diseases

TGF-β1 Variants in Chronic Beryllium Disease and Sarcoidosis

State of the Art. Does Current Knowledge Explain the Pathogenesis of Idiopathic Pulmonary Fibrosis?: A Perspective

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Transforming Growth Factor-β1 Gene Polymorphisms Are Associated with Disease Progression in Idiopathic Pulmonary Fibrosis

Cited by 163 publications

References 30 publications

Genetics of fibrosing lung diseases

Genetics of fibrosing lung diseases

TGF-β1 Variants in Chronic Beryllium Disease and Sarcoidosis

State of the Art. Does Current Knowledge Explain the Pathogenesis of Idiopathic Pulmonary Fibrosis?: A Perspective

Contact Info

Product

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Transforming Growth Factor-β₁ Gene Polymorphisms Are Associated with Disease Progression in Idiopathic Pulmonary Fibrosis