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

Abstract

Transforming growth factor-beta1 (TGF-beta1) 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-beta1 protein, located in codons 10 and 25. The objective of this study was to investigate the association between TGF-beta1 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-beta1 gene polymorphisms in codons 10 and 25 do not predispose to the development of idiopathic pulmonary fibrosis; and (2) TGF-beta1 gene polymorphisms may affect disease progression in patients with idiopathic pulmonary fibrosis.

Genetics of fibrosing lung diseases

“…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.…”

“…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.…”

TGF-β1 Variants in Chronic Beryllium Disease and Sarcoidosis

“…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.…”

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

“…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.…”