TGF-beta 1 genotype and accelerated decline in lung function of patients with cystic fibrosis

Abstract

Background-Polymorphisms in transforming growth factor (TGF)-1 associated with variations in cytokine levels are linked to fibrosis in a number of tissues. However, the contribution of this cytokine to organ fibrosis in patients with cystic fibrosis is presently unclear. This study was undertaken to examine the association between TGF-1 gene polymorphisms and the development of pulmonary dysfunction in patients with cystic fibrosis. Methods-Polymorphisms in the TGF-1 gene defining amino acids of codons 10 and 25 were determined by ARMS-PCR using DNA stored on 171 Caucasian patients who were homozygous for the F508 mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Clinical information on the patients was obtained from medical records. Results-Patients with cystic fibrosis of a TGF-1 high producer genotype for codon 10 had more rapid deterioration in lung function than those with a TGF-1 low producer genotype. The relative risk of accelerated decline in forced expiratory volume in one second (FEV 1 ) to 50% predicted and forced vital capacity (FVC) to 70% predicted of patients with a high producer genotype was 1.74 (95% CI 1.11 to 2.73) compared with 1.95 (95% CI 1.24 to 3.06) for those with a low producer genotype. Discussion-TGF-1 genotypes may have a role in mediating pulmonary dysfunction in patients with cystic fibrosis. Further work is required to determine whether inhibition of TGF-1 activity in these patients may slow disease progression. (Thorax 2000;55:459-462)

Evaluation of chemokines CXCL8 and CCL2, serotonin, and vascular endothelial growth factor serum concentrations in healthy dogs from seven breeds with variable predisposition for canine idiopathic pulmonary fibrosis

“…In humans, whether healthy people with increased CXCL8, CCL2, or TGF-β1 blood concentrations are specifically at risk for development of fibrosis has not been studied. Nevertheless, some studies highlighted the fact that IPF patients with a high TGF-β1 producing genotype are incline to have a worse prognosis and a more rapid deterioration in lung function (Arkwright et al, 2000;Alhamad et al, 2013). A single nucleotide polymorphism (rs4073T N A) was also recently found in the promoter of the CXCL8 gene and was significantly associated with higher BALF CXCL8 concentrations and an increased risk of development of IPF in humans (Ahn et al, 2011).…”

Interactions Between Secondhand Smoke and Genes That Affect Cystic Fibrosis Lung Disease

“…12,13 A case-control study involving 1306 participants found that the TT genotype at TGFβ1 position −509 was associated with more severe lung disease. 13 Our results demonstrated that secondhand smoke exposure was associated with a 22.7 percentile point decrease in cross-sectional lung function in patients with the TT genotype exposed to secondhand smoke compared with nonexposed TT homozygotes.…”

“…TGFβ1 was selected for study because genotypic variants of TGFβ1 have been shown to modify the severity of CF [11][12][13] and the development and/or severity of other chronic respiratory tract conditions, including asthma [14][15][16][17][18] and chronic obstructive pulmonary disease. [19][20][21] …”

The TNF−α –308, MCP−1 –2518 and TGF−β1 +915 polymorphisms are not associated with the development of chronic lung disease in very low birth weight infants

“…7 Several polymorphisms have been described for the TGF-b 1 gene. [17][18][19][20] The polymorphism (G-C) located within exon 1 at codon 25 (915 bp downstream of the start point) is associated with decreased production of TGF-b 1 in vitro (C allele). This polymorphism is associated with an increased frequency of lung fibrosis and a more rapid decline of lung function in patients with cystic fibrosis.…”

“…This polymorphism is associated with an increased frequency of lung fibrosis and a more rapid decline of lung function in patients with cystic fibrosis. [17][18][19][20] Recruitment of mononuclear cells to the lung and their subsequent activation is an important pathological feature of lung fibrosis and is regulated by chemotactic cytokines such as monocytes chemoattractant protein-1 (MCP-1). 21 MCP-1 has been implicated in the pathogenesis of chronic inflammatory lung diseases that have a fibrotic component.…”