The G/G genotype of transforming growth factor beta 1 (TGF‐β1) single nucleotide (+915G/C) polymorphism coincident with other host and environmental factors is associated with irreversible bronchoconstriction in asthmatics

Abstract

Irreversible airflow obstruction may develop in some cases of asthma even in absence of known risk factors such as smoking and environmental insults and despite implementing apparently appropriate therapy. This implies that genetic factors may significantly contribute to determining the severity in the course of the disease. The published reports on genetic predisposition to irreversible bronchoconstriction in asthma, however, are relatively scarce, and disregard its potential association with transforming growth factor (TGF)-beta1 gene polymorphism despite established role that TGF-beta1 plays in airway remodelling. We tested TGF-beta1 single-nucleotide polymorphisms (SNPs) at position +869 of codon 10 (leucine or proline) and position +915 of codon 25 (arginine or proline) for association with irreversible bronchoconstriction in a case-control study involving 110 patients with asthma and 109 controls. Multivariate logistic regression analysis revealed that genotype G/G at codon 25 was significantly associated with irreversible bronchoconstriction in asthmatics (odds ratio = 4.44; 95% confidence interval: 1.00-19.61; P = 0.05), but only after adjustment for gender, disease duration and smoking index. The influence of SNPs at codon 10 on irreversible airway obstruction was not significant. Our results suggest that presence of SNP (+915G/G) at codon 25 in TGF-beta1 gene may predispose to the development of irreversible bronchoconstriction in asthmatic patients, but only when coincident with the male gender, habitual smoking and relevant duration of the disease.

The –2549 –2567 del18 Polymorphism in VEGF and Irreversible Bronchoconstriction in Asthmatics

“…Disease duration also seems to play an important role, while age and gender did not seem to be significant. We confirmed the importance of this kind of complex interaction in a study where we showed that the presence of the SNP +915G/G at codon 25 in the TGFB1 gene, when coincident with other factors, may predispose to the development of irreversible bronchoconstriction in asthmatic patients [29].…”

Importance of Cytokines in Murine Allergic Airway Disease and Human Asthma

“…More than 10 studies have linked asthma frequency or severity to polymorphisms in genes that encode IL-4 (159-168), IL-13 (162, 169, 170), TNF (159, 171-177) and IL-4Rα (18, 162, 165, 168, 178-181). Several studies have also linked asthma to genes that encode the IL-1 receptor antagonist (IL-1RA) (182-184), IL-10 (185-189), IL-18 (190-194), IFN-γ (195-197), TGF-β1 (178, 185, 186, 198-202) and Stat6 (162, 203), while polymorphisms in genes that encode IL-1β (182), IL-2 (186), IL-6 (183), IL-9 (204), IL-12/27p40 (205, 206), IL-15 (207), IL-17F (208), IL-21 (209), IL-27p28 (210), LT-α (211), TSLP (212), TGF-β2 (213) and Stat4 (196) have been linked to asthma frequency or severity by fewer studies (214). Some of these studies link asthma risk to a single nucleotide polymorphism (SNP) in a cytokine gene exon (18), suggesting that polymorphic variants influence cytokine function or longevity, while other studies link asthma risk to a SNP in a cytokine promoter (164), suggesting that polymorphic variants influence cytokine production.…”

“…Negative studies also are not conclusive; they may have investigated the “wrong” polymorphic variant of a gene that really is involved in asthma pathogenesis, a specific racial or ethnic group in which polymorphic variants of the gene studied are not risk factors for asthma, or too few patients to identify a genuine association. Additionally, some SNP studies that link specific cytokines to asthma report linkage only for individuals with exposure to specific environmental factors, such as dust mite allergen (224, 225), freeway traffic (202) or tobacco smoke (222). …”

Simultaneous Stimulation with TGF-β1 and TNF-α Induces Epithelial Mesenchymal Transition in Bronchial Epithelial Cells

“…This suggests that genetic factors may contribute to a propensity for airway remodeling. Some TGF-β single-nucleotide polymorphisms are reported to be involved in asthma and, especially, the presence of single-nucleotide polymorphism +915G/C in the TGF-β gene may predispose to airway fibrosis [29]. …”