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Transforming growth factor- 1 C-509T polymorphism, oxidant stress, and early-onset childhood asthma.

ABSTRACT: Transforming growth factor (TGF)-beta1 is involved in airway inflammation and remodeling, two key processes in asthma pathogenesis. Tobacco smoke and traffic emissions induce airway inflammation and modulate TGF-beta1 gene expression. We hypothesized that the effects of functional TGF-beta1 variants on asthma occurrence vary by these exposures.We tested these hypotheses among 3,023 children who participated in the Children's Health Study.Tagging single-nucleotide polymorphisms rs4803457 C>T and C-509T (a functional promoter polymorphism) accounted for 94% of the haplotype diversity of the upstream region. Exposure to maternal smoking in utero was based on smoking by biological mother during pregnancy. Residential distance from nearest freeway was calculated based on residential address at study entry.Children with the -509TT genotype had a 1.8-fold increased risk of early persistent asthma (95% confidence interval [CI], 1.11-2.95). This association varied marginally significantly by in utero exposure to maternal smoking. Compared with children with the -509CC/CT genotype with no in utero exposure to maternal smoking, those with the -509TT genotype with such exposure had a 3.4-fold increased risk of early persistent asthma (95% CI, 1.46-7.80; interaction, P = 0.11). The association between TGF-beta1 C-509T and lifetime asthma varied by residential proximity to freeways (interaction P = 0.02). Children with the -509TT genotype living within 500 m of a freeway had over three-fold increased lifetime asthma risk (95% CI, 1.29-7.44) compared with children with CC/CT genotype living > 1500 m from a freeway.Children with the TGF-beta1 -509TT genotype are at increased risk of asthma when they are exposed to maternal smoking in utero or to traffic-related emissions.

SUBMITTER: Salam MT

PROVIDER: S-EPMC2176104 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Transforming growth factor- 1 C-509T polymorphism, oxidant stress, and early-onset childhood asthma.

Salam Muhammad T MT Gauderman W James WJ McConnell Rob R Lin Pi-Chu PC Gilliland Frank D FD

American journal of respiratory and critical care medicine 20070802 12

<h4>Rationale</h4>Transforming growth factor (TGF)-beta1 is involved in airway inflammation and remodeling, two key processes in asthma pathogenesis. Tobacco smoke and traffic emissions induce airway inflammation and modulate TGF-beta1 gene expression. We hypothesized that the effects of functional TGF-beta1 variants on asthma occurrence vary by these exposures.<h4>Objectives</h4>We tested these hypotheses among 3,023 children who participated in the Children's Health Study.<h4>Methods</h4>Taggi ...[more]

PMID: 17673695

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Project description:Importance:Whether genetic factors can identify patients at risk for radiation-induced fibrosis remains unconfirmed. Objective:To assess the association between the C-509T variant allele in the promoter region of TGFB1 and breast fibrosis 3 years after radiotherapy. Design, Setting, and Participants:This is an a priori-specified, prospective, cohort study nested in an open-label, randomized clinical trial, which was conducted in community-based and academic cancer centers to compare hypofractionated whole-breast irradiation (WBI) (42.56 Gy in 16 fractions) with conventionally fractionated WBI (50 Gy in 25 fractions) after breast-conserving surgery. In total, 287 women 40 years or older with pathologically confirmed stage 0 to IIA breast cancer treated with breast-conserving surgery were enrolled from February 2011 to February 2014. Patients were observed for a minimum of 3 years. Outcomes were compared using the 1-sided Fisher exact test and multivariable logistic regression. Exposures:A C-to-T single-nucleotide polymorphism at position -509 relative to the first major transcription start site (C-509T) of the TGFB1 gene. Main Outcomes and Measures:The primary outcome was grade 2 or higher breast fibrosis as assessed using the Late Effects Normal Tissue/Subjective, Objective, Medical Management, Analytic scale (range, 0 to 3) three years after radiotherapy. Results:Among 287 women enrolled in the trial, TGFB1 genotype and 3-year radiotherapy-induced toxicity data were available for 174 patients, of whom 89 patients (51%) with a mean (SD) age of 60 (8) years had at least 1 copy of C-509T. Grade 2 or higher breast fibrosis was present in 12 of 87 patients with C-509T (13.8%) compared with 3 of 80 patients without the allele variant (3.8%) (absolute difference, 10.0%; 95% CI, 1.7%-18.4%; P?=?.02). The results of multivariable analyses indicated that only C-509T (odds ratio, 4.47; 95% CI, 1.25-15.99; P?=?.02) and postoperative cosmetic outcome (odds ratio, 7.09; 95% CI, 2.41-20.90; P?<?.001) were significantly associated with breast fibrosis risk. Conclusions and Relevance:To date, this study seems to be the first prospective validation of a genomic marker for radiation fibrosis. The C-509T allele in TGFB1 is a key determinant of breast fibrosis risk. Assessing TGFB1 genotype may facilitate a more personalized approach to locoregional treatment decisions in breast cancer. Trial Registration:ClinicalTrials.gov identifier: NCT01266642.

Dataset Information

Transforming growth factor- 1 C-509T polymorphism, oxidant stress, and early-onset childhood asthma.

Publications

Transforming growth factor- 1 C-509T polymorphism, oxidant stress, and early-onset childhood asthma.

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