Transforming growth factor-β1 C-509T polymorphism, oxidant stress, and early-onset childhood asthma

Rationale Transforming growth factor (TGF)-beta 1 is involved in airway inflammation and remodeling, two key processes in asthma pathogenesis. Tobacco smoke and traffic emissions induce airway inflammation and modulate TGF-beta 1 gene expression. We hypothesized that the effects of functional TGF-beta 1 variants on asthma occurrence vary by these exposures. Objectives: We tested these hypotheses among 3,023 children who participated in the Children's Health Study. Methods: 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. Measurements and Main Results: Children with the -509TT genotype had a 1.8-fold increased risk of early persistent asthma (95% confidence interval [Cl], 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 ex posure to maternal smoking, those with the -509TT genotype with such exposure had a 3.4-fold increased risk of early persistent asthma (95% Cl, 1.46-7.80; interaction, P = 0.11). The association between TGF-beta 1 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% Cl, 1.29-7.44) compared with children with CC/CT genotype living > 1500 m from a freeway. Conclusions: Children with the TGF-beta 1 -509TT genotype are at increased risk of asthma when they are exposed to maternal smoking in utero or to traffic-related emissions.