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


OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Preventive Medicine, USC Keck School of Medicine, 1540 Alcazar Street, CHP 236, Los Angeles, CA 90033, USA.
Muhammad T
MT
Salam
W James
WJ
Gauderman
Rob
R
McConnell
Pi-Chu
PC
Lin
Frank D
FD
Gilliland
D000293:Adolescent; D000393:Air Pollutants / Q000009:adverse effects; D001249:Asthma / Q000235:genetics*; D001336:Automobiles; D002648:Child; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006630:Hispanic or Latino; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D014028:Tobacco Smoke Pollution / Q000009:adverse effects; D053773:Transforming Growth Factor beta1 / Q000235:genetics*; D044465:White People
D000393:Air Pollutants; D014028:Tobacco Smoke Pollution; D053773:Transforming Growth Factor beta1