Dataset Information

Associations of tumor necrosis factor G-308A with childhood asthma and wheezing.

ABSTRACT:

Rationale

Tumor necrosis factor (TNF) mediates a spectrum of airway inflammatory responses, including those to air pollutants, and is an asthma candidate gene. One TNF promoter variant (G-308A) affects expression of TNF and has been associated with inflammatory diseases; however, studies of asthma have been inconsistent. Because ozone produces oxidative stress, increased airway TNF, and inflammation, the associations of the -308 TNF polymorphism with asthma may vary by ozone exposure and variants of oxidant defense genes glutathione-S-transferase (GST) M1 and GSTP1.

Objectives

To investigate the association of TNF G-308A with asthma and wheezing and to determine whether these associations vary with ozone exposure and GSTM1 and GSTP1 genotype.

Methods

We studied associations of TNF-308 genotype with lifetime and current wheezing and asthma among 3,699 children in the Children's Health Study. We examined differences in associations with community ozone and by GSTM1 null and GSTP1 105 Ile/Val (A105G) genotype.

Results

Children with TNF-308 GG had decreased risk of asthma (odds ratio, 0.8; 95% confidence interval, 0.7-0.9) and lifetime wheezing (odds ratio, 0.8; 95% confidence interval, 0.7-0.9). The protective effects of GG genotype on wheezing outcomes were of greater magnitude in lower compared with higher ozone communities. These findings were replicated in the two cohorts of fourth-grade children recruited in 1993 and 1996. The reduction of the protective effect from the -308 GG genotype with higher ozone exposure was most marked in the GSTM1 null and GSTP1 Ile/Ile groups.

Conclusions

The TNF-308 GG genotype may have a protective role in asthma pathogenesis, depending on airway oxidative stress levels.

SUBMITTER: Li YF

PROVIDER: S-EPMC2662916 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveAssociations between single-nucleotide polymorphisms in the beta2-adrenergic receptor gene and asthma and wheeze have been inconsistent. Recent studies indicated that tobacco smoke affects beta2-adrenergic receptor gene expression and associations of beta2-adrenergic receptor gene variants with asthma in adults. We aimed to investigate the joint effects of in utero and childhood secondhand tobacco smoke exposure and 2 well-characterized functional single-nucleotide polymorphisms (Arg16Gly and Glu27Gln) of beta2-adrenergic receptor gene on asthma and wheezing in 3128 non-Hispanic and Hispanic white children of the Children's Health Study.MethodsWe fitted logistic regression models to estimate odds ratios and 95% confidence intervals for the independent and joint effects of these single-nucleotide polymorphisms and in utero and secondhand tobacco smoke exposure on asthma and wheeze outcomes.ResultsExposures to in utero maternal smoking and secondhand tobacco smoke were associated with wheezing. Children who were homozygous for the Arg16 allele and were exposed to maternal smoking in utero were at a threefold increased risk for lifetime wheeze compared with children who were unexposed and had at least 1 Gly16 allele. We found similar joint effects of secondhand tobacco smoke and Arg16Gly with wheezing. The risk for lifetime, current, and nocturnal wheeze increased with the number of smokers at home among Arg16 homozygous children. The results were consistent in 2 cohorts of children recruited in 1993 and 1996. Diplotype-based analyses were consistent with the single-nucleotide polymorphism-specific results. No associations were found for Glu27Gln.ConclusionsBoth in utero and childhood exposure to tobacco smoke were associated with an increased risk for wheeze in children, and the risks were greater for children with the Arg16Arg genotype or 2 copies of the Arg16-Gln27 diplotype. Exposures to smoking need to be taken into account when evaluating the effects of beta2-adrenergic receptor gene variants on respiratory health outcomes.