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Modification of additive effect between vitamins and ETS on childhood asthma risk according to GSTP1 polymorphism : a cross -sectional study


This study showed an additive effect of low dietary intake of vitamin A and ETS exposure
for increasing risk for asthma symptoms. Additionally, the AA GSTP1 polymorphism was associated with an increased risk for asthma in children who were
exposed to ETS and had a low dietary intake of vitamin A and carotene. Children who
were exposed to ETS were significantly more likely to report wheeze within the previous
12 months and have an asthma diagnosis. Although overall antioxidant intake was not
associated with presence of asthma symptoms, children who were exposed to ETS and
had a low vitamin A intake were more likely to report asthma symptoms. This trend
was particularly notable in children carrying the GSTP1 genotype AA, which has been associated with an increased risk for asthma. Our study
suggested that low vitamin A intake increased susceptibility to development of ETS-associated
childhood asthma by decreasing antioxidant capacity, and the oxidative stress-related
GSTP1 gene further modified this association.

Oxidative stress occurs when the generation of oxidant molecules (i.e., free radicals)
exceeds the available antioxidant defenses 30]. Inflammatory disorders such as asthma and allergic rhinitis may be mediated by oxidative
stress 25], which occurs as a result of endogenous inflammation and following environmental
exposure to toxic substances such as cigarette smoke and air pollutants in allergic
airway diseases 6]. Exposure to ETS is a major environmental factor that influences the development
and aggravation of asthma and impaired lung function in childhood 7].

Cigarette smoke inhalation increases exposure to reactive oxygen species 31] to a level that may overwhelm endogenous antioxidant defenses in asthmatic patients
who already have exacerbated levels of oxidative stress 6]. A controlled human exposure model has shown that glutathione levels are reduced
in the bronchial and nasal airways following exposure to air pollutants 32]. The body produces numerous antioxidants endogenously, but the quantity is often
insufficient to prevent oxidative stress. Exogenous antioxidants, such as dietary
nutrients, can supplement the endogenous system to help defend against free radicals.
Smoking is associated with reduced circulating concentration of antioxidants in the
blood 33]. This may be because dietary and supplemental antioxidant intake tends to be lower
in smokers than in non-smokers and because smoke-induced oxidative stress increases
the degradation or transformation of circulating antioxidant micronutrients into biologically
inactive components 34] or even into pro-oxidants 35]. Therefore, dietary antioxidant intake may influence the relationship between exposure
to ETS and the risk of asthma symptoms.

Several studies suggest that low serum levels or dietary intake of antioxidants may
be risk factors for asthma 9], 10]. Dietary vitamin A intake and serum vitamin A concentrations are significantly lower
in patients with asthma than in healthy control subjects and are lower in patients
with severe asthma than in those with mild asthma 36], 37]. One study shows that low vitamin A status increases susceptibility to cigarette
smoke-induced lung emphysema in a mouse model 38]. However, other studies suggest that dietary supplementation with vitamins, such
as vitamin A and ascorbate, does not improve lung function or asthma symptoms 39]–41]. We found no relationship between overall dietary antioxidant intake and asthma diagnosis
or wheeze in the previous 12 months, although children who were exposed to ETS and
had a low dietary vitamin A intake were more likely to report symptoms of asthma.
Dietary antioxidants may ameliorate the effects of smoking on asthma symptoms, although
future human studies that assess the benefits of antioxidant intake should focus on
selecting an appropriate exposure to oxidative stress.

Recent studies suggest that genetic factors may also contribute to an individual’s
susceptibility to respiratory disorders induced by ETS exposure 7]. GSTP1 encodes for an enzyme that belongs to a large family of GST enzymes, which are important
for detoxification of potentially harmful compounds from tobacco smoke, such as the
polyaromatic hydrocarbon molecules benzopyrene and chrysene 42], 43]. GSTP1 is widely expressed in human airways, predominantly in alveolar macrophages and epithelial
cells 44]. Polymorphisms in the GST genes, such as GSPT1 (rs1695), affect the ability to respond to excessive oxidative stress by altering
activity of the GST enzymes 45]. Based on the hypothesis that dietary intake of antioxidants and endogenous antioxidant
capacity contribute to the susceptibility to oxidative stress in asthmatic children,
researchers investigated the effects of antioxidant supplementation on ozone-related
decreases in lung function according to GSTM1 genotype 46], 47]. Children in the placebo group that lacked the GSTM1 gene had a significant reduction in FEF
after ozone exposure, whereas the GSTM1-positive children in the placebo group did not. Therefore, asthmatic children with
compromised antioxidant defense systems caused by genetic susceptibility and deficiencies
in antioxidant intake may be at increased risk for oxidative stress induced by ozone
or ETS. However, a recent meta-analysis indicates that the GSTP1 single nucleotide polymorphism rs1695 did not affect the prevalence of asthma, suggesting
that presence of GST variants contribute to airway diseases through interactions with
the environment 48].

Active GSTP1 variant proteins produced by the GSTP1 gene play a role in xenobiotic metabolism and influence susceptibility to asthma
and other diseases 49]. Some studies show that GSTP1 encodes for an important enzyme in the anti-oxidative pathway that buffers the harmful
effects of air pollution 21], 50]. The interaction between GSTP1 and different types of air pollutants has a higher information gain than other gene-air
pollutant combinations 21]. Therefore, we investigated the influence of interactions between ETS, dietary antioxidant
intake, and the GSTP1 gene on risk for childhood asthma. We also investigated the relationship between
MTHFR (rs1801133) and NQO1 (rs1800566) genes and asthma symptoms, but we did not present these data because
we did not find an association.

To the best of our knowledge, few publications have investigated the overall effects
of GST variants and ETS exposure on asthma symptoms 51]–55], and whether such effects could be modulated by dietary antioxidant intake has not
yet been explored. This was the first study to assess how ETS, low dietary vitamin
A intake, and GSTP1 genotype affect asthma symptoms in children. However, our study had some limitations.
First, this was a cross-sectional study, and therefore we could not determine causal
relationships among the factors studied. Second, we focused on only one well-known
candidate gene involved in oxidative stress, and other genes likely also regulate
the influence of ETS and dietary antioxidants. Third, our study may also have recall
bias because our dietary data were based on the semi-quantitative FFQ completed by
parents or guardians, who may have underreported unhealthy foods and overreported
healthy foods. Fourth, the number of children in the asthma group was smaller than
the number in the control group, a discrepancy that is common in community-based studies.
In addition, we did not record the use of other supplements, such as multivitamins,
and we could not confirm the association between dietary intake and serum levels of
antioxidants because we did not measure serum levels. Nonetheless, the clinical implications
of these findings are important because exposure to ETS is common in children. Further
prospective, long-term follow-up studies are needed to confirm and extend these findings.