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Background Several CD14 gene–environment interactions in relation to the development of allergic diseases have been reported, but the underlying biological mechanisms are unclear. We recently showed that CD14 methylation increased during childhood, parallelling a decreased impact of CD14 polymorphisms on soluble CD14 levels. Here, we aim to explore whether environmental stimuli during childhood affects CD14 methylation, thereby providing a biological mechanism through which environment may modulate genetic effect. Methods CD14 methylation levels were quantified in 157 children from the prospective Environment and Childhood Asthma birth cohort at ages 2 and 10. Associations between CD14 methylation levels and house dust levels of endotoxin, β(1,3)-glucans (at 2 yr only), allergens (dog, cat, and house dust mite), pet keeping and tobacco smoke exposure (TSE; questionnaire data) at 2 and 10 yr were explored. Results Children in homes without pets had larger increases in CD14 methylation through childhood (2–10 yr) compared with children with pets (2.1% increase (p = 0.003) vs. 0.4% decrease (n.s.), global p = 0.04). At 10 yr of age, lower CD14 methylation values were found in children with pets compared with children without pets at both 2 and 10 yr (5.4% vs. 7.5% [p = 0.02]). A similar trend was detected for TSE; children not exposed show larger increases in CD14 methylation, most pronounced in school-age girls exposed vs. not exposed to tobacco (5.5% vs. 7.5% methylation, p = 0.037). Conclusion Pet keeping and TSE appears to limit increase in CD14 methylation from 2 to 10 yr of age. This may partly explain the diverging CD14 allele associations with allergic diseases detected in different environments.

Background: The CHRNA 3 and 5 genes on chromosome 15 encode the alpha subunits of the nicotinic acetylcholine receptor, mediating airway cholinergic activity. Polymorphisms are associated with cigarette smoking, chronic obstructive pulmonary disease, and lung cancer. Aims: To determine possible associations between CHRNA 3/5 SNP rs8034191 and asthma or lung function in children in one local and one replicate multinational population, and assess if tobacco smoke modified the associations. Materials and methods: The rs8034191 SNP genotyped in 551 children from the environment and childhood asthma (ECA) birth cohort study in Oslo, Norway, and in 516 families from six European centers [the Genetics of Asthma International Network (GAIN) study] was tested for genotypic or allelic associations to current or history of asthma, allergic sensitization (= one positive skin prick tests), bronchial hyperresponsiveness (BHR), and lung function (FEV1% of predicted and FEV1/FVC ratio over/ below the 5th percentile). Results: Although the TT and CT genotypes at SNP rs 8034191 were overall significantly associated with BHR (OR = 3.9, 95% CI 1.510.0, p = 0.005), stratified analyses according to exposure to maternal smoking in-utero or indoor smoking at 10 yrs of age showed significant association (OR = 4.4, 95% CI 1.512.6, p = 0.006 and OR 5.6, 95% CI 1.718.5, p = 0.004, respectively) only in the non-exposed and not in exposed children. The SNPBHR association was replicated in the non-tobacco-smoke-exposed subjects in one of the GAIN centers (BHR associated with the T allele (p = 0.034)), but not in the collated GAIN populations. Asthma, allergic sensitization, and lung function were not associated with the rs8034191 alleles. Conclusion: An interaction between tobacco smoke exposure and a CHRNA3/5 polymorphism was found for BHR in children, but CHRNA3/5 was not associated with asthma or lung function.

Early intervention with inhaled corticosteroid (ICS) treatment for lung function development in childhood is debated. In view of lung function at birth, we aimed to assess if early use of ICS influenced lung function at 10 yrs of age. A 10-yr follow-up study of 614/802 children (mean age 10.9 +/- 0.9 yrs) with lung function measurements at birth in the Environment and Childhood Asthma study in Oslo included information on ICS treatment (124 with history of asthma) obtained at 2 and 10 yrs by parental interviews. Main outcomes at 10 yrs were the best values (% predicted and Z-scores) of forced expiratory volume in 1 s (FEV(1)) and mid-expiratory flow. The main explanatory factors were never, past or current use of ICS and Z-scores of the tidal flow-volume ratio t(PTEF)/t(E) [time to peak expiratory flow (t(PTEF)) and total expiratory time (t(E))] at birth. ICS treatment, reported by 11.9% of children in the population sample and 71.6% with current asthma, did not significantly influence lung function from birth to 10 yrs. The best values (and Z-scores) of FEV(1), and mid-expiratory flow were similar (p > 0.1) in subjects receiving ICS during and after 0-3 yrs of age, after 3 yrs only or currently compared with steroid naive children. Almost half of the change in lung function 0-10 yrs was explained by gender, a history of asthma and t(PTEF)/t(E) at birth. ICS treatment for asthma, reported in every eighth child by age 10 yrs, did not significantly improve lung function from birth to 10 yrs.