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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. [ABSTRACT FROM AUTHOR]

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 (FEV1) 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 tPTEF/tE [time to peak expiratory flow (tPTEF) and total expiratory time (tE)] 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 FEV1, 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 naïve children. Almost half of the change in lung function 0-10 yrs was explained by gender, a history of asthma and tPTEF/tE 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. [ABSTRACT FROM AUTHOR]

Background: CD14 is a pattern-recognition receptor for environmental LPS, and engagement of the CD14-LPS complex activates innate host defense mechanisms. Single nucleotide polymorphisms (SNPs) in the CD14 gene have been associated with soluble CD14 (sCD14) levels, but inconsistencies between studies suggest the presence of regulatory mechanisms hitherto not well understood. Objective: We sought to investigate possible associations between CD14 SNPs and sCD14 levels at different time points in childhood (at birth [cord blood] and 2 and 10 years) and to explore whether these associations were related to CD14 gene methylation. Methods: Four SNPs, rs2569191 (−1145GA), rs5744455 (−550CT or −651CT), rs2569190 (−159CT or −260CT), and rs4914 in CD14 were genotyped in 762 children from the Environmental and Childhood Asthma study. Genotype frequencies were analyzed for association with sCD14 levels in 660 babies, 346 children at age 2 years, and 360 children at age 10 years. In a subgroup of 157 children with DNA available at both 2 and 10 years of age, CD14 methylation patterns were determined and analyzed against detected CD14 gene–sCD14 associations. Results: rs2569191, rs5744455, and rs2569190 were associated with sCD14 levels at birth and 2 years, but only rs5744455 was associated with sCD14 levels at 10 years. CD14 methylation increased significantly from age 2 to 10 years, and the level of methylation was inversely correlated with sCD14 levels at 10 years. Conclusion: The reduced effect of CD14 polymorphisms on sCD14 levels from early to late childhood paralleled a small but significant increase in CD14 methylation during the same period. [Copyright &y& Elsevier]

The causal relationship between lower respiratory tract infections (LRIs) in early life and reduced lung function later in childhood is unsettled. Therefore, we assessed whether LRIs the first 2 yr of life influenced lung function development from birth to school age. In the prospective Oslo birth cohort, ‘the Environment and Childhood Asthma (ECA) study’ lung function was measured at birth in 802 infants by tidal flow volume loops and in 664 infants by passive respiratory mechanics and half yearly questionnaires, including LRI questions, were completed until 2 yr of age. The present study includes 607 children with information about LRIs the first 2 yr of life and successfully forced expiratory flow (FEF) volume measurements at the 10-yr follow-up assessment. At 10 yr of age, FEF at 50% of forced vital capacity (FEF50) (mean 95% confidence interval) was reduced in children with at least one bronchiolitis (85.0, 80.6–89.5, p = 0.020) or bronchitis (86.2, 82.6–89.8, p = 0.030) or ≥3 LRIs (83.4, 78.1–88.8, p = 0.017) when compared with no LRIs (90.6, 88.8–92.5) by 2 yr of life. The effects were significant in girls only when stratifying for gender. Among girls with later bronchiolitis compliance of the respiratory system (3.64, 3.17–4.10 vs. 4.18, 3.98–4.37, p = 0.031) and the ratio of time to peak tidal expiratory flow to total expiratory time ( tPTEF/ tE) measured at birth was significantly reduced (0. 26, 0.23–0.29 vs. 0.32, 0.30–0.33, p = 0.005) when compared with children with no LRIs. Change in lung function from birth (by tPTEF/ tE) to 10 yr of age was not significantly associated with LRIs the first 2 yr of life, and LRIs by 2 yr of life were not significantly associated with lung function at 10 yr of age in regression analyses including lung function at birth and other possible predictors of lung function at 10 yr. In our study, LRIs during the first 2 yr of life did not impair lung function development from birth until 10 yr of age. [ABSTRACT FROM AUTHOR]

Background: T cell–specific T-box transcription factor (T-bet) is a member of the T-box family of transcription factors regulating lineage commitment of TH lymphocytes toward a predominant TH1 phenotype. Asthma and allergy are common complex diseases characterized by TH2-mediated inflammation. Objective: We aimed to assess possible relationships between the T-bet gene (TBX21) and asthma and allergy in children. Method: Twelve single nucleotide polymorphisms (SNPs) in the TBX21 region were genotyped in 948 children from the Environment and Childhood Asthma study. Allele and haplotype frequencies were compared in children with and without asthma (by 10 years) and allergy (≥1 positive skin prick test response), as well as for the quantitative traits bronchial hyperresponsiveness determined by means of methacholine bronchial challenge testing, lung function determined by means of forced flow volume loops, fractional exhaled nitric oxide measurement, eosinophil count, and serum total IgE level. Results: Allergic asthma was significantly associated with 2 of the tested SNPs (rs11650354 and rs16947078) and further associated with the particular haplotype including these SNPs, with homozygote status resulting in an odds ratio of 8.3 (95% CI, 2.5-26.9) for allergic asthma. Neither nonallergic asthma or “allergy alone” nor the remaining quantitative variables were associated with TBX21 SNPs or haplotypes. Conclusion: An association between a specific TBX21 haplotype and allergic asthma in children is demonstrated for the first time and might explain previously detected associations between SNPs within TBX21 and asthma and bronchial hyperresponsiveness. [Copyright &y& Elsevier]

Background: Reduced lung function in early infancy has been associated with later obstructive airway diseases. We assessed whether reduced lung function shortly after birth predicts asthma 10 years later. Methods: We conducted a prospective birth cohort study of healthy infants in which we measured lung function shortly after birth with the use of tidal breathing flow-volume loops (the fraction of expiratory time to peak tidal expiratory flow to total expiratory time [tPTEF/tE]) in 802 infants and passive respiratory mechanics, including respiratory-system compliance, in 664 infants. At 10 years of age, 616 children (77%) were reassessed by measuring lung function, exercise-induced bronchoconstriction, and bronchial hyperresponsiveness (by means of a methacholine challenge) and by conducting a structured interview to determine whether there was a history of asthma or current asthma. Results: As compared with children whose tPTEF/tE shortly after birth was above the median, children whose tPTEF/tE was at or below the median were more likely at 10 years of age to have a history of asthma (24.3% vs. 16.2%, P=0.01), to have current asthma (14.6% vs. 7.5%, P=0.005), and to have severe bronchial hyperresponsiveness, defined as a methacholine dose of less than 1.0 μmol causing a 20% fall in the forced expiratory volume in 1 second (FEV1) (9.1% vs. 4.9%, P=0.05). As compared with children whose respiratory-system compliance was above the median, children with respiratory compliance at or below the median more often had a history of asthma (27.4% vs. 14.8%; P=0.001) and current asthma (15.0% vs. 7.7%, P=0.009), although this measure was not associated with later measurements of lung function. At 10 years of age, tPTEF/tE at birth correlated weakly with the maximal midexpiratory flow rate (r=0.10, P=0.01) but not with FEV1 or forced vital capacity. Conclusions: Reduced lung function at birth is associated with an increased risk of asthma by 10 years of age. N Engl J Med 2006;355:1682-9. [ABSTRACT FROM AUTHOR]