Early Life Predictors of Allergic Disease

BACKGROUND: The prevalence of childhood asthma has been increasing worldwide. Modern societal exposures that have been implicated as possible causes of this increase include more hygienic lifestyles, antibiotic usage, and vitamin D deficiency. While there is much evidence that the origins of allergic disease begin in infancy, the uncertainty of asthma diagnosis in the first few years of life makes it difficult to assess the impact of early environmental exposures in very young children, and intermediate phenotypes that might assist in this assessment are lacking. An additional challenge to allergic disease research is the potential for gene-by-environment interactions, in which specific exposures differentially affect children depending on genotype. The objectives of this study were to assess relations of allergic disease outcomes (total IgE, specific IgE and asthma) with: 1) exposures related to modern lifestyle including day-care, antibiotic use and vitamin D levels; 2) cytokine profiles as a potential intermediate phenotypes; and 3) day-care exposure in the context of a relevant genotype.METHODS: This study utilizes data from a birth cohort. Allergic outcomes were assessed longitudinally through 5 years. Exposure data was collected by interview, or via blood samples in the case of vitamin D, cytokines, and genotype. Relations were assessed using longitudinal analysis techniques.RESULTS: Day-care was associated with decreased total and specific IgE through age 5. Antibiotics use was not associated with any outcome. Vitamin D levels showed 1) a U-shaped association with total and specific IgE, such that both high and low levels conveyed greater risk; and 2) no association with asthma. Cytokine profiles at 3 months of age, but not at birth, were predictive of total IgE and asthma. Finally, a significant gene-by-environment interaction was found between day-care and the TLR2/-16934 gene, such that the protective day-care relation occurred only for children carrying a T-allele.CONCLUSION: This study provides evidence that childhood allergic disease is inversely associated with day-care exposure and has a U-shaped relation with 25(OH)D levels at birth. It demonstrates that cytokine profiles as early as 3 months predict allergic outcomes through age 5 years, and finally, provides an example of a gene-by-environment interaction

Effect of day care attendance on sensitization and atopic wheezing differs by Toll-like receptor 2 genotype in 2 population-based birth cohort studies.

BACKGROUND: Variation in TLR2 gene (TLR2/−16934) is associated with allergic diseases amongst farmers' children, but not amongst children not living on farms. OBJECTIVE: To test the hypothesisis that the same genetic variant which confers protection in the farming environment is associated with reduced risk of developing allergic phenotypes amongst urban children attending day-care in early life. METHODS: In two population-based birth cohorts (Manchester, UK-MAAS and Tucson, USA-IIS) participants were recruited prenatally and followed prospectively (MAAS: 3, 5, 8 and 11 years; IIS: 1, 2, 3 and 5 years). We assessed allergic sensitization and atopic wheezing at each follow-up. RESULTS: 727 children participated in Manchester and 263 in Tucson. We found no significant associations between TLR2/−16934 and sensitization and atopic wheeze in either cohort. However different pattern emerged when we explored the interaction between TLR2/−16934 and day-care attendance on these outcomes. We found a significant interaction between day-care and TLR2/-16934 on the development of sensitization in the longitudinal model in MAAS, in that children carrying T allele who attended day-care were less likely to be sensitized than those who did not attend day-care, whilst amongst AA homozygotes the association tended to be in the opposite direction. In a longitudinal model in IIS, we found a significant interaction between day-care attendance and TLR2/-16934 on the development atopic wheezing. Significant interactions between TLR2/-16934 and day-care were maintained when adjusting for socioeconomic status CONCLUSIONS: The effect of day-care on sensitization and atopic wheezing may differ among children with different variants of theTLR2 gene

Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers

The timing and mechanisms of asthma inception remain imprecisely defined. Although epigenetic mechanisms likely contribute to asthma pathogenesis, little is known about their role in asthma inception. Objective: We sought to assess whether the trajectory to asthma begins already at birth and whether epigenetic mechanisms, specifically DNA methylation, contribute to asthma inception. Methods: We used the Methylated CpG Island Recovery Assay chip to survey DNA methylation in cord blood mononuclear cells from 36 children (18 nonasthmatic and 18 asthmatic subjects by age 9 years) from the Infant Immune Study (IIS), an unselected birth cohort closely monitored for asthma for a decade. SMAD3 methylation in IIS (n = 60) and in 2 replication cohorts (the Manchester Asthma and Allergy Study [n = 30] and the Childhood Origins of Asthma Study [n = 28]) was analyzed by using bisulfite sequencing or Illumina 450K arrays. Cord blood mononuclear cell-derived IL-1b levels were measured by means of ELISA. Results: Neonatal immune cells harbored 589 differentially methylated regions that distinguished IIS children who did and did not have asthma by age 9 years. In all 3 cohorts methylation in SMAD3, the most connected node within the network of asthma-associated, differentially methylated regions, was selectively increased in asthmatic children of asthmatic mothers and was associated with childhood asthma risk. Moreover, SMAD3 methylation in IIS neonates with maternal asthma was strongly and positively associated with neonatal production of IL-1b, an innate inflammatory mediator. Conclusions: The trajectory to childhood asthma begins at birth and involves epigenetic modifications in immunoregulatory and proinflammatory pathways. Maternal asthma influences epigenetic mechanisms that contribute to the inception of this trajectory.BrightSpark Foundation McCusker Fellowship; National Institute for Health Research Respiratory and Allergy Clinical Research Facility at University Hospital of South Manchester NHS Foundation Trust; Asthma UK [301, 362, 01/012, 04/014]; BMA James Trust; Moulton Charitable Foundation; Medical Research Council (MRC) [G0601361]; North West Lung Centre Charity; [RC1HL100800]; [ES006694]; [R01AI042268]; [P01HL070831]12 month embargo; published online: 21 December 2016This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]