Association of Metabolites, Nutrients, and Toxins in Maternal and Cord Serum with Asthma, IgE, SPT, FeNO, and Lung Function in Offspring.

The role of metabolites, nutrients, and toxins (MNTs) in sera at the end of pregnancy and of their association with offspring respiratory and allergic disorders is underexplored. Untargeted approaches detecting a variety of compounds, known and unknown, are limited. In this cohort study, we first aimed at discovering associations of MNTs in grandmaternal (F0) serum with asthma, immunoglobulin E, skin prick tests, exhaled nitric oxide, and lung function parameters in their parental (F1) offspring. Second, for replication, we tested the identified associations of MNTs with disorders in their grandchildren (F2-offspring) based on F2 cord serum. The statistical analyses were sex-stratified. Using liquid chromatography/high-resolution mass spectrometry in F0, we detected signals for 2286 negative-ion lipids, 59 positive-ion lipids, and 6331 polar MNTs. Nine MNTs (one unknown MNT) discovered in F0-F1 and replicated in F2 showed higher risks of respiratory/allergic outcomes. Twelve MNTs (four unknowns) constituted a potential protection in F1 and F2. We recognized MNTs not yet considered candidates for respiratory/allergic outcomes: a phthalate plasticizer, an antihistamine, a bile acid metabolite, tryptophan metabolites, a hemiterpenoid glycoside, triacylglycerols, hypoxanthine, and polyphenol syringic acid. The findings suggest that MNTs are aspirants for clinical trials to prevent adverse respiratory/allergic outcomes.

A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing.

Background: Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of 'doctor-diagnosed asthma', thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes. Methods: We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9568 individuals from five UK birth cohorts. Results: Forty-four independent SNPs were associated with early-onset persistent, 25 with pre-school remitting, 33 with mid-childhood remitting, and 32 with late-onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 [ANXA1], p<6.7 × 10-9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction in ANXA1 expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1-/- deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge. Conclusions: Targeting this pathway in persistent disease may represent an exciting therapeutic prospect. Funding: UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust Strategic Award (108818/15/Z) provided most of the funding for this study.

Three-quarters of children hospitalized for wheezing or asthma symptoms are preschool-aged. Some will continue to experience breathing difficulties through childhood and adulthood. Others will undergo a complete resolution of their symptoms by the time they reach elementary school. The varied trajectories of young children with wheezing suggest that it is not a single disease. There are likely different genetic or environmental causes. Despite these differences, wheezing treatments for young children are 'one size fits all.' Studying the genetic underpinnings of wheezing may lead to more customized treatment options. Granell et al. studied the genetic architecture of different patterns of wheezing from infancy to adolescence. To do so, they used machine learning technology to analyze the genomes of 9,568 individuals, who participated in five studies in the United Kingdom from birth to age 18. The experiments found a new genetic variation in the ANXA1 gene linked with persistent wheezing starting in early childhood. By comparing mice with and without this gene, Granell et al. showed that the protein encoded by ANXA1 controls inflammation in the lungs in response to allergens. Animals lacking the protein develop worse lung inflammation after exposure to dust mite allergens. Identifying a new gene linked to a specific subtype of wheezing might help scientists develop better strategies to diagnose, treat, and prevent asthma. More studies are needed on the role of the protein encoded by ANXA1 in reducing allergen-triggered lung inflammation to determine if this protein or therapies that boost its production may offer relief for chronic lung inflammation.

Infant wheezing and prenatal antibiotic exposure and mode of delivery: a prospective birth cohort study.

Introduction: Assessments on whether prenatal antibiotic exposure and mode of delivery increase the risk of wheezing in infants and toddlers are inconsistent. Our goal is to evaluate the association between prenatal antibiotic use and Cesarean section with three subtypes of wheezing in infancy.Methods: An ongoing prospective three generations cohort study provides data on prenatal antibiotic use and mode of delivery. Respective questionnaire data was used to distinguish three subtypes of wheezing: any wheezing, infectious wheezing, and noninfectious wheezing. Repeated measurements of wheezing at 3, 6, and 12 months were analyzed using generalized estimation equations. Latent transition analysis assessed patterns of infant wheezing development in the first year of life.Results: The prevalence of any wheezing was highest at 12 months (40.1%). The prevalence of infectious wheezing was higher (3 months 23.8%, 6 months 33.5%, 12 months 38.5%) than of noninfectious wheezing (3 months 13.0%, 6 months 14.0%, 12 months 11.1%). About 11-13% of children had both infectious and noninfectious wheezing at 3, 6, and 12 months (3 months 10.7%, 6 months 13.9%, 12 months 13.1%). Children born via Cesarean section have approximately a 70-80% increase in the risk of any wheezing (RR = 1.83, 95% CI 1.29-2.60) and of infectious wheezing (RR = 1.72, 95% CI 1.18-2.50).Conclusions: Analyses of infectious and noninfectious wheezing subtypes suggests that children born by Cesarean sections may be more susceptible to infectious wheezing, warranting investigations into microbial factors of infectious wheezing. No significant associations were found between prenatal antibiotic exposure and wheezing types.

Oral contraceptives modify the effect of GATA3 polymorphisms on the risk of asthma at the age of 18 years via DNA methylation.

BACKGROUND: The prevalence of asthma in girls increases after puberty. Previous studies have detected associations between sex hormones and asthma, as well as between sex hormones and T helper 2 (Th2) asthma-typical immune responses. Therefore, we hypothesized that exogenous or endogenous sex hormone exposure (represented by oral contraceptive pill (OCP) use and early menarche, respectively) are associated with DNA methylation (DNA-M) of the Th2 transcription factor gene, GATA3, in turn affecting the risk of asthma in girls, possibly in interaction with genetic variants. Blood samples were collected from 245 female participants aged 18 years randomly selected for methylation analysis from the Isle of Wight birth cohort, UK. Information on use of OCPs, age at menarche, and concurrent asthma were assessed by questionnaire. Genome-wide DNA-M was determined using the Illumina Infinium HumanMethylation450 beadchip. In a first stage, we tested the interaction between sex hormone exposure and genetic variants on DNA-M of specific cytosine-phosphate-guanine (CpG) sites. In a second stage, we determined whether these CpG sites interact with genetic variants in GATA3 to explain the risk of asthma. RESULTS: Interactions between OCP use and seven single nucleotide polymorphisms (SNPs) of GATA3 were analyzed for 14 CpG sites (stage 1). The interaction between OCP use and SNP rs1269486 was found to be associated with the methylation level of cg17124583 (P = 0.002, false discovery rate (FDR) adjusted P = 0.04). DNA-M of this same CpG site was also influenced by the interaction between age at menarche and rs1269486 (P = 0.0017). In stage 2, we found that cg17124583 modified the association of SNP rs422628 with asthma risk at the age of 18 years (P = 0.006, FDR adjusted P = 0.04). Subjects with genotype AG showed an increase in average risk ratio (RR) from 0.31 (95% CI: 0.10 to 0.8) to 11.65 (95% CI: 1.71 to 79.5) when methylation level increased from 0.02 to 0.12, relative to genotype AA. CONCLUSION: A two-stage model consisting of genetic variants in the GATA3 gene, OCP use, age at menarche, and DNA-M may explain how sex hormones in women can increase the asthma prevalence after puberty.

The role of the airway epithelium and its interaction with environmental factors in asthma pathogenesis.

Asthma is an inflammatory disorder of the airways dominated by a Th2-type pattern. Because of this, most research has focused on investigating the role of allergic pathways with the hope of discovering novel therapeutic targets. Unfortunately, this strategy (which has been extended to animal models) has failed to identify any therapeutic modalities other than anti-IgE and leukotriene modifiers directed to targets known about for many years. It seems that the problem lies in placing allergy at the center of disease pathogenesis, when in practice other environmental factors may be equally if not more important in the induction and then progression of asthma. An alternative view is that asthma is primarily a defect of epithelial barrier function that, as in atopic dermatitis, allows greater access of environmental allergens, microorganisms, and toxicants to the airway tissue. Evidence is provided to show that both the physical and functional barrier of the airway epithelium is defective in asthma with disrupted tight junctions, reduced antioxidant activity, and impaired innate immunity. This explains the remarkable susceptibility of asthmatic airways to respiratory viruses and the impact of air pollutants on asthma exacerbations. It also provides a mechanism for programming of dendritic cells to drive a Th2 response in the origins of asthma. Viewing asthma primarily as an epithelial disease with adoption of a chronic wound scenario also provides a route to airway wall remodeling and the varying asthma phenotypes over the life course.

A new look at the pathogenesis of asthma.

Asthma is an inflammatory disorder of the conducting airways that has strong association with allergic sensitization. The disease is characterized by a polarized Th-2 (T-helper-2)-type T-cell response, but in general targeting this component of the disease with selective therapies has been disappointing and most therapy still relies on bronchodilators and corticosteroids rather than treating underlying disease mechanisms. With the disappointing outcomes of targeting individual Th-2 cytokines or manipulating T-cells, the time has come to re-evaluate the direction of research in this disease. A case is made that asthma has its origins in the airways themselves involving defective structural and functional behaviour of the epithelium in relation to environmental insults. Specifically, a defect in barrier function and an impaired innate immune response to viral infection may provide the substrate upon which allergic sensitization takes place. Once sensitized, the repeated allergen exposure will lead to disease persistence. These mechanisms could also be used to explain airway wall remodelling and the susceptibility of the asthmatic lung to exacerbations provoked by respiratory viruses, air pollution episodes and exposure to biologically active allergens. Variable activation of this epithelial-mesenchymal trophic unit could also lead to the emergence of different asthma phenotypes and a more targeted approach to the treatment of these. It also raises the possibility of developing treatments that increase the lung's resistance to the inhaled environment rather than concentrating all efforts on trying to suppress inflammation once it has become established.