Environmental factors play an important role in the development and exacerbation of allergic rhinitis (AR) in childhood. Indoor air pollution, such as house dust mites and secondhand smoke, can significantly increase the onset of AR, while pet dander may affect the exacerbation of AR symptoms in children. Furthermore, traffic related air pollution and pollen are outdoor air pollutants that can affect immune competency and airway responsiveness, increasing the risk of AR in children. Climate change has increased AR in children, as growth patterns of allergenic species have changed, resulting in longer pollen seasons. More extreme and frequent weather events also contribute to the deterioration of indoor air quality due to climate change. Additionally, viruses provoke respiratory tract infections, worsening the symptoms of AR, while viral infections alter the immune system. Although viruses and pollution influence development and exacerbation of AR, a variety of treatment and prevention options are available for AR patients. The protective influence of vegetation (greenness) is heavily associated with air pollution mitigation, relieving AR exacerbations, while the use of air filters can reduce allergic triggers. Oral antihistamines and intranasal corticosteroids are common pharmacotherapy for AR symptoms. In this review, we discuss the environmental risk factors for AR and summarize treatment strategies for preventing and managing AR in children.

Inhaled corticosteroids (ICS) are the most effective controller medications for asthma, and variability in ICS response is associated with genetic variation. Despite ICS treatment, some patients with poor asthma control experience severe asthma exacerbations, defined as a hospitalization or emergency room visit. We hypothesized that some individuals may be at increased risk of asthma exacerbations, despite ICS use, due to genetic factors. A GWAS of 237,726 common, independent markers was conducted in 806 Caucasian asthmatic patients from two population‐based biobanks: BioVU, at Vanderbilt University Medical Center (VUMC) in Tennessee (369 patients), and Personalized Medicine Research Project (PMRP) at the Marshfield Clinic in Wisconsin (437 patients). Using a case–control study design, the association of each SNP locus with the outcome of asthma exacerbations (defined as asthma‐related emergency department visits or hospitalizations concurrent with oral corticosteroid use), was evaluated for each population by logistic regression analysis, adjusting for age, gender and the first four principal components. A meta‐analysis of the results was conducted. Validation of expression of selected candidate genes was determined by evaluating an independent microarray expression data set. Our study identified six novel SNPs associated with differential risk of asthma exacerbations (P < 10⁻⁰⁵). The top GWAS result, rs2395672 in CMTR1, was associated with an increased risk of exacerbations in both populations (OR = 1.07, 95% CI 1.03–1.11; joint P = 2.3 × 10⁻⁰⁶). Two SNPs (rs2395672 and rs279728) were associated with increased risk of exacerbations, while the remaining four SNPs (rs4271056, rs6467778, rs2691529, and rs9303988) were associated with decreased risk. Three SNPs (rs2395672, rs6467778, and rs2691529) were present in three genes: CMTR1, TRIM24 and MAGI2. The CMTR1 mRNA transcript was significantly differentially expressed in nasal lavage samples from asthmatics during acute exacerbations, suggesting potential involvement of this gene in the development of this phenotype. We show that genetic variability may contribute to asthma exacerbations in patients taking ICS. Furthermore, our studies implicate CMTR1 as a novel candidate gene with potential roles in the pathogenesis of asthma exacerbations.

Heterogeneous therapeutic responses to leukotriene modifiers (LTMs) are likely due to variation in patient genetics. Although prior candidate gene studies implicated multiple pharmacogenetic loci, to date, no genome-wide association study (GWAS) of LTM response was reported. In this study, DNA and phenotypic information from two placebo-controlled trials (total N=526) of zileuton response were interrogated. Using a gene–environment (G × E) GWAS model, we evaluated 12-week change in forced expiratory volume in 1 second (ΔFEV₁) following LTM treatment. The top 50 single-nucleotide polymorphism associations were replicated in an independent zileuton treatment cohort, and two additional cohorts of montelukast response. In a combined analysis (discovery+replication), rs12436663 in MRPP3 achieved genome-wide significance (P=6.28 × 10⁻⁰⁸); homozygous rs12436663 carriers showed a significant reduction in mean ΔFEV₁ following zileuton treatment. In addition, rs517020 in GLT1D1 was associated with worsening responses to both montelukast and zileuton (combined P=1.25 × 10⁻⁰⁷). These findings implicate previously unreported loci in determining therapeutic responsiveness to LTMs.

Genome-wide association study (GWAS) is a powerful tool to identify novel pharmacogenetic single nucleotide polymorphisms (SNPs). Leukotriene receptor antagonists (LTRAs) are a major class of asthma medications, and genetic factors contribute to variable responses to these drugs. We used GWAS to identify novel SNPs associated with the response to the LTRA, montelukast, in asthmatics. Using genome-wide genotype and phenotypic data available from American Lung Association - Asthma Clinical Research Center (ALA-ACRC) cohorts, we evaluated 8-week change in FEV₁ related to montelukast administration in a discovery population of 133 asthmatics. The top 200 SNPs from the discovery GWAS were then tested in 184 additional samples from two independent cohorts. Twenty-eight SNP associations from the discovery GWAS were replicated. Of these, rs6475448 achieved genome-wide significance (combined P = 1.97 x 10^-09), and subjects from all four studies who were homozygous for rs6475448 showed increased ΔFEV₁ from baseline in response to montelukast. Through GWAS, we identified a novel pharmacogenomic locus related to improved montelukast response in asthmatics.

Variable responsiveness to zileuton, a leukotriene antagonist used to treat asthma, may be due in part to genetic variation. While individual SNPs were previously associated with zileuton-related lung function changes, specific quantitative trait loci (QTLs) and biological pathways that may contribute have not been identified. In this study, we investigated the hypothesis that genetic variation within biological pathways is associated with zileuton response. We performed an integrative QTL mapping and pathway enrichment study to investigate data from a GWAS of zileuton response, in addition to mRNA expression profiles and leukotriene production data from lymphoblastoid cell lines (LCLs) (derived from asthmatics) that were treated with zileuton or ethanol (control). We identified 1060 QTLs jointly associated with zileuton-related differential LTB₄ production in LCLs and lung function change in patients taking zileuton, of which eight QTLs were also significantly associated with persistent LTB₄ production in LCLs following zileuton treatment (i.e., ‘poor’ responders). Four nominally significant trans-eQTLs were predicted to regulate three candidate genes (SELL, MTF2, and GAL), the expression of which was significantly reduced in LCLs following zileuton treatment. Gene and pathway enrichment analyses of QTL associations identified multiple genes and pathways, predominantly related to phosphatidyl inositol signaling via PI3K. We validated the PI3K pathway activation status in a subset of LCLs demonstrating variable zileuton-related LTB₄ production, and show that in contrast to LCLs that responded to zileuton, the PI3K pathway was activated in poor responder LCLs. Collectively, these findings demonstrate a role for the PIK3 pathway and its targets as important determinants of differential responsiveness to zileuton.