Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma.

BACKGROUND: Most genetic studies of asthma and allergy have focused on common variation in individuals primarily of European ancestry. Studying the role of rare variation in quantitative phenotypes and in asthma phenotypes in populations of diverse ancestries can provide additional, important insights into the development of these traits. OBJECTIVE: We sought to examine the contribution of rare variants to different asthma- or allergy-associated quantitative traits in children with diverse ancestries and explore their role in asthma phenotypes. METHODS: We examined whole-genome sequencing data from children participants in longitudinal studies of asthma (n = 1035; parent-identified as 67% Black and 25% Hispanic) to identify rare variants (minor allele frequency < 0.01). We assigned variants to genes and tested for associations using an omnibus variant-set test between each of 24,902 genes and 8 asthma-associated quantitative traits. On combining our results with external data on predicted gene expression in humans and mouse knockout studies, we identified 3 candidate genes. A burden of rare variants in each gene and in a combined 3-gene score was tested for its associations with clinical phenotypes of asthma. Finally, published single-cell gene expression data in lower airway mucosal cells after allergen challenge were used to assess transcriptional responses to allergen. RESULTS: Rare variants in USF1 were significantly associated with blood neutrophil count (P = 2.18 × 10-7); rare variants in TNFRSF21 with total IgE (P = 6.47 × 10-6) and PIK3R6 with eosinophil count (P = 4.10 × 10-5) reached suggestive significance. These 3 findings were supported by independent data from human and mouse studies. A burden of rare variants in TNFRSF21 and in a 3-gene score was associated with allergy-related phenotypes in cohorts of children with mild and severe asthma. Furthermore, TNFRSF21 was significantly upregulated in bronchial basal epithelial cells from adults with allergic asthma but not in adults with allergies (but not asthma) after allergen challenge. CONCLUSIONS: We report novel associations between rare variants in genes and allergic and inflammatory phenotypes in children with diverse ancestries, highlighting TNFRSF21 as contributing to the development of allergic asthma.

African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans.

BACKGROUND: Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry. METHODS: We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American-specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults. RESULTS: Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma. CONCLUSIONS: Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases.

Longitudinal Phenotypes of Respiratory Health in a High-Risk Urban Birth Cohort.

RATIONALE: Characterization of patterns of wheezing and allergic sensitization in early life may allow for identification of specific environmental exposures impacting asthma development. OBJECTIVES: To define respiratory phenotypes in inner-city children and their associations with early-life environmental exposures. METHODS: Data were collected prospectively from 442 children in the URECA (Urban Environment and Childhood Asthma) birth cohort through age 7 years, reflecting symptoms (wheezing), aeroallergen sensitization, pulmonary function, and body mass index. Latent class mixed models identified trajectories of wheezing, allergic sensitization, and pulmonary function. Cluster analysis defined nonoverlapping groups (termed phenotypes). Potential associations between phenotypes and early-life environmental exposures were examined. MEASUREMENTS AND MAIN RESULTS: Five phenotypes were identified and mainly differentiated by patterns of wheezing and allergic sensitization (low wheeze/low atopy; low wheeze/high atopy; transient wheeze/low atopy; high wheeze/low atopy; high wheeze/high atopy). Asthma was most often present in the high-wheeze phenotypes, with greatest respiratory morbidity among children with frequent wheezing and allergic sensitization. These phenotypes differentially related to early-life exposures, including maternal stress and depression, antenatal environmental tobacco smoke, house dust microbiome, and allergen content (all P < 0.05). Prenatal smoke exposure, maternal stress, and depression were highest in the high-wheeze/low-atopy phenotype. The high-wheeze/high-atopy phenotype was associated with low household microbial richness and diversity. Early-life aeroallergen exposure was low in high-wheeze phenotypes. CONCLUSIONS: Patterns of wheezing, allergic sensitization, and lung function identified five respiratory phenotypes among inner-city children. Early-life environmental exposure to stress, depression, tobacco smoke, and indoor allergens and microbes differentially associate with specific phenotypes.

Spirometry and Impulse Oscillometry in Preschool Children: Acceptability and Relationship to Maternal Smoking in Pregnancy.

BACKGROUND: Comparisons of the technical acceptability of spirometry and impulse oscillometry (IOS) and clinical correlations of the measurements have not been well studied in young children. There are no large studies focused on African American and Hispanic children. OBJECTIVES: We sought to (1) compare the acceptability of spirometry and IOS in 3- to 5-year-old children and (2) examine the relationship of maternal smoking during pregnancy to later lung function. METHODS: Spirometry and IOS were attempted at 4 sites from the Urban Environmental and Childhood Asthma Study birth cohort at ages 3, 4, and 5 years (472, 471, and 479 children, respectively). We measured forced expiratory flow in 0.5 s (forced expiratory volume in 0.5 seconds [FEV0.5]) with spirometry and area of reactance (AX), resistance and reactance at 5 Hz (R5 and X5, respectively) using IOS. RESULTS: Children were more likely to achieve acceptable maneuvers with spirometry than with IOS at age 3 (60% vs 46%, P < .001) and 5 years (89% vs 84%, P = .02). Performance was consistent among the 4 study sites. In children without recurrent wheeze, there were strong trends for higher FEV0.5 and lower R5 and AX over time. Maternal smoking during pregnancy was associated with higher AX at ages 4 and 5 years (P < .01 for both years). There was no significant difference in FEV0.5 between children with and without in utero exposure to smoking. CONCLUSION: There is a higher rate of acceptable maneuvers with spirometry compared with IOS, but IOS may be a better indicator of peripheral airway function in preschool children.

Early-life home environment and risk of asthma among inner-city children.

BACKGROUND: Environmental exposures in early life appear to play an important role in the pathogenesis of childhood asthma, but the potentially modifiable exposures that lead to asthma remain uncertain. OBJECTIVE: We sought to identify early-life environmental risk factors for childhood asthma in a birth cohort of high-risk inner-city children. METHODS: We examined the relationship of prenatal and early-life environmental factors to the occurrence of asthma at 7 years of age among 442 children. RESULTS: Higher house dust concentrations of cockroach, mouse, and cat allergens in the first 3 years of life were associated with lower risk of asthma (for cockroach allergen: odds ratio per interquartile range increase in concentration, 0.55; 95% CI, 0.36-0.86; P < .01). House dust microbiome analysis using 16S ribosomal RNA sequencing identified 202 and 171 bacterial taxa that were significantly (false discovery rate < 0.05) more or less abundant, respectively, in the homes of children with asthma. A majority of these bacteria were significantly correlated with 1 of more allergen concentrations. Other factors associated significantly positively with asthma included umbilical cord plasma cotinine concentration (odds ratio per geometric SD increase in concentration, 1.76; 95% CI, 1.00-3.09; P = .048) and maternal stress and depression scores. CONCLUSION: Among high-risk inner-city children, higher indoor levels of pet or pest allergens in infancy were associated with lower risk of asthma. The abundance of a number of bacterial taxa in house dust was associated with increased or decreased asthma risk. Prenatal tobacco smoke exposure and higher maternal stress and depression scores in early life were associated with increased asthma risk.

Pathways through which asthma risk factors contribute to asthma severity in inner-city children.

BACKGROUND: Pathway analyses can be used to determine how host and environmental factors contribute to asthma severity. OBJECTIVE: To investigate pathways explaining asthma severity in inner-city children. METHODS: On the basis of medical evidence in the published literature, we developed a conceptual model to describe how 8 risk-factor domains (allergen sensitization, allergic inflammation, pulmonary physiology, stress, obesity, vitamin D, environmental tobacco smoke [ETS] exposure, and rhinitis severity) are linked to asthma severity. To estimate the relative magnitude and significance of hypothesized relationships among these domains and asthma severity, we applied a causal network analysis to test our model in an Inner-City Asthma Consortium study. Participants comprised 6- to 17-year-old children (n = 561) with asthma and rhinitis from 9 US inner cities who were evaluated every 2 months for 1 year. Asthma severity was measured by a longitudinal composite assessment of day and night symptoms, exacerbations, and controller usage. RESULTS: Our conceptual model explained 53.4% of the variance in asthma severity. An allergy pathway (linking allergen sensitization, allergic inflammation, pulmonary physiology, and rhinitis severity domains to asthma severity) and the ETS exposure pathway (linking ETS exposure and pulmonary physiology domains to asthma severity) exerted significant effects on asthma severity. Among the domains, pulmonary physiology and rhinitis severity had the largest significant standardized total effects on asthma severity (-0.51 and 0.48, respectively), followed by ETS exposure (0.30) and allergic inflammation (0.22). Although vitamin D had modest but significant indirect effects on asthma severity, its total effect was insignificant (0.01). CONCLUSIONS: The standardized effect sizes generated by a causal network analysis quantify the relative contributions of different domains and can be used to prioritize interventions to address asthma severity.

Influence of early-life exposures on food sensitization and food allergy in an inner-city birth cohort.

OBJECTIVE: Previous data suggest that food allergy (FA) might be more common in inner-city children; however, these studies have not collected data on both sensitization and clinical reactivity or early-life exposures. METHODS: Children in the Urban Environment and Childhood Asthma birth cohort were followed through age 5 years. Household exposures, diet, clinical history, and physical examinations were assessed yearly; levels of specific IgE to milk, egg, and peanut were measured at 1, 2, 3, and 5 years of age. On the basis of sensitization (IgE ≥0.35 kU/L) and clinical history over the 5-year period, children were classified as having FA or being possibly allergic, sensitized but tolerant, or not allergic/not sensitized. RESULTS: Five hundred sixteen children were included. Overall, 55.4% were sensitized (milk, 46.7%; egg, 31.0%; and peanut, 20.9%), whereas 9.9% were categorized as having FA (peanut, 6.0%; egg, 4.3%; and milk, 2.7%; 2.5% to >1 food). The remaining children were categorized as possibly allergic (17.0%), sensitized but tolerant (28.5%), and not sensitized (44.6%). Eighteen (3.5%) reported reactions to foods for which IgE levels were not measured. Food-specific IgE levels were similar in children with FA versus sensitized but tolerant children, except for egg, levels of which were higher in patients with FA at ages 1 and 2 years. FA was associated with recurrent wheeze, eczema, aeroallergen sensitization, male sex, breast-feeding, and lower endotoxin exposure in year 1 but not with race/ethnicity, income, tobacco exposure, maternal stress, or early introduction of solid foods. CONCLUSIONS: Even given that this was designed to be a high-risk cohort, the cumulative incidence of FA is extremely high, especially considering the strict definition of FA that was applied and that only 3 common allergens were included.

Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children.

BACKGROUND: Research has underscored the effects of exposure and sensitization to allergens on the severity of asthma in inner-city children. It has also revealed the limitations of environmental remediation and guidelines-based therapy in achieving greater disease control. METHODS: We enrolled inner-city children, adolescents, and young adults with persistent asthma in a randomized, double-blind, placebo-controlled, parallel-group trial at multiple centers to assess the effectiveness of omalizumab, as compared with placebo, when added to guidelines-based therapy. The trial was conducted for 60 weeks, and the primary outcome was symptoms of asthma. RESULTS: Among 419 participants who underwent randomization (at which point 73% had moderate or severe disease), omalizumab as compared with placebo significantly reduced the number of days with asthma symptoms, from 1.96 to 1.48 days per 2-week interval, a 24.5% decrease (P<0.001). Similarly, omalizumab significantly reduced the proportion of participants who had one or more exacerbations from 48.8 to 30.3% (P<0.001). Improvements occurred with omalizumab despite reductions in the use of inhaled glucocorticoids and long-acting beta-agonists. CONCLUSIONS: When added to a regimen of guidelines-based therapy for inner-city children, adolescents, and young adults, omalizumab further improved asthma control, nearly eliminated seasonal peaks in exacerbations, and reduced the need for other medications to control asthma. (Funded by the National Institute of Allergy and Infectious Diseases and Novartis; ClinicalTrials.gov number, NCT00377572.).

Mediator release assay for assessment of biological potency of German cockroach allergen extracts.

BACKGROUND: Cockroach is an important allergen in inner-city asthma. The diagnosis and treatment of cockroach allergy has been impeded by the lack of standardized cockroach extracts. OBJECTIVE: We investigated the utility of a mediator release assay based on rat basophil leukemia (RBL) cells for comparing the potency of German cockroach extracts. METHODS: RBL cells (line 2H3) transfected with human FcepsilonRI were passively sensitized with sera from subjects with cockroach allergy and stimulated with serial dilutions of 3 commercial cockroach extracts (1:10 weight/volume). In addition, the in-house prepared extract was tested in separate experiments with pooled sera that produced optimal performance in the RBL assay. N-hexosaminidase release (NHR) was used as a marker of RBL cell degranulation and was examined in relation to the intradermal skin test (ID(50)EAL) and serum cockroach-specific and total IgE levels. RESULTS: The median cockroach-specific IgE concentration in 60 subjects was 0.72 kU(A)/L (interquartile range, 0.35-2.97 kU(A)/L); 19 sera (responders) produced a minimum 10% NHR to more than 1 extract. Responders had higher median cockroach-specific IgE (7.4 vs 1.0 kU(A)/L) and total IgE (429 vs 300 kU/L) levels than nonresponders. Ranking of extract potency was consistent between the mediator release assay and the ID(50)EAL. For the in-house prepared cockroach extract, the dose-response curves were shifted according to the concentration of the extract. NHR was reproducible between different experiments by using pooled sera. CONCLUSION: The mediator release assay measures biologic potency and correlates with the ID(50)EAL. It should be further evaluated to determine whether it could be used to replace intradermal skin test titration for assessing the potency of cockroach extract.

Health effects of indoor nitrogen dioxide and passive smoking on urban asthmatic children.

BACKGROUND: Nitrogen dioxide (NO(2)) and environmental tobacco smoke (ETS) have been associated with adverse respiratory effects. OBJECTIVE: We sought to assess the effect of NO(2) and ETS on asthma morbidity among children in inner-city environments. METHODS: Asthmatic children between the ages of 4 and 9 years had exposure to NO(2) and ETS measured by using Palmes tubes in the home and urinary cotinine. A baseline interview and telephone assessments at 3, 6, and 9 months evaluated health service use, asthma symptoms, and peak flow rates. RESULTS: Gas stoves were present in 87.8% of 469 homes. The median level of indoor NO(2) was 29.8 ppb compared with the US national outdoor median of 18 ppb. Of 1444 children, 48% had urinary cotinine/creatinine ratios of greater than 30 ng/mg. The median level of the cotinine/creatinine ratio was 42.4 ng/mg in smoking homes compared with 18.0 ng/mg in nonsmoking homes. The relative risk for asthma symptoms with increased NO(2) exposure was 1.75 (95% CI, 1.10-2.78) in children who did not have positive skin test responses. Higher NO(2) exposure resulted in lower peak flows during colder months (relative risk, 1.46; 95% CI, 1.07-1.97). Higher ETS exposure in colder months was weakly associated with lower peak flows (relative risk, 1.21; 95% CI, 0.99-1.47). There was no effect of ETS exposure on symptoms or use of health care services. CONCLUSION: Higher levels of indoor NO(2) are associated with increased asthma symptoms in nonatopic children and decreased peak flows. CLINICAL IMPLICATIONS: Interventions to reduce NO(2) exposure, such as venting of gas stoves, might help reduce asthma morbidity.

Asthma and panic in young adults: a 20-year prospective community study.

RATIONALE: Psychologic factors are increasingly recognized to influence the onset and course of asthma. Previous cross-sectional community-based studies have provided evidence for a relatively specific association between asthma and panic. OBJECTIVES: To examine concurrent and longitudinal associations between asthma and panic in young adults. MEASUREMENTS AND MAIN RESULTS: Prospective community-based cohort study of young adults (n = 591) followed between ages 19 and 40. Information was derived from six subsequent semistructured diagnostic interviews conducted by professionals. Cross-sectionally (over the whole study period), asthma was more strongly associated with panic disorder (odds ratio [OR] = 4.0; 95% confidence interval [CI], 1.7, 9.3) than with any panic, which included panic disorder and panic attacks (OR = 2.1; 95% CI, 1.1, 4.5). Longitudinally, after adjusting for potentially confounding variables, active asthma predicted subsequent panic disorder (OR = 4.5; 95% CI, 1.1, 20.1), and the presence of panic disorder predicted subsequent asthma activity (OR = 6.3; 95% CI, 2.8, 14.0). Asthma predicted any panic (OR = 2.7; 95% CI, 1.1, 7.1), whereas any panic did not predict subsequent asthma activity. Associations were stronger in smokers than in nonsmokers, and stronger in women than in men. Smoking, early-childhood anxiety, and a family history of allergy were important confounders of the asthma-panic association. CONCLUSIONS: This is the first long-term follow-up study on asthma and panic. It showed dose-response-type relationships between panic and asthma, and bidirectional longitudinal associations between the two conditions. It provided evidence for familial factors and smoking as possible shared etiologic explanations.

Understanding the seasonal pattern of childhood asthma: results from the National Cooperative Inner-City Asthma Study (NCICAS).

OBJECTIVE: To contrast the seasonal patterns of asthma symptoms and utilization and determine the impact of allergen sensitivity, environmental tobacco smoke (ETS) exposure, and air pollution on the seasonal patterns of asthma. STUDY DESIGN: Participants in the National Cooperative Inner-City Asthma Study (NCICAS) were tracked for approximately 4 years after allergen skin testing and determination of exposure to ETS. Air pollution data were obtained from EPA monitoring sites in NCICAS cities. RESULTS: Asthma symptoms (wheeze) and health care utilization (unscheduled visits and hospitalization) had similar seasonal patterns, with low points during the summer months of June through August and a distinct autumn peak beginning in September. Seasonal patterns were similar among children with no allergen skin test reactivity, those reactive only to indoor allergens, and those reactive to outdoor allergens. ETS exposure, whether defined by self-report or urinary cotinine/creatinine ratio, was not related to the observed seasonal patterns. Among the pollutants evaluated, only the seasonal pattern of SO(2) coincided with that of asthma morbidity. CONCLUSIONS: Atopy, ETS, and most air pollutants do not appear to contribute to the distinct asthma seasonal pattern. On a population level, changes in symptoms are mirrored by changes in utilization.

Nurse staffing and postsurgical adverse events: an analysis of administrative data from a sample of U.S. hospitals, 1990-1996.

OBJECTIVE: To examine the impact of nurse staffing on selected adverse events hypothesized to be sensitive to nursing care between 1990 and 1996, after controlling for hospital characteristics. DATA SOURCES/STUDY SETTING: The yearly cross-sectional samples of hospital discharges for states participating in the National Inpatient Sample (NIS) from 1990-1996 were combined to form the analytic sample. Six states were included for 1990-1992, four states were added for the period 1993-1994, and three additional states were added in 1995-1996. STUDY DESIGN: The study design was cross-sectional descriptive. DATA COLLECTION/EXTRACTION METHODS: Data for patients aged 18 years and older who were discharged between 1990 and 1996 were used to create hospital-level adverse event indicators. Hospital-level adverse event data were defined by quality indicators developed by the Health Care Utilization Project (HCUP). These data were matched to American Hospital Association (AHA) data on community hospital characteristics, including registered nurse (RN) and licensed practical/vocational nurse (LPN) staffing hours, to examine the relationship between nurse staffing and four postsurgical adverse events: venous thrombosis/pulmonary embolism, pulmonary compromise after surgery, urinary tract infection, and pneumonia. Multivariate modeling using Poisson regression techniques was used. PRINCIPAL FINDINGS: An inverse relationship was found between RN hours per adjusted inpatient day and pneumonia (p < .05) for routine and emergency patient admissions. CONCLUSIONS: The inverse relationship between pneumonia and nurse staffing are consistent with previous findings in the literature. The results provide additional evidence for health policy makers to consider when making decisions about required staffing levels to minimize adverse events.