Multi-ancestry genome-wide association study of asthma exacerbations.

BACKGROUND: Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. METHODS: A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10-5 ) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. RESULTS: One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele ) = 0.82, p = 9.05 × 10-6 and replication: ORT allele  = 0.89, p = 5.35 × 10-3 ) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele  = 0.85, p = 3.10 × 10-5 and replication: ORC allele  = 0.89, p = 1.30 × 10-2 ). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. CONCLUSIONS: This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.

A genome-wide association study of asthma hospitalizations in adults.

BACKGROUND: Little is known about the genetic determinants of severe asthma exacerbations. OBJECTIVES: We aimed to identify genetic variants associated with asthma hospitalizations. METHODS: We conducted a genome-wide association study of asthma hospitalizations in 34,167 white British adults with asthma, 1,658 of whom had at least 1 asthma-related hospitalization. This analysis was conducted by using logistic regression under an additive genetic model with adjustment for age, sex, body mass index, smoking status, and the first 5 principal components derived from genotypic data. We then analyzed data from 2 cohorts of Latino children and adolescents for replication and conducted quantitative trait locus and functional annotation analyses. RESULTS: At the chromosome 6p21.3 locus, the single-nucleotide polymorphism (SNP) rs56151658 (8 kb from the promoter of HLA-DQB1) was most significantly associated with asthma hospitalizations (for test allele A, odds ratio = 1.36 [95% CI = 1.22-1.52]; P = 3.11 × 10-8); 21 additional SNPs in this locus were associated with asthma hospitalizations at a P value less than 1 × 10-6. In the replication cohorts, multiple SNPs in strong linkage disequilibrium with rs56151658 were associated with severe asthma exacerbations at a P value of .01 or less in the same direction of association as in the discovery cohort. Three HLA genes (HLA-DQA2, HLA-DRB6, and HLA-DOB) were also shown to mediate the estimated effects of the SNPs associated with asthma hospitalizations through effects on gene expression in lung tissue. CONCLUSIONS: We identified strong candidate genes for asthma hospitalizations in adults in the region for class II HLA genes through genomic, quantitative trait locus, and summary data-based mendelian randomization analyses.

A genome-wide association study of severe asthma exacerbations in Latino children and adolescents.

Severe asthma exacerbations are a major cause of school absences and healthcare costs in children, particularly those in high-risk racial/ethnic groups.To identify susceptibility genes for severe asthma exacerbations in Latino children and adolescents, we conducted a meta-analysis of genome-wide association studies (GWAS) in 4010 Latino youth with asthma in four independent cohorts, including 1693 Puerto Ricans, 1019 Costa Ricans, 640 Mexicans, 256 Brazilians and 402 members of other Latino subgroups. We then conducted methylation quantitative trait locus, expression quantitative trait locus and expression quantitative trait methylation analyses to assess whether the top single nucleotide polymorphism (SNP) in the meta-analysis is linked to DNA methylation and gene expression in nasal (airway) epithelium in separate cohorts of Puerto Rican and Dutch children and adolescents.In the meta-analysis of GWAS, an SNP in FLJ22447 (rs2253681) was significantly associated with 1.55 increased odds of severe asthma exacerbation (95% CI 1.34-1.79, p=6.3×10-9). This SNP was significantly associated with DNA methylation of a CpG site (cg25024579) at the FLJ22447 locus, which was in turn associated with increased expression of KCNJ2-AS1 in nasal airway epithelium from Puerto Rican children and adolescents (ß=0.10, p=2.18×10-7).SNP rs2253681 was significantly associated with both DNA methylation of a cis-CpG in FLJ22447 and severe asthma exacerbations in Latino youth. This may be partly explained by changes in airway epithelial expression of a gene recently implicated in atopic asthma in Puerto Rican children and adolescents (KCNJ2-AS1).

2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group.

The 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group was coordinated and supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. It is designed to improve patient care and support informed decision making about asthma management in the clinical setting. This update addresses six priority topic areas as determined by the state of the science at the time of a needs assessment, and input from multiple stakeholders:A rigorous process was undertaken to develop these evidence-based guidelines. The Agency for Healthcare Research and Quality's (AHRQ) Evidence-Based Practice Centers conducted systematic reviews on these topics, which were used by the Expert Panel Working Group as a basis for developing recommendations and guidance. The Expert Panel used GRADE (Grading of Recommendations, Assessment, Development and Evaluation), an internationally accepted framework, in consultation with an experienced methodology team for determining the certainty of evidence and the direction and strength of recommendations based on the evidence. Practical implementation guidance for each recommendation incorporates findings from NHLBI-led patient, caregiver, and clinician focus groups. To assist clincians in implementing these recommendations into patient care, the new recommendations have been integrated into the existing Expert Panel Report-3 (EPR-3) asthma management step diagram format.

Correction: Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritization.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritisation.

A systematic review of pharmacogenomic studies capturing adverse drug reactions (ADRs) related to asthma medications was undertaken, and a survey of Pharmacogenomics in Childhood Asthma (PiCA) consortia members was conducted. Studies were eligible if genetic polymorphisms were compared with suspected ADR(s) in a patient with asthma, as either a primary or secondary outcome. Five studies met the inclusion criteria. The ADRs and polymorphisms identified were change in lung function tests (rs1042713), adrenal suppression (rs591118), and decreased bone mineral density (rs6461639) and accretion (rs9896933, rs2074439). Two of these polymorphisms were replicated within the paper, but none had external replication. Priorities from PiCA consortia members (representing 15 institution in eight countries) for future studies were tachycardia (SABA/LABA), adrenal suppression/crisis and growth suppression (corticosteroids), sleep/behaviour disturbances (leukotriene receptor antagonists), and nausea and vomiting (theophylline). Future pharmacogenomic studies in asthma should collect relevant ADR data as well as markers of efficacy.

Asthma management in school: parents' and school personnel perspectives.

Objective: Effective asthma management at school can help students with asthma stay healthy, learn better and participate fully during their school day. This study sought to understand school-based asthma care from the perspective of parents and school personnel to improve asthma care at school. Methods: A cross-sectional study was conducted in Hartford, CT. School personnel from 59 schools and 322 parents/guardians were invited to participate. Four cross-sectional surveys using Likert-type scales assessed parental and school personnel satisfaction, confidence in managing asthma, policy awareness, management of asthma during physical activity, and perceived gaps surrounding school-based asthma care. Results: 263/322 (82%) eligible parents of children with asthma (mean age 8.5 ± 4.3, 56% Hispanic, 30% African American) completed surveys. Thirty six school nurses (62%), 131 teachers (8%), 14 coaches (14%), and 17 school principals (29%) participated. 90% of parents were satisfied with asthma management in school. School nurses were more aware of asthma policies than teachers (74% vs. 24%, p < 0.001). 34% of school nurses, 30% of teachers and 36% of coaches were unaware of asthma-related absences. 14% of physical education teachers/coaches reported no asthma training. Conclusion: In this convenience sample of parents and school personnel, parents reported overall satisfaction regarding the asthma care their children receive at school, yet a number of gaps pertaining to school-based asthma care were identified. Increased asthma training and enhanced communication among school personnel is needed to address these gaps. National guidelines and resources are readily available to improve asthma care at school.

Primary care clinician adherence with asthma guidelines: the National Asthma Survey of Physicians.

Background and objectives: Although primary care clinicians provide >60% of U.S. asthma care, no nationally representative study has examined variation in adherence among primary care groups to four cornerstone domains of the Expert Panel Report-3 asthma guidelines: assessment/monitoring, patient education, environmental assessment, and medications. We used the 2012 National Asthma Survey of Physicians: National Ambulatory Medical Care Survey to compare adherence by family/general medicine practitioners (FM/GM), internists, pediatricians and Community Health Center mid-level clinicians (CHC). Methods: Adherence was self-reported (n = 1355 clinicians). Adjusted odds of almost always adhering to each recommendation (≥75% of the time) were estimated controlling for clinician/practice characteristics, and agreement and self-efficacy with guideline recommendations. Results: A higher percentage of pediatricians adhered to most assessment/monitoring recommendations compared to FM/GM and other groups (e.g. 71.6% [SE 4.0] almost always assessed daytime symptoms versus 50.6% [SE 5.1]-51.1% [SE 5.8], t-test p < 0.05) but low percentages from all groups almost always performed spirometry (6.8% [SE 2.0]-16.8% [SE 4.7]). Pediatricians were more likely to provide asthma action/treatment plans than FM/GM and internists. Internists were more likely to assess school/work triggers than pediatricians and CHC (environmental assessment). All groups prescribed inhaled corticosteroids for daily control (84.0% [SE 3.7]-90.7% [SE 2.5]) (medications). In adjusted analyses, pediatric specialty, high self-efficacy and frequent specialist referral were associated with high adherence. Conclusions: Pediatricians were more likely to report high adherence than other clinicians. Self- efficacy and frequent referral were also associated with adherence. Adherence was higher for history-taking recommendations and lower for recommendations involving patient education, equipment and expertise.

Building Bridges for Asthma Care: Reducing school absence for inner-city children with health disparities.

BACKGROUND: Children with asthma are at increased risk for experiencing health and educational disparities because of increased school absence. School nurses are well positioned to support asthma management and improve school attendance. OBJECTIVE: We sought to implement and assess the effect of the Building Bridges for Asthma Care Program on improving school attendance and measures of asthma control. METHODS: Children with asthma (age, 5-14 years) in the Denver Public School System (n = 240) and the Hartford Public School System (n = 223) were enrolled in the Building Bridges Program during the 2013-2014 and 2014-2015 school years and followed until the end of the second school year. The primary outcome was school absence, with secondary outcomes, including asthma control, measured based on Childhood Asthma Control Test or the Asthma Control Test scores and rescue inhaler use. RESULTS: Participants experienced a 22% absolute decrease in school absenteeism, the number of children with an Asthma Control Test/Childhood Asthma Control Test score of less than the control threshold of 20 decreased from 42.7% to 28.8%, and bronchodilator use greater than 2 times per week decreased from 35.8% to 22.9% (all changes were significant, P < .01). CONCLUSIONS: Children enrolled in the Building Bridges for Asthma Care Program experienced reduced school absence and improved asthma control.

Managing Asthma in Adolescents and Adults: 2020 Asthma Guideline Update From the National Asthma Education and Prevention Program.

Importance: Asthma is a major public health problem worldwide and is associated with excess morbidity, mortality, and economic costs associated with lost productivity. The National Asthma Education and Prevention Program has released the 2020 Asthma Guideline Update with updated evidence-based recommendations for treatment of patients with asthma. Objective: To report updated recommendations for 6 topics for clinical management of adolescents and adults with asthma: (1) intermittent inhaled corticosteroids (ICSs); (2) add-on long-acting muscarinic antagonists; (3) fractional exhaled nitric oxide; (4) indoor allergen mitigation; (5) immunotherapy; and (6) bronchial thermoplasty. Evidence Review: The National Heart, Lung, and Blood Advisory Council chose 6 topics to update the 2007 asthma guidelines based on results from a 2014 needs assessment. The Agency for Healthcare Research and Quality conducted systematic reviews of these 6 topics based on literature searches up to March-April 2017. Reviews were updated through October 2018 and used by an expert panel (n = 19) that included asthma content experts, primary care clinicians, dissemination and implementation experts, and health policy experts to develop 19 new recommendations using the GRADE method. The 17 recommendations for individuals aged 12 years or older are reported in this Special Communication. Findings: From 20 572 identified references, 475 were included in the 6 systematic reviews to form the evidence basis for these recommendations. Compared with the 2007 guideline, there was no recommended change in step 1 (intermittent asthma) therapy (as-needed short-acting ß2-agonists [SABAs] for rescue therapy). In step 2 (mild persistent asthma), either daily low-dose ICS plus as-needed SABA therapy or as-needed concomitant ICS and SABA therapy are recommended. Formoterol in combination with an ICS in a single inhaler (single maintenance and reliever therapy) is recommended as the preferred therapy for moderate persistent asthma in step 3 (low-dose ICS-formoterol therapy) and step 4 (medium-dose ICS-formoterol therapy) for both daily and as-needed therapy. A short-term increase in the ICS dose alone for worsening of asthma symptoms is not recommended. Add-on long-acting muscarinic antagonists are recommended in individuals whose asthma is not controlled by ICS-formoterol therapy for step 5 (moderate-severe persistent asthma). Fractional exhaled nitric oxide testing is recommended to assist in diagnosis and monitoring of symptoms, but not alone to diagnose or monitor asthma. Allergen mitigation is recommended only in individuals with exposure and relevant sensitivity or symptoms. When used, allergen mitigation should be allergen specific and include multiple allergen-specific mitigation strategies. Subcutaneous immunotherapy is recommended as an adjunct to standard pharmacotherapy for individuals with symptoms and sensitization to specific allergens. Sublingual immunotherapy is not recommended specifically for asthma. Bronchial thermoplasty is not recommended as part of standard care; if used, it should be part of an ongoing research effort. Conclusions and Relevance: Asthma is a common disease with substantial human and economic costs globally. Although there is no cure or established means of prevention, effective treatment is available. Use of the recommendations in the 2020 Asthma Guideline Update should improve the health of individuals with asthma.

Building Bridges for Asthma Care Program: A School-Centered Program Connecting Schools, Families, and Community Health-Care Providers.

Asthma imposes tremendous burden on children, families, and society. Successful management requires coordinated care among children, families, health providers, and schools. Building Bridges for Asthma Care Program, a school-centered program to coordinate care for successful asthma management, was developed, implemented, and evaluated. The program consists of five steps: (1) identify students with asthma; (2) assess asthma risk/control; (3) engage the family and student at risk; (4) provide case management and care coordination, including engagement of health-care providers; and (5) prepare for next school year. Implementation occurred in 28 schools from two large urban school districts in Colorado and Connecticut. Significant improvements were noted in the proportions of students with completed School Asthma Care Plans, a quick-relief inhaler at school, Home Asthma Action/Treatment Plans and inhaler technique (p < .01 for all variables). Building Bridges for Asthma Care was successfully implemented extending asthma care to at-risk children with asthma through engagement of schools, health providers, and families.

T-Cell Receptor Excision Circles in Newborns with Congenital Heart Disease.

OBJECTIVES: To determine if children with congenital heart disease (CHD) have lower newborn T-cell receptor excision circles (TREC) levels than the general population and to evaluate if low TREC levels in newborns with CHD are associated with clinical complications such as hospitalization for infection. STUDY DESIGN: The Connecticut Newborn Screening Program reported TREC levels for newborns with CHD delivered between October 2011 and September 2016 at 2 major Connecticut children's hospitals. TREC levels for children with CHD were compared with the general population. TREC levels and outcome measures, including hospitalization for infection, were compared. RESULTS: We enrolled 575 participants with CHD in the study. The median TREC level for newborns with CHD was lower than the general population (180.1 copies/µL vs 312.5 copies/µL; P < .01). patients with CHD requiring hospitalization for infection had lower median TREC levels than their counterparts (143.0 copies/µL vs 186.7 copies/µL; P < .01). The combination of prematurity and low TREC level had a strong relationship to hospitalization for infection (area under the receiver operative characteristic curve of 0.89). There was no association between TREC level and CHD severity. CONCLUSIONS: Newborns with CHD demonstrated lower TREC levels than the general population. Low TREC levels were associated with hospitalization for infection in preterm children with CHD. Study limitations include that this was a retrospective chart review. These findings may help to identify newborns with CHD at highest risk for infection, allowing for potential opportunities for intervention.

Hair cortisol, perceived stress, and social support in mother-child dyads living in an urban neighborhood.

Women and children belonging to a racial/ethnic minority bear a disproportionate burden of psychosocial stress that increases their vulnerability to adverse health outcomes. Hair cortisol has been rapidly advanced as a biomarker of the intensity and course of the stress response over time and may provide an opportunity to increase our understanding of the role of psychological stress in health. However, research on the link between hair cortisol levels and subjective measures of maternal and child stress among low-income and minority individuals is limited. The goal of this study was to examine the association between stress and hair cortisol in low income, minority women and children who experience disproportionate exposure to chronic stress. A convenience sample of 54 minority mother/child dyads from a busy primary care clinic in the second poorest medium-sized city in the US participated in the study. Mothers self-reported perceived stress, social support, household characteristics and other demographic factors, and their children (ages 7-14 years) reported on the perceived level of safety in their neighborhood and exposure to violence as markers of child stress. Three-centimeter hair samples were collected from both mothers and children during the clinic visit, and hair cortisol levels were assessed via enzyme-linked immunosorbent assays. Linear regression models examined associations between maternal and child hair cortisol, and between hair cortisol and perceived stress level in women, and moderation by social support. Maternal hair cortisol was not significantly associated with mother's perceived stress. Maternal and child hair cortisol levels were positively associated (p = .007) but this association was not moderated by maternal perceived social support. These findings suggest that hair cortisol is strongly associated among this sample of minority mother-child dyads and is not moderated by social support.

Diffusion-weighted MRI of the lung at 3T evaluated using echo-planar-based and single-shot turbo spin-echo-based acquisition techniques for radiotherapy applications.

PURPOSE: To compare single-shot echo-planar (SS-EPI)-based and turbo spin-echo (SS-TSE)-based diffusion-weighted imaging (DWI) in Non-Small Cell Lung Cancer (NSCLC) patients and to characterize the distributions of apparent diffusion coefficient (ADC) values generated by the two techniques. METHODS: Ten NSCLC patients were enrolled in a prospective IRB-approved study to compare and optimize DWI using EPI and TSE-based techniques for radiotherapy planning. The imaging protocol included axial T2w, EPI-based DWI and TSE-based DWI on a 3 T Philips scanner. Both EPI-based and TSE-based DWI sequences used three b values (0, 400, and 800 s/mm2 ). The acquisition times for EPI-based and TSE-based DWI were 5 and 8 min, respectively. DW-MR images were manually coregistered with axial T2w images, and tumor volume contoured on T2w images were mapped onto the DWI scans. A pixel-by-pixel fit of tumor ADC was calculated based on monoexponential signal behavior. Tumor ADC mean, standard deviation, kurtosis, and skewness were calculated and compared between EPI and TSE-based DWI. Image distortion and ADC values between the two techniques were also quantified using fieldmap analysis and a NIST traceable ice-water diffusion phantom, respectively. RESULTS: The mean ADC for EPI and TSE-based DWI were 1.282 ± 0.42 × 10-3 and 1.211 ± 0.31 × 10-3  mm2 /s. The average skewness and kurtosis were 0.14 ± 0.4 and 2.43 ± 0.40 for DWI-EPI and -0.06 ± 0.69 and 2.89 ± 0.62 for DWI-TSE. Fieldmap analysis showed a mean distortion of 13.72 ± 8.12 mm for GTV for DWI-EPI and 0.61 ± 0.4 mm for DWI-TSE. ADC values obtained using the diffusion phantom for the two techniques were within 0.03 × 10-3  mm2 /s with respect to each other as well as the established values. CONCLUSIONS: Diffusion-weighted turbo spin-echo shows better geometrical accuracy compared to DWI-EPI. Mean ADC values were similar with both acquisitions but the shape of the histograms was different based on the skewness and kurtosis values. The impact of differences in respiratory technique on ADC values requires further investigation.

Impact of daily soft-tissue image guidance to prostate on pelvic lymph node (PLN) irradiation for prostate patients receiving SBRT.

PURPOSE: To determine the impact of using fiducial match for daily image-guidance on pelvic lymph node (PLN) coverage for prostate cancer patients receiving stereotactic body radiation therapy (SBRT). METHODS: Thirty patients underwent SBRT treatment to the prostate and PLN from 2014 to 2016. Each patient received either 800cGy × 5 or 500cGy × 5 to the prostate and 500cGy × 5 to the PLN. A 5 mm clinical target volume (CTV)-to-planning target volume (PTV) margin around the PLN was used for planning. Two registrations with planning computed tomography (PCT) for each of the daily cone beam CTs (CBCTs) were performed: a rigid registration to fiducials and to the bony anatomy. The average translational difference between fiducial and bony match as well as percentage of fractions with differences > 5mm were calculated. Changes in bladder and rectal volume as well as center-of-mass (COM) position from simulation parameters, and their correlation with translational difference were also evaluated. The dosimetric impact of the translational differences was calculated by shifting the plan isocenter. RESULTS: The average translational difference between fiducial and bony match was 0.06 ± 0.82, 2.1 ± 4.1, -2.8 ± 4.3, and 5.5 ± 4.2 mm for lateral, vertical, longitudinal, and vector directions. The average change in bladder and rectal volume from simulation was -67.2 ± 163.04 cc (-12 ± 52%) and -1.6 ± 18.75 (-2 ± 30%) cc. The average change in COM of bladder from the simulation position was 0.34 ± 2.49, 4.4 ± 8.1, and -3.9 ± 7.5 mm along the LR, AP, and SI directions. The corresponding COM change for the rectum was 0.17 ± 1.9, 1.34 ± 3.5, and -0.6 ± 5.2 mm. CONCLUSIONS: The 5 mm margin covered ~75% of fractions receiving PLN irradiation with SBRT, daily CBCT and fiducial-guided setup. The dosimetric impact on PLN coverage was significant in 19% of fractions or 25% of patients. A larger translational shift was due to variation in rectal volume and changes in COM position of the bladder and rectum. A consistent bladder positioning and/or rectum filling compared with presimulation volume were essential for adequate coverage of PLN in a hypofractionated treatment regime.

Obesity and Airway Dysanapsis in Children with and without Asthma.

RATIONALE: For unclear reasons, obese children with asthma have higher morbidity and reduced response to inhaled corticosteroids. OBJECTIVES: To assess whether childhood obesity is associated with airway dysanapsis (an incongruence between the growth of the lungs and the airways) and whether dysanapsis is associated with asthma morbidity. METHODS: We examined the relationship between obesity and dysanapsis in six cohorts of children with and without asthma, as well as the relationship between dysanapsis and clinical outcomes in children with asthma. Adjusted odds ratios (ORs) were calculated for each cohort and in a combined analysis of all cohorts; longitudinal analyses were also performed for cohorts with available data. Hazard ratios (HRs) for clinical outcomes were calculated for children with asthma in the Childhood Asthma Management Program. MEASUREMENTS AND MAIN RESULTS: Being overweight or obese was associated with dysanapsis in both the cross-sectional (OR, 1.95; 95% confidence interval [CI], 1.62-2.35 [for overweight/obese compared with normal weight children]) and the longitudinal (OR, 4.31; 95% CI, 2.99-6.22 [for children who were overweight/obese at all visits compared with normal weight children]) analyses. Dysanapsis was associated with greater lung volumes (FVC, vital capacity, and total lung capacity) and lesser flows (FEV1 and forced expiratory flow, midexpiratory phase), and with indicators of ventilation inhomogeneity and anisotropic lung and airway growth. Among overweight/obese children with asthma, dysanapsis was associated with severe disease exacerbations (HR, 1.95; 95% CI, 1.38-2.75) and use of systemic steroids (HR, 3.22; 95% CI, 2.02-5.14). CONCLUSIONS: Obesity is associated with airway dysanapsis in children. Dysanapsis is associated with increased morbidity among obese children with asthma and may partly explain their reduced response to inhaled corticosteroids.

Genome-wide interaction study of dust mite allergen on lung function in children with asthma.

BACKGROUND: Childhood asthma is likely the result of gene-by-environment (G × E) interactions. Dust mite is a known risk factor for asthma morbidity. Yet, there have been no genome-wide G × E studies of dust mite allergen on asthma-related phenotypes. OBJECTIVE: We sought to identify genetic variants whose effects on lung function in children with asthma are modified by the level of dust mite allergen exposure. METHODS: A genome-wide interaction analysis of dust mite allergen level and lung function was performed in a cohort of Puerto Rican children with asthma (Puerto Rico Genetics of Asthma and Lifestyle [PRGOAL]). Replication was attempted in 2 independent cohorts, the Childhood Asthma Management Program (CAMP) and the Genetics of Asthma in Costa Rica Study. RESULTS: Single nucleotide polymorphism (SNP) rs117902240 showed a significant interaction effect on FEV1 with dust mite allergen level in PRGOAL (interaction P = 3.1 × 10-8), and replicated in the same direction in CAMP white children and CAMP Hispanic children (combined interaction P = .0065 for replication cohorts and 7.4 × 10-9 for all cohorts). Rs117902240 was positively associated with FEV1 in children exposed to low dust mite allergen levels, but negatively associated with FEV1 in children exposed to high levels. This SNP is on chromosome 8q24, adjacent to a binding site for CCAAT/enhancer-binding protein beta, a transcription factor that forms part of the IL-17 signaling pathway. None of the SNPs identified for FEV1/forced vital capacity replicated in the independent cohorts. CONCLUSIONS: Dust mite allergen exposure modifies the estimated effect of rs117902240 on FEV1 in children with asthma. Analysis of existing data suggests that this SNP may have transcription factor regulatory functions.

A Multiomics Approach to Identify Genes Associated with Childhood Asthma Risk and Morbidity.

Childhood asthma is a complex disease. In this study, we aim to identify genes associated with childhood asthma through a multiomics "vertical" approach that integrates multiple analytical steps using linear and logistic regression models. In a case-control study of childhood asthma in Puerto Ricans (n = 1,127), we used adjusted linear or logistic regression models to evaluate associations between several analytical steps of omics data, including genome-wide (GW) genotype data, GW methylation, GW expression profiling, cytokine levels, asthma-intermediate phenotypes, and asthma status. At each point, only the top genes/single-nucleotide polymorphisms/probes/cytokines were carried forward for subsequent analysis. In step 1, asthma modified the gene expression-protein level association for 1,645 genes; pathway analysis showed an enrichment of these genes in the cytokine signaling system (n = 269 genes). In steps 2-3, expression levels of 40 genes were associated with intermediate phenotypes (asthma onset age, forced expiratory volume in 1 second, exacerbations, eosinophil counts, and skin test reactivity); of those, methylation of seven genes was also associated with asthma. Of these seven candidate genes, IL5RA was also significant in analytical steps 4-8. We then measured plasma IL-5 receptor α levels, which were associated with asthma age of onset and moderate-severe exacerbations. In addition, in silico database analysis showed that several of our identified IL5RA single-nucleotide polymorphisms are associated with transcription factors related to asthma and atopy. This approach integrates several analytical steps and is able to identify biologically relevant asthma-related genes, such as IL5RA. It differs from other methods that rely on complex statistical models with various assumptions.

A meta-analysis of genome-wide association studies of asthma in Puerto Ricans.

Puerto Ricans are disproportionately affected with asthma in the USA. In this study, we aim to identify genetic variants that confer susceptibility to asthma in Puerto Ricans.We conducted a meta-analysis of genome-wide association studies (GWAS) of asthma in Puerto Ricans, including participants from: the Genetics of Asthma in Latino Americans (GALA) I-II, the Hartford-Puerto Rico Study and the Hispanic Community Health Study. Moreover, we examined whether susceptibility loci identified in previous meta-analyses of GWAS are associated with asthma in Puerto Ricans.The only locus to achieve genome-wide significance was chromosome 17q21, as evidenced by our top single nucleotide polymorphism (SNP), rs907092 (OR 0.71, p=1.2×10-12) at IKZF3 Similar to results in non-Puerto Ricans, SNPs in genes in the same linkage disequilibrium block as IKZF3 (e.g. ZPBP2, ORMDL3 and GSDMB) were significantly associated with asthma in Puerto Ricans. With regard to results from a meta-analysis in Europeans, we replicated findings for rs2305480 at GSDMB, but not for SNPs in any other genes. On the other hand, we replicated results from a meta-analysis of North American populations for SNPs at IL1RL1, TSLP and GSDMB but not for IL33Our findings suggest that common variants on chromosome 17q21 have the greatest effects on asthma in Puerto Ricans.

Understanding clinicians' attitudes toward a mobile health strategy to childhood asthma management: A qualitative study.

OBJECTIVES: Mobile technology for childhood asthma can provide real-time data to enhance care. What real-time adherence information clinicians want, how they may use it, and if the data meet their clinical needs have not been fully explored. Our goal was to determine whether pediatric primary care and pulmonary clinicians believe if a sensor-based mobile intervention is useful in caring for patients with asthma. METHODS: We recruited participants from 3 urban, primary care and 1 pulmonary practice from July to September 2015 in Hartford, CT. Forty-one participated in four focus groups, which included a demonstration of the technology. Participants were probed with open-ended questions on the type, frequency, and format of inter-visit patient information they found useful. RESULTS: 41 participants (mean age 49 (±13.7) years) were board-certified clinicians (41% MDs and 20% mid-level practitioners), practiced medicine on an average of 19 (±14) years, were primarily white (59%) and women (78%). Clinicians wanted 1) adherence to prescribed inhaler therapy and 2) data on inhaler technique. Clinicians wanted it at the time of a scheduled clinic visit but also wanted inter-visit alerts for excessive use of rescue therapy. Pulmonologists liked the mobile spirometer's provision of inter-visit lung function data; pediatricians did not share this view. Concerns with data accuracy were raised due to families who shared inhalers, access to smartphones, and protection of health information. CONCLUSIONS: Overall, clinicians view an asthma mobile health technology as enhancing the patient-centered medical home. Pediatric primary care clinicians and pulmonologists want different information from a mobile app.