Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma.

BACKGROUND: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients. METHODS: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry. RESULTS: When quintupling the dose of fluticasone (to 250 µg twice a day) was compared with adding salmeterol (50 µg twice a day) and doubling the fluticasone (to 100 µg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age. CONCLUSIONS: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.).

Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations.

BACKGROUND: Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited. METHODS: We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 µg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 µg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids. RESULTS: The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06). CONCLUSIONS: In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129 .).

Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma.

BACKGROUND: Studies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking. METHODS: In a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial. RESULTS: Participants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events. CONCLUSIONS: Among young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA ClinicalTrials.gov number, NCT01606319.).

CYP2C19 and STAT6 Variants Influence the Outcome of Proton Pump Inhibitor Therapy in Pediatric Eosinophilic Esophagitis.

OBJECTIVE: Proton pump inhibitors (PPIs) are an effective treatment for eosinophilic esophagitis (EoE); however, only 30% to 60% of patients respond. Common genetic variants in CYP2C19 and STAT6 associate with PPI plasma concentration and magnitude of inflammatory response, respectively. Our objective was to determine if genetic variation in the genes for CYP2C19 and STAT6 influence differentiation between PPI responsive esophageal eosinophilia versus PPI nonresponsive EoE (PPI-REE, PPI-nonresponsive EoE). METHODS: Genomic DNA was isolated from 92 esophageal tissue biopsies collected from participants of a prospective clinical trial of high-dose PPI therapy for esophageal eosinophilia in children. RESULTS: Of the 92 patients examined, 57 (62%) were PPI-REE and 35 (38%) were PPI-nonresponsive EoE. Forty-six of the 92 patients were further characterized by pH probe monitoring; there was no association between reflux index and carriage of CYP2C1917 (P = 0.35). In children who received a PPI dose between ≥1.54 and ≤2.05 mg/kg/day, binary logistic regression modeling showed that carriage of CYP2C1917 associated with PPI-nonresponsive EoE (odds ratio (OR) [95% confidence interval (CI)] = 7.71 [1.21, 49.11], P = 0.031). Carriage of STAT6 allelic variant rs1059513 predicts PPI-REE (OR [95% CI] = 6.16 [1.44, 26.4], P = 0.028), whereas carriage of STAT6 rs324011 synergizes with CYP2C1917 to predict PPI-nonresponsive EoE (rs324011 OR [95% CI] = 5.56 [1.33, 20.72], P = 0.022; CYP2C1917 OR [95% CI] = 8.19[1.42, 50.57], P = 0.023). CONCLUSIONS: Common variants in CYP2C19 and STAT6 associate with a PPI-nonresponsive EoE outcome of PPI therapy for esophageal eosinophilia suggesting that response rates may be improved by adopting a genotype-guided approach to PPI dosing.

Income is an independent risk factor for worse asthma outcomes.

BACKGROUND: Socioeconomic status (SES) is associated with asthma morbidity in observational studies, but the factors underlying this association are uncertain. OBJECTIVE: We investigated whether 3 SES correlates-low income, low education, and high perceived stress-were independent risk factors for treatment failure and asthma exacerbations in the context of a randomized controlled trial. METHODS: The effect of low SES (household income of <$50,000/y and household educational level of less than a Bachelor's degree) and high perceived stress (defined as a score of >20 on a perceived stress scale) on asthma morbidity was analyzed in 381 participants by using Poisson regression models. The primary outcome was treatment failure (defined in the trial protocol as a significant clinical or airflow deterioration), and the secondary outcome was asthma exacerbations requiring systemic corticosteroids. RESULTS: Fifty-four percent of participants had a low income, 40% had a low educational level, and 17% had high perceived stress levels. Even after adjusting for race and other important confounders, participants with lower income had higher rates of both treatment failures (rate ratio, 1.6; 95% CI, 1.1-2.3; P = .03) and exacerbations (rate ratio, 1.9; 95% CI, 1.1-3.3; P = .02). Adherence with inhaled corticosteroids was similarly high for both income categories. Education and perceived stress were not significantly associated with either outcome. CONCLUSIONS: In the context of a randomized controlled trial, participants with lower income were more likely to experience adverse asthma outcomes independent of education, perceived stress, race, and medication adherence.

The phosphatidylinositide 3-kinase (PI3K) signaling pathway is a determinant of zileuton response in adults with asthma.

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.

Association of free vitamin D3 concentrations and asthma treatment failures in the VIDA Trial.

BACKGROUND: Use of vitamin D3 serum concentrations as a biomarker of vitamin D status is questionable because of variation in vitamin D binding protein. OBJECTIVE: To determine associations between free vitamin D3 concentrations and rates of treatment failure and exacerbations in patients with asthma participating in the Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma (VIDA) trial. METHODS: Free concentrations were directly measured by enzyme-linked immunosorbent assay and stratified into low, medium, and high groups: less than 5pg/mL (n = 65), 5 to 9pg/mL (n = 84), and greater than 9pg/mL (n = 48) after 12 weeks of supplementation with oral vitamin D3 and associated with outcomes. RESULTS: Outcomes did not associate with free concentrations: overall treatment failure rates were 0.60 (95% confidence interval [CI] 0.46-0.78), 0.53 (95%CI 0.40- 0.70), and 0.69 (95%CI 0.54-0.90)/person-year (P = .51), respectively; overall exacerbation rates were 0.28 (95%CI 0.17-0.48), 0.15 (95%CI 0.08-0.30) and 0.42 (95%CI 0.27-0.66)/person-year (P = .22). Mean (standard deviation) baseline free concentrations were lower in non-Hispanic blacks and Hispanics compared with non-Hispanic whites: 4.10 (1.33) and 4.38 (1.11) pg/mL vs 5.16 (1.65) pg/ml, (P < .001 and P = 0.038), respectively. Mean (standard deviation) baseline free concentrations differed between females and males: 4.57 (1.58) and 5.08 (1.41) (P = .026); and between non-overweight (body mass index [BMI] < 25) and overweight (BMI > 25): 5.45 (1.86) vs 4.54 (1.39) (P < .001). The free fraction differed by race and sex but not by BMI. CONCLUSION: The use of free concentrations was inferior to total concentrations as a biomarker of efficacy of vitamin D3 supplementation in VIDA trial participants. Future studies of vitamin D status in patients with asthma should measure both free and total concentrations to better understand which marker of vitamin D function is most informative.

Association between CYP2C19 extensive metabolizer phenotype and childhood anti-reflux surgery following failed proton pump inhibitor medication treatment.

When pediatric gastroesophageal reflux disease (GERD) that is refractory to proton pump inhibitor (PPI) medication treatment is identified in clinical practice and anti-reflux surgery (ARS) is being considered, genetic factors related to PPI metabolism by the CYP2C19 enzyme are currently not part of the clinical decision-making process. Our objective was to test the hypothesis that the distribution of the extensive metabolizer (EM) phenotypes among children undergoing ARS after failing PPI therapy would differ compared to controls (children with no history of ARS). We conducted a case-control study between children across the Nemours Health System from 2000 to 2014 who received ARS after failing PPI therapy and a control group comprised of healthy children. Our results demonstrated 2.9% of ARSs vs 20.8% of controls were poor metabolizers (PMs), 55.9% of ARSs vs 49.0% of controls were normal metabolizers (NMs), and 41.2% of ARSs vs 30.2% of controls were EMs; p = 0.035. Next, we performed a multiple-regression model to account for race as a potential confounding variable and the EM group was significantly associated with ARS compared to controls (OR 9.78, CI 1.25-76.55, p < 0.03). CONCLUSION: Among children with medically refractory GERD despite PPI therapy, carriage of CYP2C19*17 allele corresponding to the EM phenotype was associated with ARS. Prospective comparative personalized medicine effectiveness studies are needed to determine if CYP2C19 genotype-guided dosing improves response to PPI therapy without a corresponding increase in adverse effects in children. What is known: • Anti-reflux surgery (ARS) is one of the most common surgical procedures performed in children for the indication of refractory gastroesophageal reflux disease (GERD). What is new: • Individualizing PPI medication dosing based on CYP2C19 diplotype may avoid GERD treatment failures and reduce the need for anti-reflux surgery (ARS).

Free 25(OH)D concentrations are associated with atopy and lung function in children with asthma.

BACKGROUND: Evidence suggests free mono-hydroxyvitamin D (25[OH]D) concentrations are more strongly linked to certain outcomes than total concentrations; however, no studies have examined the relation between free 25(OH)D and respiratory or allergic disease. OBJECTIVE: To examine associations between total and free 25(OH)D concentrations and asthma outcomes. METHODS: We quantified total and free 25(OH)D concentrations in 137 Peruvian children with asthma and 152 children without asthma and examined associations with asthma outcomes. RESULTS: Mean age ± SD was 13 ± 2.5 years, and 50.2% were boys. Mean total and measured free 25(OH)D concentrations were 29 ± 9.5 ng/mL and 5.0 ± 1.3 pg/mL, respectively. Lower free but not total 25(OH)D concentrations were significantly associated with atopy in all children (total, odds ratio [OR] 1.3 per 10-ng/mL decrease, 95% confidence interval [CI] 0.95-1.7, P = .12; vs free, OR 1.3 per 1-pg/mL decrease, 95% CI 1.0-1.6, P = .02) and children with asthma (total, OR 1.1 per 10-ng/mL decrease, 95% CI 0.75-1.7, P = .57; vs free, OR 1.6 per 1-pg/mL decrease, 95% CI 1.0-2.5, P = .04). Free but not total 25(OH)D levels were significantly associated with pre-bronchodilator forced expiratory volume in 1 second (total, 0.11 L, -0.12 to 0.34, P = .34; vs free, 0.20 L, 0.021-0.39, P = .03) and forced vital capacity (total, 0.13 L, -0.12 to 0.37, P = .31; vs free, 0.22 L, 0.026-0.42, P = .03) Z-scores in children with asthma. CONCLUSION: Atopy, forced expiratory volume in 1 second, and forced vital capacity were more strongly linked to free than to total 25(OH)D concentrations, suggesting the free form might be more relevant in modulating allergic disease risk and pulmonary function in children with asthma.

Individualized therapy for persistent asthma in young children.

BACKGROUND: Phenotypic presentations in young children with asthma are varied and might contribute to differential responses to asthma controller medications. METHODS: The Individualized Therapy for Asthma in Toddlers study was a multicenter, randomized, double-blind, double-dummy clinical trial in children aged 12 to 59 months (n = 300) with asthma necessitating treatment with daily controller (Step 2) therapy. Participants completed a 2- to 8-week run-in period followed by 3 crossover periods with daily inhaled corticosteroids (ICSs), daily leukotriene receptor antagonists, and as-needed ICS treatment coadministered with albuterol. The primary outcome was differential response to asthma medication based on a composite measure of asthma control. The primary analysis involved 2 stages: determination of differential response and assessment of whether 3 prespecified features (aeroallergen sensitization, previous exacerbations, and sex) predicted a differential response. RESULTS: Seventy-four percent (170/230) of children with analyzable data had a differential response to the 3 treatment strategies. Within differential responders, the probability of best response was highest for a daily ICS and was predicted by aeroallergen sensitization but not exacerbation history or sex. The probability of best response to daily ICS was further increased in children with both aeroallergen sensitization and blood eosinophil counts of 300/µL or greater. In these children daily ICS use was associated with more asthma control days and fewer exacerbations compared with the other treatments. CONCLUSIONS: In young children with asthma necessitating Step 2 treatment, phenotyping with aeroallergen sensitization and blood eosinophil counts is useful for guiding treatment selection and identifies children with a high exacerbation probability for whom treatment with a daily ICS is beneficial despite possible risks of growth suppression.

Gastro-oesophageal reflux and worse asthma control in obese children: a case of symptom misattribution?

BACKGROUND: Obese children for unknown reasons report greater asthma symptoms. Asthma and obesity both independently associate with gastro-oesophageal reflux symptoms (GORS). Determining if obesity affects the link between GORS and asthma will help elucidate the obese-asthma phenotype. OBJECTIVE: Extend our previous work to determine the degree of associations between the GORS and asthma phenotype. METHODS: We conducted a cross-sectional study of lean (20%-65% body mass index, BMI) and obese (≥95% BMI) children aged 10-17 years old with persistent, early-onset asthma. Participants contributed demographics, GORS and asthma questionnaires and lung function data. We determined associations between weight status, GORS and asthma outcomes using multivariable linear and logistic regression. Findings were replicated in a second well-characterised cohort of asthmatic children. RESULTS: Obese children had seven times higher odds of reporting multiple GORS (OR=7.7, 95% CI 1.9 to 31.0, interaction p value=.004). Asthma symptoms were closely associated with GORS scores in obese patients (r=0.815, p<0.0001) but not in leans (r=0.291, p=0.200; interaction p value=0.003). Higher GORS scores associated with higher FEV1-per cent predicted (p=0.003), lower airway resistance (R10, p=0.025), improved airway reactance (X10, p=0.005) but significantly worse asthma control (Asthma Control Questionnaire, p=0.007). A significant but weaker association between GORS and asthma symptoms was seen in leans compared with obese in the replicate cohort. CONCLUSION: GORS are more likely to associate with asthma symptoms in obese children. Better lung function among children reporting gastro-oesophageal reflux and asthma symptoms suggests that misattribution of GORS to asthma may be a contributing mechanism to excess asthma symptoms in obese children.

Dynamic response of C-type natriuretic peptide and its aminoterminal propeptide (NTproCNP) to growth hormone treatment in children with short stature.

OBJECTIVE: C-type natriuretic peptide (CNP) and its aminoterminal propeptide (NTproCNP) are potential biomarkers of recombinant human growth hormone (rhGH) efficacy. The objective of this study was to describe the pharmacodynamics of plasma CNP and NTproCNP levels in response to rhGH treatment and to identify the optimal time of sampling after starting rhGH. DESIGN: This was a prospective, observational study. Subjects were treated with rhGH for 1 year, with blood sampled at regular intervals. PATIENTS: Eighteen prepubertal children, eight with low levels of GH on biochemical testing and ten with idiopathic short stature, completed the study. MEASUREMENTS: Blood levels of CNP, NTproCNP, GH, insulin-like growth factor-I, leptin and bone-specific alkaline phosphatase were measured. Anthropometrics were obtained. RESULTS: Plasma levels of both CNP and NTproCNP reached peak levels 7-28 days after starting rhGH treatment and then declined to intermediate levels through the first year. Plasma NTproCNP levels after 14 days trended towards a correlation with height velocity after 6 and 12 months of treatment. Unexpectedly, serum GH levels measured 2 and 28 days after starting rhGH correlated strongly with height velocity after 6 and 12 months of treatment. CONCLUSIONS: This study identified 14 days after starting rhGH treatment as the optimal time for assessing CNP and NTproCNP levels as biomarkers of rhGH efficacy. Additionally, we identified GH levels as a potential biomarker. Larger, prospective studies are now needed to test the clinical utility of these biomarkers.

Overweight children report qualitatively distinct asthma symptoms: analysis of validated symptom measures.

BACKGROUND: Past studies of asthma in overweight/obese children have been inconsistent. The reason overweight/obese children commonly report worse asthma control remains unclear. OBJECTIVE: To determine qualitative differences in symptoms between lean and overweight/obese children with early-onset, atopic asthma. METHODS: We conducted a cross-sectional analytic study of lean (20% to 65% body mass index) and overweight/obese (≥85% body mass index) 10- to 17-year-old children with persistent, early-onset asthma. Participants completed 2 to 3 visits to provide a complete history, qualitative and quantitative asthma symptom characterization, and lung function testing. We determined associations between weight status and symptoms using multivariable linear and logistic regression methods. RESULTS: Overweight/obese and lean asthmatic children displayed similar lung function. Despite lower fraction of exhaled nitric oxide (30.0 vs 62.6 ppb; P = .037) and reduced methacholine responsiveness (PC20FEV1 1.87 vs 0.45 mg/mL; P < .012), overweight/obese children reported more than thrice frequent rescue treatments (3.7 vs 1.1 treatments/wk; P = .0002) than did lean children. Weight status affected the child's primary symptom reported with loss of asthma control (Fisher exact test; P = .003); overweight/obese children more often reported shortness of breath (odds ratio = 11.8; 95% CI, 1.41-98.7) and less often reported cough (odds ratio = 0.26; 95% CI, 0.08-0.82). Gastroesophageal reflux scores were higher in overweight/obese children (9.6 vs 23.2; P = .003) and appear to mediate overweight/obesity-related asthma symptoms. CONCLUSIONS: Overweight/obese children with early-onset asthma display poorer asthma control and a distinct pattern of symptoms. Greater shortness of breath and ß-agonist use appears to be partially mediated via esophageal reflux symptoms. Overweight children with asthma may falsely attribute exertional dyspnea and esophageal reflux to asthma, leading to excess rescue medication use.

Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene.

Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. FEV(1)) before and after the administration of a short-acting ß(2)-agonist, the most common rescue medications used for the treatment of asthma. BDR also serves as a test of ß(2)-agonist efficacy. BDR is a complex trait that is partly under genetic control. A genome-wide association study (GWAS) of BDR, quantified as percent change in baseline FEV(1) after administration of a ß(2)-agonist, was performed with 1,644 non-Hispanic white asthmatic subjects from six drug clinical trials: CAMP, LOCCS, LODO, a medication trial conducted by Sepracor, CARE, and ACRN. Data for 469,884 single-nucleotide polymorphisms (SNPs) were used to measure the association of SNPs with BDR using a linear regression model, while adjusting for age, sex, and height. Replication of primary P-values was attempted in 501 white subjects from SARP and 550 white subjects from DAG. Experimental evidence supporting the top gene was obtained via siRNA knockdown and Western blotting analyses. The lowest overall combined P-value was 9.7E-07 for SNP rs295137, near the SPATS2L gene. Among subjects in the primary analysis, those with rs295137 TT genotype had a median BDR of 16.0 (IQR = [6.2, 32.4]), while those with CC or TC genotypes had a median BDR of 10.9 (IQR = [5.0, 22.2]). SPATS2L mRNA knockdown resulted in increased ß(2)-adrenergic receptor levels. Our results suggest that SPATS2L may be an important regulator of ß(2)-adrenergic receptor down-regulation and that there is promise in gaining a better understanding of the biological mechanisms of differential response to ß(2)-agonists through GWAS.

Genetic predictors associated with improvement of asthma symptoms in response to inhaled corticosteroids.

BACKGROUND: To date, genome-wide association studies (GWASs) of inhaled corticosteroid (ICS) response in asthmatic patients have focused primarily on lung function and exacerbations. OBJECTIVE: We hypothesized that GWAS analysis could identify novel genetic markers predicting a symptomatic response to ICSs. METHODS: We analyzed differences in asthma symptoms in response to ICSs in 124 white children from the Childhood Asthma Management Program (CAMP) trial using scores from diary cards. Of the 440,862 single nucleotide polymorphisms (SNPs) analyzed, the top 100 ranked SNPs were pursued for replication initially in subjects from the pediatric Childhood Asthma Research and Education trials (77 white children) and then in subjects from the adult Asthma Clinical Research Network (110 white adults) and Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol trials (110 white adults). RESULTS: The lowest P value for GWAS analysis in the CAMP trial was 8.94 × 10(-8) (rs2388639). Of the 60 SNPs available in the Childhood Asthma Research and Education Network trials, rs1558726 (combined P = 1.02 × 10(-5)), rs2388639 (combined P = 8.56 × 10(-9)), and rs10044254 (combined P = 9.16 × 10(-8)) independently replicated. However, these 3 SNPs were not additionally replicated in the adult asthmatic patients of the remaining trials. rs10044254 lies in the intronic region of F-box and leucine-rich repeat protein 7 (FBXL7) and is associated with decreased expression in immortalized B cells derived from CAMP participants. CONCLUSIONS: We have identified a novel SNP, rs10044254, associated with both decreased expression of FBXL7 and improved symptomatic response to ICSs in 2 independent pediatric cohorts. Our results suggest that there might be a specific genetic mechanism regulating symptomatic response to ICSs in children that does not carry over to adults.

Effect of a soy isoflavone supplement on lung function and clinical outcomes in patients with poorly controlled asthma: a randomized clinical trial.

IMPORTANCE: Soy isoflavone supplements are used to treat several chronic diseases, although the data supporting their use are limited. Some data suggest that supplementation with soy isoflavone may be an effective treatment for patients with poor asthma control. OBJECTIVE: To determine whether a soy isoflavone supplement improves asthma control in adolescent and adult patients with poorly controlled disease. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized, double-blind, placebo-controlled trial conducted between May 2010 and August 2012 at 19 adult and pediatric pulmonary and allergy centers in the American Lung Association Asthma Clinical Research Centers network. Three hundred eighty-six adults and children aged 12 years or older with symptomatic asthma while taking a controller medicine and low dietary soy intake were randomized, and 345 (89%) completed spirometry at week 24. INTERVENTIONS: Participants were randomly assigned to receive soy isoflavone supplement containing 100 mg of total isoflavones (n=193) or matching placebo (n=193) in 2 divided doses administered daily for 24 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome measure was change in forced expiratory volume in the first second (FEV1) at 24 weeks. Secondary outcome measures were symptoms, episodes of poor asthma control, Asthma Control Test score (range, 5-25; higher scores indicate better control), and systemic and airway biomarkers of inflammation. RESULTS: Mean changes in prebronchodilator FEV1 over 24 weeks were 0.03 L (95% CI, -0.01 to 0.08 L) in the placebo group and 0.01 L (95% CI, -0.07 to 0.07 L) in the soy isoflavone group, which were not significantly different (P = .36). Mean changes in symptom scores on the Asthma Control Test (placebo, 1.98 [95% CI, 1.42-2.54] vs soy isoflavones, 2.20 [95% CI, 1.53-2.87]; positive values indicate a reduction in symptoms), number of episodes of poor asthma control (placebo, 3.3 [95% CI, 2.7-4.1] vs soy isoflavones, 3.0 [95% CI, 2.4-3.7]), and changes in exhaled nitric oxide (placebo, -3.48 ppb [95% CI, -5.99 to -0.97 ppb] vs soy isoflavones, 1.39 ppb [95% CI, -1.73 to 4.51 ppb]) did not significantly improve more with the soy isoflavone supplement than with placebo. Mean plasma genistein level increased from 4.87 ng/mL to 37.67 ng/mL (P < .001) in participants receiving the supplement. CONCLUSIONS AND RELEVANCE: Among adults and children aged 12 years or older with poorly controlled asthma while taking a controller medication, use of a soy isoflavone supplement, compared with placebo, did not result in improved lung function or clinical outcomes. These findings suggest that this supplement should not be used for patients with poorly controlled asthma. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01052116.

Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma.

BACKGROUND: The response to treatment for asthma is characterized by wide interindividual variability, with a significant number of patients who have no response. We hypothesized that a genomewide association study would reveal novel pharmacogenetic determinants of the response to inhaled glucocorticoids. METHODS: We analyzed a small number of statistically powerful variants selected on the basis of a family-based screening algorithm from among 534,290 single-nucleotide polymorphisms (SNPs) to determine changes in lung function in response to inhaled glucocorticoids. A significant, replicated association was found, and we characterized its functional effects. RESULTS: We identified a significant pharmacogenetic association at SNP rs37972, replicated in four independent populations totaling 935 persons (P=0.0007), which maps to the glucocorticoid-induced transcript 1 gene (GLCCI1) and is in complete linkage disequilibrium (i.e., perfectly correlated) with rs37973. Both rs37972 and rs37973 are associated with decrements in GLCCI1 expression. In isolated cell systems, the rs37973 variant is associated with significantly decreased luciferase reporter activity. Pooled data from treatment trials indicate reduced lung function in response to inhaled glucocorticoids in subjects with the variant allele (P=0.0007 for pooled data). Overall, the mean (±SE) increase in forced expiratory volume in 1 second in the treated subjects who were homozygous for the mutant rs37973 allele was only about one third of that seen in similarly treated subjects who were homozygous for the wild-type allele (3.2±1.6% vs. 9.4±1.1%), and their risk of a poor response was significantly higher (odds ratio, 2.36; 95% confidence interval, 1.27 to 4.41), with genotype accounting for about 6.6% of overall inhaled glucocorticoid response variability. CONCLUSIONS: A functional GLCCI1 variant is associated with substantial decrements in the response to inhaled glucocorticoids in patients with asthma.

Polygenic heritability estimates in pharmacogenetics: focus on asthma and related phenotypes.

Although accurate measures of heritability are required to understand the pharmacogenetic basis of drug treatment response, these are generally not available, as it is unfeasible to give medications to individuals for which treatment is not indicated. Using a polygenic linear mixed modeling approach, we estimated lower bounds on the heritability of asthma and the heritability of two related drug-response phenotypes, bronchodilator response and airway hyperreactivity, using genome-wide single nucleotide polymorphism (SNP) data from existing asthma cohorts. Our estimate of the heritability for bronchodilator response is 28.5% (SE 16%, P=0.043) and airway hyperresponsiveness is 51.1% (SE 34%, P=0.064), whereas we estimate asthma genetic liability at 61.5% (SE 16%, P<0.001). Our results agree with the previously published estimates of the heritability of these traits, suggesting that the linear mixed modeling method is useful for computing the heritability of other pharmacogenetic traits. Furthermore, our results indicate that multiple SNP main effects, including SNPs as yet unidentified by genome-wide association study methods, together explain a sizable portion of the heritability of these traits.

Association of CYP2C19 polymorphisms and lansoprazole-associated respiratory adverse effects in children.

OBJECTIVE: To determine whether cytochrome P450 (CYP)2C19 haplotype associates with lansoprazole-associated adverse event frequency. STUDY DESIGN: Respiratory adverse events from a clinical trial of lansoprazole in children with asthma were analyzed for associations with extensive or poor metabolizer (PM) phenotype based on CYP2C19 haplotypes. Carriers of CYP2C19*2, *3, *8, or *9 alleles were PMs; carriers of 2 wild-type alleles were extensive metabolizers (EMs). Plasma concentrations of lansoprazole were determined in PM and EM phenotypes. RESULTS: The frequency of upper respiratory infection among PMs (n = 45) was higher than that among EMs (n = 91), which in turn was higher than that in placebo subjects (n = 135; P = .0039). The frequency of sore throat (ST) was similarly distributed among EMs and PMs (P = .0015). The OR (95% CI) for upper respiratory infections in PMs was 2.46 (1.02-5.96) (P = .046); for EMs, the OR (95% CI) was 1.55 (0.86-2.79). The OR (95% CI) for ST in EMs and PMs was 2.94 (1.23-7.05, P = .016) vs 1.97 (1.09-3.55, P = .024), respectively. Mean ± SD plasma concentrations of lansoprazole were higher in PMs than in EMs: 207 ± 179 ng/mL vs 132 ± 141 ng/mL (P = .04). CONCLUSIONS: Lansoprazole-associated upper respiratory infections and ST in children are related in part to CYP2C19 haplotype. Our data suggest that lansoprazole-associated adverse events in children may be mitigated by adjusting the conventional dose in PMs. Additional studies are required to replicate our findings.

Asthma severity, exacerbation risk, and controller treatment burden in underweight and obese children.

OBJECTIVE: The relationship between weight status and asthma characteristics in children remains inadequately defined. Very little has been published on the risk of exacerbation, physician perception of severity, and the level controller treatment prescribed to underweight and obese children with asthma in a real-world setting. METHODS: We assessed the diagnostic severity, pulmonary function, exacerbation prevalence, and controller treatment level in 10,559 new asthma patients seen at one of four pediatric asthma subspecialty clinics among three BMI groups. Participants were analyzed by body mass index (BMI)-percentile based on Centers for Disease Control & Prevention classification. Multivariable logistic regression models were used to assess the associations between BMI-percentile cohort group and asthma outcomes. RESULTS. Underweight asthmatics were rare (2.5%) relative to obese asthmatics but appeared to have the greatest impairment in forced vital capacity and had the greatest controller treatment burden. Obese asthmatic children made up 26.2% of our cohort and were more likely to have severe disease (odds ratio (OR) 1.40, 95% confidence interval (CI) 1.06-1.85) and airflow obstruction (OR 1.36, 95% CI 1.16-1.59) compared to normal weight asthmatics. Obese asthmatics were not at greater risk for exacerbation (OR 1.41, 95% CI 0.64-3.11) or high treatment burden (OR 1.03, 95% CI 0.83-1.28). CONCLUSIONS. Obesity is more common than underweight status among children with asthma. Both underweight and obese children with asthma have worse lung function and asthma-related outcomes compared to similar normal weight children, though the phenotypic characteristics of underweight and obese asthmatics differed considerably.