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1.  Clinical Predictors and Outcomes of Consistent Bronchodilator Response in the Childhood Asthma Management Program 
Among asthmatics, bronchodilator response (BDR) to inhaled ß2- adrenergic agonists is variable, and the significance of a consistent response over time is unknown.
We assessed baseline clinical variables and determined the clinical outcomes associated with a consistently positive BDR over 4 years in children with mild-moderate persistent asthma.
In the 1,041 participants in the Childhood Asthma Management Program (CAMP), subjects with a change in FEV1 of 12% or greater (and 200mLs) after inhaled ß2 agonist at each of their yearly follow-up visits (consistent BDR) were compared with those who did not have a consistent BDR.
We identified 52 children with consistent BDR over the 4-year trial. Multivariable logistic regression modeling demonstrated that baseline pre-bronchodilator FEV1 (OR=0.71, p<0.0001), log 10 IgE level (OR=1.97, p=0.002), and lack of treatment with inhaled corticosteroids (OR=0.31, p=0.009) were associated with a consistent BDR. Individuals who had a consistent BDR had more hospital visits (p=0.007), required more prednisone bursts (p=0.0007), had increased nocturnal awakenings due to asthma (p<0.0001), and missed more days of school (p=0.03) than non-responders during the 4-year follow-up.
We have identified predictors of consistent BDR and determined that this phenotype is associated with poor clinical outcomes.
PMCID: PMC2947830  PMID: 18848350
asthma; consistent bronchodilator response; outcomes
2.  Airway wall thickness is increased in COPD patients with bronchodilator responsiveness 
Respiratory Research  2014;15(1):84.
Bronchodilator responsiveness (BDR) is a common but variable phenomenon in COPD. The CT characteristics of airway dimensions that differentiate COPD subjects with BDR from those without BDR have not been well described. We aimed to assess airway dimensions in COPD subjects with and without BDR.
We analyzed subjects with GOLD 1–4 disease in the COPDGene® study who had CT airway analysis. We divided patients into two groups: BDR + (post bronchodilator ΔFEV1 ≥ 10%) and BDR-(post bronchodilator ΔFEV1 < 10%). The mean wall area percent (WA%) of six segmental bronchi in each subject was quantified using VIDA. Using 3D SLICER, airway wall thickness was also expressed as the square root wall area of an airway of 10 mm (Pi10) and 15 mm (Pi15) diameter. %Emphysema and %gas trapping were also calculated.
2355 subjects in the BDR-group and 1306 in the BDR + group formed our analysis. The BDR + group had a greater Pi10, Pi15, and mean segmental WA% compared to the BDR-group. In multivariate logistic regression using gender, race, current smoking, history of asthma, %emphysema, %gas trapping, %predicted FEV1, and %predicted FVC, airway wall measures remained independent predictors of BDR. Using a threshold change in FEV1 ≥ 15% and FEV1 ≥ 12% and 200 mL to divide patients into groups, the results were similar.
BDR in COPD is independently associated with CT evidence of airway pathology. This study provides us with greater evidence of changes in lung structure that correlate with physiologic manifestations of airflow obstruction in COPD.
PMCID: PMC4198908  PMID: 25248436
Bronchodilator responsiveness; Airway wall thickness; Chronic obstructive pulmonary disease; Airflow obstruction
3.  Development of a Pharmacogenetic Predictive Test in asthma: proof of concept 
Pharmacogenetics and genomics  2010;20(2):86-93.
To assess the feasibility of developing a Combined Clinical and Pharmacogenetic Predictive Test, comprised of multiple single nucleotide polymorphisms (SNPs) that is associated with poor bronchodilator response (BDR).
We genotyped SNPs that tagged the whole genome of the parents and children in the Childhood Asthma Management Program (CAMP) and implemented an algorithm using a family-based association test that ranked SNPs by statistical power. The top eight SNPs that were associated with BDR comprised the Pharmacogenetic Predictive Test. The Clinical Predictive Test was comprised of baseline forced expiratory volume in 1 s (FEV1). We evaluated these predictive tests and a Combined Clinical and Pharmacogenetic Predictive Test in three distinct populations: the children of the CAMP trial and two additional clinical trial populations of asthma. Our outcome measure was poor BDR, defined as BDR of less than 20th percentile in each population. BDR was calculated as the percent difference between the prebronchodilator and postbronchodilator (two puffs of albuterol at 180 μg/puff) FEV1 value. To assess the predictive ability of the test, the corresponding area under the receiver operating characteristic curves (AUROCs) were calculated for each population.
The AUROC values for the Clinical Predictive Test alone were not significantly different from 0.50, the AUROC of a random classifier. Our Combined Clinical and Pharmacogenetic Predictive Test comprised of genetic polymorphisms in addition to FEV1 predicted poor BDR with an AUROC of 0.65 in the CAMP children (n= 422) and 0.60 (n= 475) and 0.63 (n= 235) in the two independent populations. Both the Combined Clinical and Pharmacogenetic Predictive Test and the Pharmacogenetic Predictive Test were significantly more accurate than the Clinical Predictive Test (AUROC between 0.44 and 0.55) in each of the populations.
Our finding that genetic polymorphisms with a clinical trait are associated with BDR suggests that there is promise in using multiple genetic polymorphisms simultaneously to predict which asthmatics are likely to respond poorly to bronchodilators.
PMCID: PMC3654515  PMID: 20032818
asthma; bronchodilator response; personalized medicine; pharmacogenetic test; predictive medicine
4.  Assessment of Bronchodilator Responsiveness Following Methacholine-Induced Bronchoconstriction in Children With Asthma 
The aim of this study was to investigate bronchodilator responsiveness (BDR) following methacholine-induced bronchoconstriction and to determine differences in BDR according to clinical parameters in children with asthma.
The methacholine challenge test was performed in 145 children with mild to moderate asthma, and the provocative concentration causing a 20% decline in FEV1 (PC20) was determined. Immediately after the challenge test, patients were asked to inhale short-acting β2-agonists (SABAs) to achieve BDR, which was assessed as the change in FEV1% predicted×100/post-methacholine FEV1% predicted. For each subject, the asthma medication, blood eosinophil count, serum total IgE, serum eosinophil cationic protein level, and skin prick test result were assessed.
The FEV1 (mean±SD) values of the 145 patients were 90.5±10.9% predicted, 64.2±11.5% predicted, and 86.2±11.2% predicted before and after methacholine inhalation, and following the administration of a SABA, respectively. The BDR did not differ significantly according to asthma medication, age, or gender. However, BDR in the atopy group (37.4±17.7%) was significantly higher than that in the non-atopy group (30.5±10.7%; P=0.037). Patients with blood eosinophilia (38.6±18.1%) displayed increased BDR compared with patients without eosinophilia (32.0±13.8%; P=0.037).
In children with mild to moderate asthma, the responsiveness to short-acting bronchodilators after methacholine-induced bronchoconstriction was not related to asthma medication, but was higher in children with atopy and/or peripheral blood eosinophilia.
PMCID: PMC3178822  PMID: 21966604
Atopy; asthma; beta-adrenergic agonist; child; eosinophilia; methacholine
5.  A polymorphism in the thyroid hormone receptor gene is associated with bronchodilator response in asthmatics 
The pharmacogenomics journal  2012;13(2):130-136.
A pro-asthmatic culture milieu and β2-agonist (isoproterenol) were previously shown to regulate the expression of select transcription factors (TFs) within human airway epithelial and smooth muscle cells. This study tests 1116 single nucleotide polymorphisms (SNPs) across 98 of these TF genes for association with bronchodilator response (BDR) in asthma patients. Genotyping was conducted using the Illumina HumanHap550v3 Beadchip in 403 non-Hispanic White asthmatic children and their parents. SNPs were evaluated for association with BDR using family and population-based analyses. Forty-two SNPs providing p values < 0.1 in both analyses were then genotyped in three adult asthma trials. One SNP 5’ of the thyroid hormone receptor beta gene was associated with BDR in the childhood population and two adult populations (p value = 0.0012). This investigation identified a novel locus for inter-individual variability in BDR and represents a translation of a cellular drug-response study to potential personalization of clinical asthma management.
PMCID: PMC3349771  PMID: 22212731
Bronchodilator response; transcription factor; association; thyroid hormone receptor β; asthma; pharmacogenetics
6.  A genome-wide association study of bronchodilator response in asthmatics 
The pharmacogenomics journal  2013;14(1):41-47.
Reversibility of airway obstruction in response to β2-agonists is highly variable among asthmatics, which is partially attributed to genetic factors. In a genome-wide association study of acute bronchodilator response (BDR) to inhaled albuterol, 534,290 single nucleotide polymorphisms (SNPs) were tested in 403 white trios from the Childhood Asthma Management Program using five statistical models to determine the most robust genetic associations. The primary replication phase included 1397 polymorphisms in three asthma trials (pooled n=764). The second replication phase tested 13 SNPs in three additional asthma populations (n=241, n=215, and n=592). An intergenic SNP on chromosome 10, rs11252394, proximal to several excellent biological candidates, significantly replicated (p=1.98×10−7) in the primary replication trials. An intronic SNP (rs6988229) in the collagen (COL22A1) locus also provided strong replication signals (p=8.51×10−6). This study applied a robust approach for testing the genetic basis of BDR and identified novel loci associated with this drug response in asthmatics.
PMCID: PMC3706515  PMID: 23508266
pharmacogenetics; asthma; bronchodilator response; genome-wide association study; albuterol
7.  Variability of bronchodilator response and effects of inhaled corticosteroid treatment in obstructive airways disease. Dutch CNSLD Study Group. 
Thorax  1993;48(7):722-729.
BACKGROUND--In the day to day care of obstructive airways diseases (asthma and chronic obstructive pulmonary disease) important decisions such as disease classification and choice of therapy are based on assessment of the bronchodilator response. However, surprisingly little is known of the long term course of the bronchodilator response in patients with obstructive airways disease. METHODS--Data from a multicentre trial were used in which 274 patients aged 18-60 years with airways obstruction were selected with PC20 < 8 mg/ml and FEV1 < 95% CI of predicted. FEV1 was measured before and 20 minutes after 1000 micrograms terbutaline and 40 minutes after an additional 80 micrograms ipratropium bromide. Data were analysed from 185 patients who were followed up for 21 months (five measurements). Four different expressions of bronchodilator response (BDR) were examined for change under long term therapy, long term variability, and prognostic value in predicting response to inhaled corticosteroids. RESULTS--There was a significant reduction in BDR of 117 ml after three months of treatment with a beta 2 agonist plus a corticosteroid (BA + CS), but not after bronchodilators only. Significant reductions with BA + CS were also found in BDR as a percentage of initial FEV1, and in BDR as a percentage of predicted FEV1. Bronchodilator tests were quite variable (SD 186 ml or 11% of initial value) and less than half of the patients could consistently be classified as "irreversible" with recommended cutoff levels. The bronchodilator response at the start of the study proved to be a poor predictor of improvement in FEV1 under BA + CS treatment (correct prediction 60%). CONCLUSIONS--Bronchodilator responses decrease substantially with inhaled corticosteroid therapy, and within subject variability is considerable both in asthma and chronic obstructive pulmonary disease. Dichotomous decisions on whether patients are "irreversible" according to any single bronchodilator measurement should therefore be made with great caution. The bronchodilator response cannot be used accurately as a predictor of response to inhaled corticosteroids in obstructive airways disease.
PMCID: PMC464656  PMID: 8153921
8.  Diagnostic accuracy of the bronchodilator response in children 
The bronchodilator response (BDR) reflects the reversibility of airflow obstruction and is recommended as an adjunctive test to diagnose asthma. The validity of the commonly used definition of BDR, a 12% or greater change in FEV1 from baseline, has been questioned in childhood.
We sought to examine the diagnostic accuracy of the BDR test by using 3 large pediatric cohorts.
Cases include 1041 children with mild-to-moderate asthma from the Childhood Asthma Management Program.
Control subjects (nonasthmatic and nonwheezing) were chosen from Project Viva and Home Allergens, 2 population-based pediatric cohorts. Receiver operating characteristic curves were constructed, and areas under the curve were calculated for different BDR cutoffs.
A total of 1041 cases (59.7% male; mean age, 8.9 ± 2.1 years) and 250 control subjects (46.8% male; mean age, 8.7 ± 1.7 years) were analyzed, with mean BDRs of 10.7% ± 10.2% and 2.7% ± 8.4%, respectively. The BDR test differentiated asthmatic patients from nonasthmatic patients with a moderate accuracy (area under the curve, 73.3%).
Despite good specificity, a cutoff of 12% was associated with poor sensitivity (35.6%). A cutoff of less than 8% performed significantly better than a cutoff of 12% (P = .03, 8% vs 12%).
Our findings highlight the poor sensitivity associated with the commonly used 12% cutoff for BDR. Although our data show that a threshold of less than 8% performs better than 12%, given the variability of this test in children, we conclude that it might be not be appropriate to choose a specific BDR cutoff as a criterion for the diagnosis of asthma.
PMCID: PMC3759549  PMID: 23683464
Asthma; bronchodilator response; diagnosis
9.  The role of inhaled and/or nasal corticosteroids on the bronchodilator response 
Korean Journal of Pediatrics  2010;53(11):951-956.
To compare the profiles of the bronchodilator response (BDR) among children with asthma and/or allergic rhinitis (AR) and to determine whether BDR in these children is reduced by treatment with inhaled and/or nasal corticosteroid.
Sixty-eight children with asthma (mean age, 10.9 years), 45 children with comorbid asthma and AR (mean age, 10.5 years), and 44 children with AR alone (mean age, 10.2 years) were investigated. After a 2-week baseline period, all children were treated with inhaled fluticasone propionate (either 100 or 250 µg b.i.d., tailored to asthma severity) or nasal fluticasone propionate (one spray b.i.d. in each nostril) or both, according to the condition. Before and 2 weeks after starting treatment, all children were evaluated with spirometry and bronchodilator testing. BDR was calculated as a percent change from the forced expiratory volume in 1 second (FEV1) at baseline.
The mean BDR was 10.3% [95% confidence interval (CI) 8.3-12.4%] in children with asthma, 9.0% (95% CI 7.3-10.9%) in subjects with asthma and AR, and 5.0% (95% CI 4.1-5.9%) in children with AR alone (P<0.001). After treatment, the mean BDR was reduced to 5.2% (95% CI 4.2-6.3%) (P<0.001) in children with asthma and to 4.5% (95% CI 3.5-5.5%) (P<0.001) in children with asthma and AR. However, children with rhinitis showed no significant change in BDR after treatment, with the mean value being 4.7% (95% CI 3.7-5.8%) (P=0.597).
The findings of this study imply that an elevated BDR in children with AR cannot be attributed to nasal inflammation alone and highlights the close relationship between the upper and lower airways.
PMCID: PMC3012275  PMID: 21218017
Bronchodilator response; Nasal corticosteroids; Inhaled corticosteroids; Asthma; Allergic rhinitis
10.  ARG1 Is a Novel Bronchodilator Response Gene 
Rationale: Inhaled β-agonists are one of the most widely used classes of drugs for the treatment of asthma. However, a substantial proportion of patients with asthma do not have a favorable response to these drugs, and identifying genetic determinants of drug response may aid in tailoring treatment for individual patients.
Objectives: To screen variants in candidate genes in the steroid and β-adrenergic pathways for association with response to inhaled β-agonists.
Methods: We genotyped 844 single nucleotide polymorphisms (SNPs) in 111 candidate genes in 209 children and their parents participating in the Childhood Asthma Management Program. We screened the association of these SNPs with acute response to inhaled β-agonists (bronchodilator response [BDR]) using a novel algorithm implemented in a family-based association test that ranked SNPs in order of statistical power. Genes that had SNPs with median power in the highest quartile were then taken for replication analyses in three other asthma cohorts.
Measurements and Main Results: We identified 17 genes from the screening algorithm and genotyped 99 SNPs from these genes in a second population of patients with asthma. We then genotyped 63 SNPs from four genes with significant associations with BDR, for replication in a third and fourth population of patients with asthma. Evidence for association from the four asthma cohorts was combined, and SNPs from ARG1 were significantly associated with BDR. SNP rs2781659 survived Bonferroni correction for multiple testing (combined P value = 0.00048, adjusted P value = 0.047).
Conclusions: These findings identify ARG1 as a novel gene for acute BDR in both children and adults with asthma.
PMCID: PMC2556451  PMID: 18617639
pharmacogenetics; asthma; bronchodilator agents
11.  Regulatory Haplotypes in ARG1 Are Associated with Altered Bronchodilator Response 
Rationale: β2-agonists, the most common treatment for asthma, have a wide interindividual variability in response, which is partially attributed to genetic factors. We previously identified single nucleotide polymorphisms in the arginase 1 (ARG1) gene, which are associated with β2-agonist bronchodilator response (BDR).
Objectives: To identify cis-acting haplotypes in the ARG1 locus that are associated with BDR in patients with asthma and regulate gene expression in vitro.
Methods: We resequenced ARG1 in 96 individuals and identified three common, 5′ haplotypes (denoted 1, 2, and 3). A haplotype-based association analysis of BDR was performed in three independent, adult asthma drug trial populations. Next, each haplotype was cloned into vectors containing a luciferase reporter gene and transfected into human airway epithelial cells (BEAS-2B) to ascertain its effect on gene expression.
Measurements and Main Results: BDR varied by haplotype in each of the three populations with asthma. Individuals with haplotype 1 were more likely to have higher BDR, compared to those with haplotypes 2 and 3, which is supported by odds ratios of 1.25 (95% confidence interval, 1.03–1.71) and 2.18 (95% confidence interval, 1.34–2.52), respectively. Luciferase expression was 50% greater in cells transfected with haplotype 1 compared to haplotypes 2 and 3.
Conclusions: The identified ARG1 haplotypes seem to alter BDR and differentially regulate gene expression with a concordance of decreased BDR and reporter activity from haplotypes 2 and 3. These findings may facilitate pharmacogenetic tests to predict individuals who may benefit from other therapeutic agents in addition to β2-agonists for optimal asthma management.
Clinical trial registered with (NCT00156819, NCT00046644, and NCT00073840).
PMCID: PMC3056223  PMID: 20851928
pharmacogenetics; asthma; β2-agonist
12.  Bronchodilator Responsiveness in Wheezy Infants and Toddlers is Not Associated with Asthma Risk Factors 
Pediatric Pulmonology  2011;47(5):421-428.
There are limited data assessing bronchodilator responsiveness (BDR) in infants and toddlers with recurrent wheezing, and factors associated with a positive response.
In a multicenter study of children ≤ 36 months old we assessed the prevalence of and factors associated with BDR among infants/toddlers with recurrent episodes of wheezing.
Forced expiratory flows and volumes using the raised-volume rapid thoracic compression method were measured in 76 infants/toddlers (mean (sd) age 16.8 (7.6) mos.) with recurrent wheezing before and after administration of albuterol. Prior history of hospitalization or emergency department treatment for wheezing, use of inhaled or systemic corticosteroids, physician treatment of eczema, environmental tobacco smoke exposure, and family history of asthma or allergic rhinitis were ascertained.
Using the published upper limit of normal for post bronchodilator change (FEV0.5 ≥ 13% and/or FEF25–75 ≥ 24%) in healthy infants, 24% (n=18) of children in our study exhibited BDR. The BDR response was not associated with any clinical factor other than body size. Dichotomizing subjects into responders (defined by published limits of normal)or by quartile to identify children with the greatest change from baseline (4th quartile vs. other) did not identify any other factor associated with BDR.
Approximately one quarter of infants/toddlers with recurrent wheezing exhibited BDR at their clinical baseline. However, BDR in wheezy infants/toddlers was not associated with established clinical asthma risk factors.
PMCID: PMC3325342  PMID: 22006677
recurrent wheezing; infants; pulmonary function; raised-volume rapid thoracoabdominal compression; bronchodilator responsiveness; asthma
13.  Oscillometric and spirometric bronchodilator response in preschool children with and without asthma 
Bronchodilator responses (BDR) are routinely used in the diagnosis and management of asthma; however, their acceptability and repeatability have not been evaluated using quality control criteria for preschool children.
To compare conventional spirometry with an impulse oscillometry system (IOS) in healthy and asthmatic preschool children.
Data from 30 asthmatic children and 29 controls (two to six years of age) who underwent IOS and spirometry before and after salbutamol administration were analyzed.
Stable asthmatic subjects significantly differed versus controls in their spirometry-assessed BDR (forced expiratory volume in 1 s [FEV1], forced vital capacity and forced expiratory flow at 25% to 75% of forced vital capacity) as well as their IOS-assessed BDR (respiratory resistance at 5 Hz [Rrs5], respiratory reactance at 5 Hz and area under the reactance curve). However, comparisons based on the area under the ROC curve for ΔFEV1 % initial versus ΔRrs5 % initial were 0.82 (95% CI 0.71 to 0.93) and 0.75 (95% CI 0.62 to 0.87), respectively. Moreover, the sensitivity and specificity for ΔFEV1 ≥9% were 0.53 and 0.93, respectively. Importantly, sensitivity increased to 0.63 when either ΔFEV1 ≥9% or ΔRrs5 ≥29% was considered as an additional criterion for the diagnosis of asthma.
The accuracy of asthma diagnosis in preschool children may be increased by combining spirometry with IOS when measuring BDR.
PMCID: PMC3411394  PMID: 22891189
Asthma; Bronchodilator agents; Oscillometry; Preschool; Spirometry
14.  Genetic association analysis of COPD candidate genes with bronchodilator responsiveness 
Respiratory medicine  2008;103(4):552-557.
Airflow limitation in COPD patients is not fully reversible. However, there may be large variability in bronchodilator responsiveness (BDR) among COPD patients, and familial aggregation of BDR suggests a genetic component. Therefore we investigated the association between six candidate genes and BDR in subjects with severe COPD. A total of 389 subjects from the National Emphysema Treatment Trial (NETT) were analyzed. Bronchodilator responsiveness to albuterol was expressed in three ways: absolute change in FEV1, change in FEV1 as a percent of baseline FEV1, and change in FEV1 as a percent of predicted FEV1. Genotyping was completed for 122 single nucleotide polymorphisms (SNPs) in six candidate genes (EPHX1, SFTPB, TGFB1, SERPINE2, GSTP1, ADRB2). Associations between BDR phenotypes and SNP genotypes were tested using linear regression, adjusting for age, sex, pack-years of smoking, and height. Genes associated with BDR phenotypes in the NETT subjects were assessed for replication in 127 pedigrees from the Boston Early-Onset COPD (EOCOPD) Study. Three SNPs in EPHX1 (p = 0.009 – 0.04), three SNPs in SERPINE2 (p = 0.004 – 0.05) and two SNPs in ADRB2 (0.04 – 0.05) were significantly associated with BDR phenotypes in NETT subjects. BDR. One SNP in EPHX1 (rs1009668, p = 0.04) was significantly replicated in EOCOPD subjects. SNPs in SFTPB, TGFB1, and GSTP1 genes were not associated with BDR. In conclusion, a polymorphism of EPHX1 was associated with bronchodilator responsiveness phenotypes in subjects with severe COPD.
PMCID: PMC2745950  PMID: 19111454
bronchodilator responsiveness; chronic obstructive pulmonary disease; genetics; association analysis
15.  Genome‐wide linkage analysis of pulmonary function in families of children with asthma in Costa Rica 
Thorax  2006;62(3):224-230.
Although asthma is highly prevalent among certain Hispanic subgroups, genetic determinants of asthma and asthma‐related traits have not been conclusively identified in Hispanic populations. A study was undertaken to identify genomic regions containing susceptibility loci for pulmonary function and bronchodilator responsiveness (BDR) in Costa Ricans.
Eight extended pedigrees were ascertained through schoolchildren with asthma in the Central Valley of Costa Rica. Short tandem repeat (STR) markers were genotyped throughout the genome at an average spacing of 8.2 cM. Multipoint variance component linkage analyses of forced expiratory volume in 1 second (FEV1) and FEV1/ forced vital capacity (FVC; both pre‐bronchodilator and post‐bronchodilator) and BDR were performed in these eight families (pre‐bronchodilator spirometry, n = 640; post‐bronchodilator spirometry and BDR, n = 624). Nine additional STR markers were genotyped on chromosome 7. Secondary analyses were repeated after stratification by cigarette smoking.
Among all subjects, the highest logarithm of the odds of linkage (LOD) score for FEV1 (post‐bronchodilator) was found on chromosome 7q34–35 (LOD = 2.45, including the additional markers). The highest LOD scores for FEV1/FVC (pre‐bronchodilator) and BDR were found on chromosomes 2q (LOD = 1.53) and 9p (LOD = 1.53), respectively. Among former and current smokers there was near‐significant evidence of linkage to FEV1/FVC (post‐bronchodilator) on chromosome 5p (LOD = 3.27) and suggestive evidence of linkage to FEV1 on chromosomes 3q (pre‐bronchodilator, LOD = 2.74) and 4q (post‐bronchodilator, LOD = 2.66).
In eight families of children with asthma in Costa Rica, there is suggestive evidence of linkage to FEV1 on chromosome 7q34–35. In these families, FEV1/FVC may be influenced by an interaction between cigarette smoking and a locus (loci) on chromosome 5p.
PMCID: PMC2117166  PMID: 17099076
16.  Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene 
PLoS ONE  2013;8(2):e56179.
Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data.
PMCID: PMC3572953  PMID: 23457522
17.  The utility of forced expiratory flow between 25% and 75% of vital capacity in predicting childhood asthma morbidity and severity 
The Journal of Asthma  2012;49(6):586-592.
The forced expiratory volume in one second (FEV1), felt to be an objective measure of airway obstruction, is often normal in asthmatic children. The forced expiratory flow between 25% and 75% of vital capacity (FEF25-75) reflects small airway patency and has been found to be reduced in children with asthma. The aim of this study was to determine if FEF25-75 is associated with increased childhood asthma severity and morbidity in the setting of a normal FEV1, and to determine if bronchodilator responsiveness (BDR) as defined by FEF25-75 identifies more childhood asthmatics than does BDR defined by FEV1.
The Children’s Hospital Boston Pulmonary Function Test database was queried and the most recent spirometry result was retrieved for 744 children diagnosed with asthma between 10–18 years of age between October 2000 and October 2010. Electronic medical records in the 1 year prior and the 1 year following the date of spirometry were examined for asthma severity (mild, moderate or severe) and morbidity outcomes for three age, race and gender-matched subgroups: group A (n= 35) had a normal FEV1, FEV1/FVC and FEF25-75; Group B (n= 36) had solely a diminished FEV1/FVC; and Group C (n=37) had a normal FEV1, low FEV1/FVC and low FEF25-75. Morbidity outcomes analyzed included the presence of hospitalization, emergency department visit, intensive care unit admission, asthma exacerbation, and systemic steroid use.
Subjects with a low FEF25-75 (Group C) had nearly 3 times the odds (OR 2.8, p<0.01) of systemic corticosteroid use and 6 times the odds of asthma exacerbations (OR 6.3, p>0.01) compared with those who had normal spirometry (Group A). Using FEF25-75 to define bronchodilator responsiveness identified 53% more subjects with asthma than did using a definition based on FEV1.
A low FEF25-75 in the setting of a normal FEV1 is associated with increased asthma severity, systemic steroid use and asthma exacerbations in children. In addition, using the percent change in FEF25-75 from baseline may be helpful in identifying bronchodilator responsiveness in asthmatic children with a normal FEV1.
PMCID: PMC3398223  PMID: 22742446
spirometry; childhood asthma; FEF25-75; bronchodilator responsiveness
18.  Acute bronchodilator responsiveness and health outcomes in COPD patients in the UPLIFT trial 
Respiratory Research  2011;12(1):6.
Debate continues as to whether acute bronchodilator responsiveness (BDR) predicts long-term outcomes in COPD. Furthermore, there is no consensus on a threshold for BDR.
At baseline and during the 4-year Understanding Potential Long-term Improvements in Function with Tiotropium (UPLIFT®) trial, patients had spirometry performed before and after administration of ipratropium bromide 80 mcg and albuterol 400 mcg. Patients were split according to three BDR thresholds: ≥12% + ≥200 mL above baseline (criterion A), ≥15% above baseline (criterion B); and ≥10% absolute increase in percent predicted FEV1 values (criterion C). Several outcomes (pre-dose spirometry, exacerbations, St. George's Respiratory Questionnaire [SGRQ] total score) were assessed according to presence or absence of BDR in the treatment groups.
5783 of 5993 randomized patients had evaluable pre- and post-bronchodilator spirometry at baseline. Mean age (SD) was 64 (8) years, with 75% men, mean post-bronchodilator FEV1 1.33 ± 0.44 L (47.6 ± 12.7% predicted) and 30% current smokers. At baseline, 52%, 66%, and 39% of patients had acute BDR using criterion A, B, and C, respectively. The presence of BDR was variable at follow-up visits. Statistically significant improvements in spirometry and health outcomes occurred with tiotropium regardless of the baseline BDR or criterion used.
A large proportion of COPD patients demonstrate significant acute BDR. BDR in these patients is variable over time and differs according to the criterion used. BDR status at baseline does not predict long-term response to tiotropium. Assessment of acute BDR should not be used as a decision-making tool when prescribing tiotropium to patients with COPD.
PMCID: PMC3027109  PMID: 21219660
19.  The Relationship of the Bronchodilator Response (BDR) Phenotype to Poor Asthma Control in Children with Normal Spirometry 
The Journal of pediatrics  2011;158(6):953-959.e1.
The purpose of this study was to determine the relationship of poor asthma control to bronchodilator response (BDR) phenotypes in children with normal spirometry.
Asthmatic children were assessed for clinical indices of poorly controlled asthma. Pre and post bronchodilator spirometry were performed and the percent BDR determined. Multivariate logistic regression assessed the relationship of the clinical indices to BDR at ≥8%, ≥10% and ≥12% BDR thresholds.
There were 510 controller naïve, and 169 on controller medication. In the controller naïve population the mean age (± 1SD) was 9.5 (3.4), 57.1% were male, 85.7% Hispanic. Demographics were similar in both populations. In the adjusted profile, significant clinical relationships were found particularly to positive BDR phenotypes ≥10% and ≥12% versus negative responses including younger age, (odds ratios (OR) 2.0, 2.5; P <.05), atopy (OR 1.9, 2.6;P< .01), nocturnal symptoms in females (OR 3.4, 3.8;P< .01); beta2 agonist use (OR 1.7, 2.8;P< .01); and exercise limitation (OR 2.2, 2.5;P< .01) only in the controller naïve population.
The BDR phenotype ≥10% is significantly related to poor asthma control providing a potentially useful objective tool in controller naïve children even when prebronchodilator spirometry is normal.
PMCID: PMC3160763  PMID: 21232757
Pulmonary function; Pediatric; Bronchial asthma
20.  Logistic Regression Model for Prediction of Airway Reversibility Using Peak Expiratory Flow 
Tanaffos  2012;11(1):49-54.
Using peak expiratory flow (PEF) as an alternative to spirometry parameters (FEV1 and FVC), for detection of airway reversibility in diseases with airflow limitation is challenging. We developed logistic regression (LR) model to discriminate bronchodilator responsiveness (BDR) and then compared the results of models with a performance of >18%, >20%, and >22% increase in ΔPEF% (PEF change relative to baseline), as a predictor for bronchodilator responsiveness (BDR).
Materials and Methods
PEF measurements of pre-bronchodilator, post-bronchodilator and ΔPEF% of 90 patients with asthma (44) and chronic obstructive pulmonary disease (46) were used as inputs of model and the output was presence or absence of the BDR.
Although ΔPEF% was a poor discriminator, LR model could improve the accuracy of BDR. Sensitivity, specificity, positive predictive value, and negative predictive value of LR were 68.89%, 67.27%, 71.43%, and 78.72%, respectively.
The LR is a reliable method that can be used clinically to predict BDR based on PEF measurements.
PMCID: PMC4153189  PMID: 25191401
Peak expiratory flow; Spirometry; Airway reversibility; Logistic regression
21.  A methodology to establish a database to study gene environment interactions for childhood asthma 
Gene-environment interactions are likely to explain some of the heterogeneity in childhood asthma. Here, we describe the methodology and experiences in establishing a database for childhood asthma designed to study gene-environment interactions (PAGES - Paediatric Asthma Gene Environment Study).
Children with asthma and under the care of a respiratory paediatrician are being recruited from 15 hospitals between 2008 and 2011. An asthma questionnaire is completed and returned by post. At a routine clinic visit saliva is collected for DNA extraction. Detailed phenotyping in a proportion of children includes spirometry, bronchodilator response (BDR), skin prick reactivity, exhaled nitric oxide and salivary cotinine. Dietary and quality of life questionnaires are completed. Data are entered onto a purpose-built database.
To date 1045 children have been invited to participate and data collected in 501 (48%). The mean age (SD) of participants is 8.6 (3.9) years, 57% male. DNA has been collected in 436 children. Spirometry has been obtained in 172 children, mean % predicted (SD) FEV1 97% (15) and median (IQR) BDR is 5% (2, 9). There were differences in age, socioeconomic status, severity and %FEV1 between the different centres (p≤0.024). Reasons for non-participation included parents not having time to take part, children not attending clinics and, in a small proportion, refusal to take part.
It is feasible to establish a national database to study gene-environment interactions within an asthmatic paediatric population; there are barriers to participation and some different characteristics in individuals recruited from different centres. Recruitment to our study continues and is anticipated to extend current understanding of asthma heterogeneity.
PMCID: PMC3019209  PMID: 21134251
22.  Decreased response to inhaled steroids in overweight and obese asthmatic children 
The mechanisms and consequences of the observed association between obesity and childhood asthma are unclear.
To determine the effect of obesity on treatment responses to inhaled corticosteroids in asthmatic children.
We performed a post hoc analysis to evaluate the interaction between body mass index (BMI) and treatment with inhaled budesonide on lung function in the Childhood Asthma Management Program (CAMP) trial. Participants were then stratified into overweight/obese and non-overweight, and their response to inhaled budesonide was analyzed longitudinally over the 4 years of the trial.
There was a significant interaction between BMI and budesonide for pre-BD FEV1/FVC (P=0.0007) and bronchodilator response (BDR) (P=0.049), and a non-significant trend for an interaction between BMI and budesonide on pre-BD FEV1 (P=0.15). Non-overweight children showed significant improvement with inhaled budesonide in lung function (FEV1, FEV1/FVC, and BDR) during the early (years 1–2) and late stages (years 3–4) of the trial. Overweight/obese children had improved FEV1 and BDR during the early but not the late stage of the trial, and showed no improvement in FEV1/FVC. When comparing time points where both groups showed significant response, the degree of improvement among non-overweight children was significantly greater than in overweight/obese children at most visits. Non-overweight children had a 44% reduction in the risk of ER visits or hospitalizations throughout the trial (P=0.001); there was no reduction in risk among overweight/obese (P=0.97).
Compared to children of normal weight, overweight/obese children in CAMP showed a decreased response to inhaled budesonide on measures of lung function and ER visits/hospitalizations for asthma.
PMCID: PMC3056233  PMID: 21377042
Asthma; obesity; pediatric asthma; childhood obesity; budesonide
23.  Asthma Diagnosis and Airway Bronchodilator Response in HIV-infected Individuals 
Despite the high prevalence of respiratory symptoms and obstructive lung disease in HIV-infected persons, the prevalence of bronchodilator reversibility (BDR) and asthma has not been systematically studied during the era of combination antiretroviral therapy (ART).
To determine the prevalence of asthma diagnosis and related pulmonary function abnormalities in an HIV-infected cohort and to identify potential mechanisms.
A cross-sectional analysis of 223 HIV-infected individuals with data on respiratory symptoms and diagnoses, pulmonary function, sputum cell counts, and asthma-related cytokines and chemokines in serum/sputum.
Doctor-diagnosed asthma was present in 46 (20.6%) and BDR (≥200ml and ≥12% increase in FEV1 or FVC) in 20 participants (9.0%). Pulmonary symptoms and function were worse in those with doctor-diagnosed asthma. Doctor-diagnosed asthma was independently associated with female sex (p=0.04), body mass index >29.6kg/m2 (vs.<29.6kg/m2) (p=0.03), history of bacterial or Pneumocystis pneumonia (p=0.01), and with not currently taking ART (p=0.04), and in univariate analysis with parental history of asthma (n=180; p=0.004). High sputum eosinophil percentages (>2.3% based on the highest decile) were more likely in those with doctor-diagnosed asthma (p=0.02) or BDR (p=0.02). Doctor-diagnosed asthma tended to be more common with high sputum IL-4 (p=0.02) and RANTES (p=0.02), while BDR was associated with high plasma macrophage inflammatory protein (MIP)-1α (p=0.002), and sputum MIP-1β levels (p=0.001).
Asthma diagnosis and BDR are prevalent in an HIV-infected outpatient cohort, and associations with family history, obesity, allergic inflammation, prior infection, the absence of ART, and elevated HIV-stimulated cytokines suggest possible mechanisms of HIV-associated asthma.
PMCID: PMC3294124  PMID: 22177327
HIV; asthma; airway obstruction; allergy
24.  Exhaled Nitric Oxide Predicts Persistence of Wheezing, Exacerbations, and Decline in Lung Function in Wheezy Infants and Toddlers 
There are limited data assessing the predictive value of fraction of exhaled nitric oxide (FENO) for persistence of wheezing, exacerbations, or lung function change over time in infants/toddlers with recurrent wheezing.
In an ongoing longitudinal cohort of infants and toddlers with recurrent wheezing compare predictive values of single-breath FENO (SB-FENO), tidal-breathing mixed-expired FENO (tidal-FENO), bronchodilator responsiveness (BDR), and the Castro-Rodriquez asthma predictive index (API) for persistence of wheezing, exacerbations, and lung function change through age 3 yrs.
Enrollment forced expiratory flows and volumes (iPFTs) were measured in 44 infants/toddlers using the raised-volume rapid thoracoabdominal compression method. SB-FENO was measured at 50 mL/sec, and tidal-FENO was measured during awake tidal breathing. Clinical outcomes were assessed at age 3 yrs. in 42 infants. Follow-up iPFTs were completed between ages 2.5-3 yrs. in 32 subjects.
An enrollment SB-FENO concentration ≥30 ppb predicted persistence of wheezing at age 3 years with a sensitivity of 77%, a specificity of 94%, and an area under the curve (AUC) of 0.86 (95% CI: 0.74 – 0.98). The sensitivity, specificity, positive predictive, and negative predictive values of SB-FENO for persistence of wheezing and exacerbations were superior to tidal-FENO, BDR, and the API. SB-FENO ≥30 ppb and tidal FENO ≥7 ppb measured at enrollment was associated with a decline in both FEV0.5 and FEF25-75 between enrollment and age 3 years.
In wheezy infants/toddlers SB-FENO was superior to tidal-FENO, BDR, and the API in predicting future exacerbations and persistence of wheezing at age 3 years. Both SB-FENO and tidal FENO were associated with lung function decline over time.
PMCID: PMC3839057  PMID: 24261945
exhaled nitric oxide; FENO; recurrent wheezing; infants; pulmonary function; raised-volume rapid thoracic compression
25.  ITGB5 and AGFG1 variants are associated with severity of airway responsiveness 
BMC Medical Genetics  2013;14:86.
Airway hyperresponsiveness (AHR), a primary characteristic of asthma, involves increased airway smooth muscle contractility in response to certain exposures. We sought to determine whether common genetic variants were associated with AHR severity.
A genome-wide association study (GWAS) of AHR, quantified as the natural log of the dosage of methacholine causing a 20% drop in FEV1, was performed with 994 non-Hispanic white asthmatic subjects from three drug clinical trials: CAMP, CARE, and ACRN. Genotyping was performed on Affymetrix 6.0 arrays, and imputed data based on HapMap Phase 2, was used to measure the association of SNPs with AHR using a linear regression model. Replication of primary findings was attempted in 650 white subjects from DAG, and 3,354 white subjects from LHS. Evidence that the top SNPs were eQTL of their respective genes was sought using expression data available for 419 white CAMP subjects.
The top primary GWAS associations were in rs848788 (P-value 7.2E-07) and rs6731443 (P-value 2.5E-06), located within the ITGB5 and AGFG1 genes, respectively. The AGFG1 result replicated at a nominally significant level in one independent population (LHS P-value 0.012), and the SNP had a nominally significant unadjusted P-value (0.0067) for being an eQTL of AGFG1.
Based on current knowledge of ITGB5 and AGFG1, our results suggest that variants within these genes may be involved in modulating AHR. Future functional studies are required to confirm that our associations represent true biologically significant findings.
PMCID: PMC3765944  PMID: 23984888
Asthma; Airway hyperresponsiveness; Genome-wide association study; ITGB5; AGFG1

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