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1.  Predictors of Response to Tiotropium Versus Salmeterol in Adults with Asthma1 
The Journal of allergy and clinical immunology  2013;132(5):10.1016/j.jaci.2013.08.003.
Tiotropium has activity as an asthma controller. However, predictors of a positive response to tiotropium have not been described.
To describe individual and differential response of patients with asthma to salmeterol and tiotropium, when added to an ICS, as well as predictors of a positive clinical response.
Data from the double-blind, three-way crossover NHLBI Asthma Clinical Research Network’s TALC trial ( number, NCT00565266) were analyzed for individual and differential treatment responses to salmeterol and tiotropium, and predictors of a positive response to the endpoints FEV1, morning peak expiratory flow (AM PEF), and asthma control days (ACDs).
While approximately equal numbers of patients showed a differential response to salmeterol and tiotropium in terms of AM PEF (90 and 78, respectively), and ACDs (49 and 53, respectively), more showed a differential response to tiotropium for FEV1 (104) than salmeterol (62). An acute response to a short-acting bronchodilator, especially albuterol, predicted a positive clinical response to tiotropium for FEV1 (OR 4.08 [CI 2.00–8.31], P < 0.001) and AM PEF (OR 2.12 [CI 1.12–4.01], P = 0.021), as did a decreased FEV1/FVC ratio (FEV1 response increased 0.39% of baseline for every 1% decrease in the FEV1/FVC ratio). Higher cholinergic tone was also a predictor, while ethnicity, gender, atopy, IgE Level, sputum eosinophils, FENO, asthma duration, and BMI were not.
While these results need confirmation, predictors of a positive clinical response to tiotropium include a positive response to albuterol and airway obstruction, factors which could help identify appropriate patients for this therapy.
PMCID: PMC3826080  PMID: 24084072
asthma; tiotropium; salmeterol; responder analysis; predictor of response
2.  Glucocorticoid Receptor Hetero-Complex Gene STIP1 Is Associated with Improved Lung Function in Asthmatics Treated with Inhaled Corticosteroids 
Corticosteroids exert their anti-inflammatory action by binding and activating the intracellular the glucocorticoid receptor (GR) hetero-complex.
Evaluate the genes HSPCB, HSPCA, STIP1, HSPA8, DNAJB1, PTGES3, FKBP5, and FKBP4 on corticosteroid response.
Caucasian asthmatics (382) randomized to once daily flunisolide or conventional inhaled corticosteroid therapy were genotyped. Outcome measures were baseline FEV1, % predicted FEV1, and % change in FEV1 after corticosteroid treatment. Multivariable analyses adjusted for age, gender, and height, were performed fitting the most appropriate genetic model based on quantitative mean derived from ANOVA models to determine if there was an independent effect of polymorphisms on change in FEV1 independent of baseline level.
Positive recessive model correlations for STIP1 SNPs were observed for baseline FEV1 [rs4980524, p=0.009; rs6591838, p=0.0045; rs2236647, p=0.002; and rs2236648; p=0.013], baseline % predicted FEV1 [rs4980524, p=0.002; rs6591838, p=0.017; rs2236647, p=0.003; and rs2236648; p=0.008] ; % change in FEV1 at 4 weeks [rs4980524, p=0.044; rs6591838, p=0.016; rs2236647; p=0.01] and 8 weeks therapy [rs4980524, p=0.044; rs6591838, p=0.016; rs2236647; p=0.01]. Haplotypic associations were observed for baseline FEV1 and % change in FEV1 at 4 weeks therapy [p=0.05 and p=0.01, respectively]. Significant trends towards association were observed for baseline % predicted FEV1 and % change in FEV1 at 8 weeks therapy. Positive correlations between haplotypes and % change in FEV1 were also observed.
STIP1 genetic variations may play a role in regulating corticosteroid response in asthmatics with reduced lung function. Replication in a second asthma population is required to confirm these observations.
Clinical Implications
Identifying genes that regulate corticosteroid responses could allow a priori determination of individual responses to corticosteroid therapy, leading to more effective dosing and/or selection of drug therapies for treating asthma.
PMCID: PMC4317788  PMID: 19254810
corticosteroid; pharmacogenetics; glucocorticoid receptor; SNP; heat shock protein; heat shock organizing protein; immunophilin
4.  The Irreversible Component of Persistent Asthma 
Irreversible airflow obstruction or limitation occurs in some patients with asthma, may develop early in life and becomes more common as asthma becomes more severe. Efforts to understand irreversible airflow obstruction or limitation have been hampered by the lack of a standardized definition of the phenotype and by the lack of appropriate research models. Unfortunately, it appears that currently available asthma treatments do not prevent this important asthma complication. Herein, the evidence of an irreversible component of asthma, its underlying pathology and the limitations of current asthma treatments are reviewed.
PMCID: PMC4283201  PMID: 19895980
asthma; airway remodeling; irreversible airway obstruction; irreversible airflow limitation
5.  Risk Factors for Montelukast Treatment Failure in Step-Down Therapy for Controlled Asthma 
Leukotriene receptor antagonists including montelukast are an option for step-down therapy for mild asthmatics controlled on low-dose inhaled corticosteroids (ICS). Because some patients fail montelukast step-down therapy, it would be helpful for clinicians to be able to predict the risk of treatment failure.
To determine patient characteristics associated with montelukast treatment failure and develop a clinical index to predict the risk of montelukast treatment failure.
Using the 165 participants in the Leukotriene or Corticosteroid or Corticosteroid-Salmeterol Study (LOCCS) trial who were stepped down from low-dose ICS to montelukast, we determined associations between enrollment variables and treatment failure. We constructed a montelukast failure index to predict the risk of montelukast treatment failure during step-down. To assess its specificity for montelukast, index performance was evaluated in the other LOCCS treatment groups.
Characteristics independently associated with montelukast treatment failure included age of asthma onset <10 years old (OR = 2.39; 95% CI = 1.17–5.02; p = .018), need for steroid burst in the last year (OR = 2.39; 95% CI = 1.13–5.09; p = .022), and pre-bronchodilator forced expiratory volume in 1 s (FEV1) (OR = 1.44 per 10% lower % predicted; 95% CI = 1.07–1.97; p = .016). A montelukast failure index was generated from these three variables (range: −5 to 7 points). Scores <0 predicted low risk (<0.20) of treatment failure, whereas scores >5 predicted high risk (>0.60) of treatment failure.
Early asthma onset, worse asthma control in the last year, and lower pre-bronchodilator FEV1 are associated with montelukast treatment failure. A montelukast failure index is proposed to quantify the risk of failure prior to treatment initiation.
PMCID: PMC4277696  PMID: 22029858
asthma; leukotrienes; therapy
6.  Asthma Outcomes: Pulmonary Physiology 
Outcomes of pulmonary physiology have a central place in asthma clinical research.
At the request of National Institutes of Health (NIH) institutes and other federal agencies, an expert group was convened to provide recommendations on the use of pulmonary function measures as asthma outcomes that should be assessed in a standardized fashion in future asthma clinical trials and studies to allow for cross-study comparisons.
Our subcommittee conducted a comprehensive search of PubMed to identify studies that focused on the validation of various airway response tests used in asthma clinical research. The subcommittee classified the instruments as core (to be required in future studies), supplemental (to be used according to study aims and in a standardized fashion), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011.
A list of pulmonary physiology outcomes that applies to both adults and children older than 6 years was created. These outcomes were then categorized into core, supplemental, and emerging. Spirometric outcomes (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and FEV1/FVC) are proposed as core outcomes for study population characterization, for observational studies, and for prospective clinical trials. Bronchodilator reversibility and pre- and post-bronchodilator FEV1 also are core outcomes for study population characterization and observational studies.
The subcommittee considers pulmonary physiology outcomes of central importance in asthma and proposes spirometric outcomes as core outcomes for all future NIH-initiated asthma clinical research.
PMCID: PMC4263032  PMID: 22386510
Spirometry; airway responsiveness; peak expiratory flow monitoring; lung volumes; gas exchange
7.  Effect of Vitamin D3 on Asthma Treatment Failures in Adults With Symptomatic Asthma and Lower Vitamin D Levels 
JAMA  2014;311(20):2083-2091.
In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency.
To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels.
The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute’s AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized.
Oral vitamin D3 (100 000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained.
The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care).
Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28%[95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%–35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6–1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2–120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2–135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1–27.7 µg/d]).
Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma.
TRIAL REGISTRATION Identifier: NCT01248065
PMCID: PMC4217655  PMID: 24838406
8.  Genome-wide association study identifies TH1 pathway genes associated with lung function in asthmatic patients 
Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function.
We sought to identify novel lung function loci specifically for asthma and to confirm lung function loci identified in general populations.
Genome-wide association studies of lung function (percent predicted FEV1 [ppFEV1], percent predicted forced vital capacity, and FEV1/forced vital capacity ratio) were performed in 4 white populations of European descent (n = 1544), followed by meta-analyses.
Seven of 28 previously identified lung function loci (HHIP, FAM13A, THSD4, GSTCD, NOTCH4-AGER, RARB, and ZNF323) identified in general populations were confirmed at single nucleotide polymorphism (SNP) levels (P < .05). Four of 32 loci (IL12A, IL12RB1, STAT4, and IRF2) associated with ppFEV1 (P < 10−4) belong to the TH1 or IL-12 cytokine family pathway. By using a linear additive model, these 4 TH1 pathway SNPs cumulatively explained 2.9% to 7.8% of the variance in ppFEV1 values in 4 populations (P = 3 × 10−11). Genetic scores of these 4 SNPs were associated with ppFEV1 values (P = 2 × 10−7) and the American Thoracic Society severe asthma classification (P = .005) in the Severe Asthma Research Program population. TH2 pathway genes (IL13, TSLP, IL33, and IL1RL1) conferring asthma susceptibility were not associated with lung function.
Genes involved in airway structure/remodeling are associated with lung function in both general populations and asthmatic subjects. TH1 pathway genes involved in anti-virus/bacterial infection and inflammation modify lung function in asthmatic subjects. Genes associated with lung function that might affect asthma severity are distinct from those genes associated with asthma susceptibility.
PMCID: PMC3746327  PMID: 23541324
Lung function; FEV1; asthma; TH1; IL12A; IL12RB1; STAT4; IRF2
9.  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
10.  Biomarker Surrogates Do Not Accurately Predict Sputum Eosinophils and Neutrophils in Asthma 
Sputum eosinophils (Eos) are a strong predictor of airway inflammation, exacerbations, and aid asthma management, whereas sputum neutrophils (Neu) indicate a different severe asthma phenotype, potentially less responsive to TH2-targeted therapy. Variables such as blood Eos, total IgE, fractional exhaled nitric oxide (FeNO) or FEV1% predicted, may predict airway Eos, while age, FEV1%predicted, or blood Neu may predict sputum Neu. Availability and ease of measurement are useful characteristics, but accuracy in predicting airway Eos and Neu, individually or combined, is not established.
To determine whether blood Eos, FeNO, and IgE accurately predict sputum eosinophils, and age, FEV1% predicted, and blood Neu accurately predict sputum neutrophils (Neu).
Subjects in the Wake Forest Severe Asthma Research Program (N=328) were characterized by blood and sputum cells, healthcare utilization, lung function, FeNO, and IgE. Multiple analytical techniques were utilized.
Despite significant association with sputum Eos, blood Eos, FeNO and total IgE did not accurately predict sputum Eos, and combinations of these variables failed to improve prediction. Age, FEV1%predicted and blood Neu were similarly unsatisfactory for prediction of sputum Neu. Factor analysis and stepwise selection found FeNO, IgE and FEV1% predicted, but not blood Eos, correctly predicted 69% of sputum Eos
Despite statistically significant associations FeNO, IgE, blood Eos and Neu, FEV1%predicted, and age are poor surrogates, separately and combined, for accurately predicting sputum eosinophils and neutrophils.
PMCID: PMC3704048  PMID: 23706399
asthma phenotypes; sputum eosinophils and neutrophils; inflammatory biomarker surrogates; TH2 biomarkers; fractional exhaled nitric oxide
Pharmacogenetics and genomics  2013;23(6):324-328.
While accurate measures of heritability are needed to understand the pharmacogenetic basis of drug treatment response, these are generally not available, since 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 asthma heritability and the heritability of two related drug-response phenotypes, bronchodilator response and airway hyperreactivity, using genome-wide 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), while we estimate asthma genetic liability at 61.5% (se 16%, p < 0.001). Our results agree with previously published estimates of the heritability of these traits, suggesting that the LMM 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 GWAS methods, together explain a sizable portion of the heritability of these traits.
PMCID: PMC3767309  PMID: 23532052
Asthma; Pharmacogenetics; Heritability; Bronchodilator Response; Airway Hyperresponsiveness
This is the first large pharmacogenetic investigation of the inflammatory IL-4/IL-13 pathway in patients with moderate-to-severe asthma. We analyzed genomic DNA from participants in a 12-week placebo-controlled efficacy trial of pitrakinra (1, 3, or 10 mg twice daily), a novel IL-4/IL-13 pathway antagonist ( NCT00801853).
The primary hypothesis for this analysis is that amino acid changes in the 3′ end of the IL-4 receptor α gene (IL4RA) or closely proximal variants would predict reductions in asthma exacerbations for subjects randomized to pitrakinra therapy.
Nineteen IL4RA single nucleotide polymorphisms (SNPs) were tested in 407 non-Hispanic white subjects for association with the primary clinical end point of asthma exacerbations and changes in secondary end points for asthma symptom scores.
The most consistent pharmacogenetic associations were observed for the correlated tagging SNPs rs8832 and rs1029489 in the IL4RA 3′ untranslated and proximal regions, respectively. Subjects homozygous for the rs8832 common G allele randomized to pitrakinra (placebo group nonsignificant) had decreased asthma exacerbations and decreased nocturnal awakenings and activities limited by asthma. There was also a significant pitrakinra dose-response relationship (placebo/1 mg/3 mg/10 mg) for exacerbations in subjects homozygous for the common allele in rs1029489 (P = .005) and rs8832 (P = .009) and the intronic SNPs rs3024585, rs3024622, and rs4787956 (P = .03).
This study demonstrates a significant pharmacogenetic interaction between anti–IL-4 receptor a therapy and IL4RA gene variation, identifying an asthma subgroup that is more responsive to therapy with this antagonist.
PMCID: PMC3992925  PMID: 22541248
Pharmacogenetics; pitrakinra; IL-4 receptor; asthma therapy; IL-4 receptor antagonist
The pharmacogenomics journal  2012;13(4):306-311.
Inhaled corticosteroids are the most commonly used controller medications prescribed for asthma. Two single-nucleotide polymorphisms (SNPs), rs1876828 in CRHR1 and rs37973 in GLCCI1, have previously been associated with corticosteroid efficacy. We studied data from four existing clinical trials of asthmatics who received inhaled corticosteroids and had lung function measured by forced expiratory volume in one second (FEV1) before and after the period of such treatment. We combined the two SNPs rs37973 and rs1876828 into a predictive test of FEV1 change using a Bayesian model, which identified patients with good or poor steroid response (highest or lowest quartile, respectively) with predictive performance of 65.7% (p = 0.039 vs. random) area under the receiver-operator characteristic curve in the training population and 65.9% (p = 0.025 vs. random) in the test population. These findings show that two genetic variants can be combined into a predictive test that achieves similar accuracy and superior replicability compared with single SNP predictors.
PMCID: PMC3434304  PMID: 22641026
Pharmacogenetics; Asthma; Glucocorticoids; Predictive Modeling
Rationale: Increasing body mass index (BMI) has been associated with less fractional exhaled nitric oxide (FeNO). This may be explained by an increase in the concentration of asymmetric dimethyl arginine (ADMA) relative to l-arginine, which can lead to greater nitric oxide synthase uncoupling.
Objectives: To compare this mechanism across age of asthma onset groups and determine its association with asthma morbidity and lung function.
Methods: Cross-sectional study of participants from the Severe Asthma Research Program, across early- (<12 yr) and late- (>12 yr) onset asthma phenotypes.
Measurements and Main Results: Subjects with late-onset asthma had a higher median plasma ADMA level (0.48 μM, [interquartile range (IQR), 0.35–0.7] compared with early onset, 0.37 μM [IQR, 0.29–0.59], P = 0.01) and lower median plasma l-arginine (late onset, 52.3 [IQR, 43–61] compared with early onset, 51 μM [IQR 39–66]; P = 0.02). The log of plasma l-arginine/ADMA was inversely correlated with BMI in the late- (r = −0.4, P = 0.0006) in contrast to the early-onset phenotype (r = −0.2, P = 0.07). Although FeNO was inversely associated with BMI in the late-onset phenotype (P = 0.02), the relationship was lost after adjusting for l-arginine/ADMA. Also in this phenotype, a reduced l-arginine/ADMA was associated with less IgE, increased respiratory symptoms, lower lung volumes, and worse asthma quality of life.
Conclusions: In late-onset asthma phenotype, plasma ratios of l-arginine to ADMA may explain the inverse relationship of BMI to FeNO. In addition, these lower l-arginine/ADMA ratios are associated with reduced lung function and increased respiratory symptom frequency, suggesting a role in the pathobiology of the late-onset phenotype.
PMCID: PMC3570651  PMID: 23204252
asthma; obesity; age of asthma onset; ADMA; arginine
As a part of the longitudinal Chronic Obstructive Pulmonary Disease (COPD) study, Subpopulations and Intermediate Outcome Measures in COPD study (SPIROMICS), blood samples are being collected from 3200 subjects with the goal of identifying blood biomarkers for sub-phenotyping patients and predicting disease progression. To determine the most reliable sample type for measuring specific blood analytes in the cohort, a pilot study was performed from a subset of 24 subjects comparing serum, Ethylenediaminetetraacetic acid (EDTA) plasma, and EDTA plasma with proteinase inhibitors (P100™).
105 analytes, chosen for potential relevance to COPD, arranged in 12 multiplex and one simplex platform (Myriad-RBM) were evaluated in duplicate from the three sample types from 24 subjects. The reliability coefficient and the coefficient of variation (CV) were calculated. The performance of each analyte and mean analyte levels were evaluated across sample types.
20% of analytes were not consistently detectable in any sample type. Higher reliability and/or smaller CV were determined for 12 analytes in EDTA plasma compared to serum, and for 11 analytes in serum compared to EDTA plasma. While reliability measures were similar for EDTA plasma and P100 plasma for a majority of analytes, CV was modestly increased in P100 plasma for eight analytes. Each analyte within a multiplex produced independent measurement characteristics, complicating selection of sample type for individual multiplexes.
There were notable detectability and measurability differences between serum and plasma. Multiplexing may not be ideal if large reliability differences exist across analytes measured within the multiplex, especially if values differ based on sample type. For some analytes, the large CV should be considered during experimental design, and the use of duplicate and/or triplicate samples may be necessary. These results should prove useful for studies evaluating selection of samples for evaluation of potential blood biomarkers.
PMCID: PMC3928911  PMID: 24397870
Chronic obstructive pulmonary disease; COPD; SPIROMICS; Biomarkers; Blood analytes; Multiplex assays; P100 plasma; Serum; EDTA plasma; Pilot study
Rationale: The function of the P2X7 nucleotide receptor protects against exacerbation in people with mild-intermittent asthma during viral illnesses, but the impact of disease severity and maintenance therapy has not been studied.
Objectives: To evaluate the association between P2X7, asthma exacerbations, and incomplete symptom control in a more diverse population.
Methods: A matched P2RX7 genetic case-control was performed with samples from Asthma Clinical Research Network trial participants enrolled before July 2006, and P2X7 pore activity was determined in whole blood samples as an ancillary study to two trials completed subsequently.
Measurements and Main Results: A total of 187 exacerbations were studied in 742 subjects, and the change in asthma symptom burden was studied in an additional 110 subjects during a trial of inhaled corticosteroids (ICS) dose optimization. African American carriers of the minor G allele of the rs2230911 loss-of-function single nucleotide polymorphism were more likely to have a history of prednisone use in the previous 12 months, with adjustment for ICS and long-acting β2-agonists use (odds ratio, 2.7; 95% confidence interval, 1.2–6.2; P = 0.018). Despite medium-dose ICS, attenuated pore function predicted earlier exacerbations in incompletely controlled patients with moderate asthma (hazard ratio, 3.2; confidence interval, 1.1–9.3; P = 0.033). After establishing control with low-dose ICS in patients with mild asthma, those with attenuated pore function had more asthma symptoms, rescue albuterol use, and FEV1 reversal (P < 0.001, 0.03, and 0.03, respectively) during the ICS adjustment phase.
Conclusions: P2X7 pore function protects against exacerbations of asthma and loss of control, independent of baseline severity and the maintenance therapy.
PMCID: PMC3570642  PMID: 23144325
asthma; P2X7; exacerbation; Asthma Clinical Research Network; corticosteroids
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
No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms.
To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment–based adjustment in preventing treatment failure in adults with mild to moderate asthma.
Design, Setting, and Participants
A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n=114 assigned to physician assessment–based adjustment [101 completed], n=115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n=113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010.
For physician assessment–based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use.
Main Outcome Measure
The primary outcome was time to treatment failure.
There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment–based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment–based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment–based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3).
Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment–based adjustment of inhaled corticosteroids in time to treatment failure.
Trial Registration Identifier: NCT00495157
PMCID: PMC3697088  PMID: 22968888
The IL6R SNP rs4129267 has recently been identified as an asthma susceptibility locus in subjects of European ancestry but has not been characterized with respect to asthma severity. The SNP rs4129267 is in linkage disequilibrium (r2=1) with the IL6R coding SNP rs2228145 (Asp358Ala). This IL6R coding change increases IL6 receptor shedding and promotes IL6 transsignaling.
To evaluate the IL6R SNP rs2228145 with respect to asthma severity phenotypes.
The IL6R SNP rs2228145 was evaluated in subjects of European ancestry with asthma from the Severe Asthma Research Program (SARP). Lung function associations were replicated in the Collaborative Study on the Genetics of Asthma (CSGA) cohort. Serum soluble IL6 receptor (sIL6R) levels were measured in subjects from SARP. Immunohistochemistry was used to qualitatively evaluate IL6R protein expression in BAL cells and endobronchial biopsies.
The minor C allele of IL6R SNP rs2228145 was associated with lower ppFEV1 in the SARP cohort (p=0.005), the CSGA cohort (0.008), and in combined cohort analysis (p=0.003). Additional associations with ppFVC, FEV1/FVC, and PC20 were observed. The rs2228145 C allele (Ala358) was more frequent in severe asthma phenotypic clusters. Elevated serum sIL6R was associated with lower ppFEV1 (p=0.02) and lower ppFVC (p=0.008) (N=146). IL6R protein expression was observed in BAL macrophages, airway epithelium, vascular endothelium, and airway smooth muscle.
The IL6R coding SNP rs2228145 (Asp358Ala) is a potential modifier of lung function in asthma and may identify subjects at risk for more severe asthma. IL6 transsignaling may have a pathogenic role in the lung.
PMCID: PMC3409329  PMID: 22554704
soluble interleukin 6 receptor; sIL6R; interleukin 6; IL6; asthma; pulmonary lung function; severe asthma; IL6 transsignaling; genetic variation; SNP rs2228145
Thorax  2012;67(5):450-455.
The National Heart, Lung and Blood Institute (NHLBI) Asthma Clinical Research Network (ACRN) recently completed its work after 20 years of collaboration as a multicentre clinical trial network. When formed, its stated mission was to perform multiple controlled clinical trials for treating patients with asthma by dispassionately examining new and existing therapies, and to rapidly communicate its findings to the medical community. The ACRN conducted 15 major clinical trials. In addition, clinical data, manual of operations, protocols and template informed consents from all ACRN trials are available via NHLBI BioLINCC ( This network contributed major insights into the use of inhaled corticosteroids, short-acting and long-acting ß-adrenergic agonists, leukotriene receptor antagonists, and novel agents (tiotropium, colchicine and macrolide antibiotics). They also pioneered studies of the variability in drug response, predictors of treatment response and pharmacogenetics. This review highlights the major research observations from the ACRN that have impacted the current management of asthma.
PMCID: PMC3709602  PMID: 22514237
The New England journal of medicine  2011;365(13):1173-1183.
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.
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.
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.
A functional GLCCI1 variant is associated with substantial decrements in the response to inhaled glucocorticoids in patients with asthma. (Funded by the National Institutes of Health and others; number, NCT00000575.)
PMCID: PMC3667396  PMID: 21991891
22.  Severe Asthma 
The National Heart, Lung, and Blood Institute Severe Asthma Research Program (SARP) has characterized over the past 10 years 1,644 patients with asthma, including 583 individuals with severe asthma. SARP collaboration has led to a rapid recruitment of subjects and efficient sharing of samples among participating sites to conduct independent mechanistic investigations of severe asthma. Enrolled SARP subjects underwent detailed clinical, physiologic, genomic, and radiological evaluations. In addition, SARP investigators developed safe procedures for bronchoscopy in participants with asthma, including those with severe disease. SARP studies revealed that severe asthma is a heterogeneous disease with varying molecular, biochemical, and cellular inflammatory features and unique structure–function abnormalities. Priorities for future studies include recruitment of a larger number of subjects with severe asthma, including children, to allow further characterization of anatomic, physiologic, biochemical, and genetic factors related to severe disease in a longitudinal assessment to identify factors that modulate the natural history of severe asthma and provide mechanistic rationale for management strategies.
PMCID: PMC3297096  PMID: 22095547
asthma; remodeling; inflammation; bronchoscopy; imaging
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
OBJECTIVE: Inhaled corticosteroids (ICSs) are the most effective medications available for patients with persistent asthma of all severities and currently are recommended as the preferred asthma controller therapy by the National Heart, Lung and Blood Institute. Nevertheless, lingering concerns about potential adverse systemic effects of ICSs contribute to their underuse. This review discusses the safety of ICSs with respect to potential systemic effects of most concern to physicians and patients. METHODS: Articles reporting on the safety of ICSs in children and adults with persistent asthma were identified from the Medline database from January 1966 through December 2003, reference lists of review articles and international respiratory meetings. RESULTS: Ocular effects of ICSs and ICS effects on bone mineral density and adrenal function are minimal in patients maintained on recommended ICS doses. One-year growth studies in children have shown decreased growth velocity with ICSs, but long-term studies with inhaled budesonide and beclomethasone show no effect on final adult height, suggesting that these effects are transient. In addition, extensive data from the Swedish Medical Birth Registry show no increased risk of adverse perinatal outcomes when inhaled budesonide is administered to pregnant women with asthma. CONCLUSIONS: ICSs have minimal systemic effects in most patients when taken at recommended doses. The benefits of ICS therapy clearly outweigh the risks of uncontrolled asthma, and ICSs should be prescribed routinely as first-line therapy for children and adults with persistent disease.
PMCID: PMC2569377  PMID: 16775906
Rationale: Recent studies suggest that people with asthma of different racial backgrounds may respond differently to various therapies.
Objectives: To use data from well-characterized participants in prior Asthma Clinical Research Network (ACRN) trials to determine whether racial differences affected asthma treatment failures.
Methods: We analyzed baseline phenotypes and treatment failure rates (worsening asthma resulting in systemic corticosteroid use, hospitalization, emergency department visit, prolonged decrease in peak expiratory flow, increase in albuterol use, or safety concerns) in subjects participating in 10 ACRN trials (1993–2003). Self-declared race was reported in each trial and treatment failure rates were stratified by race.
Measurements and Main Results: A total of 1,200 unique subjects (whites = 795 [66%]; African Americans = 233 [19%]; others = 172 [14%]; mean age = 32) were included in the analyses. At baseline, African Americans had fewer asthma symptoms (P < 0.001) and less average daily rescue inhaler use (P = 0.007) than whites. There were no differences in baseline FEV1 (% predicted); asthma quality of life; bronchial hyperreactivity; or exhaled nitric oxide concentrations. A total of 147 treatment failures were observed; a significantly higher proportion of African Americans (19.7%; n = 46) experienced a treatment failure compared with whites (12.7%; n = 101) (odds ratio = 1.7; 95% confidence interval, 1.2–2.5; P = 0.007). When stratified by treatment, African Americans receiving long-acting β-agonists were twice as likely as whites to experience a treatment failure (odds ratio = 2.1; 95% confidence interval, 1.3–3.6; P = 0.004), even when used with other controller therapies.
Conclusions: Despite having fewer asthma symptoms and less rescue β-agonist use, African-Americans with asthma have more treatment failures compared with whites, especially when taking long-acting β-agonists.
PMCID: PMC3361331  PMID: 21885625
asthma; long-acting β-agonist; African Americans; race; treatment failure

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