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1.  Mechanisms of Airway Hyperresponsiveness in Asthma: The Past, Present and Yet to Come 
Airway hyperresponsiveness (AHR) has long been considered a cardinal feature of asthma. The development of the measurement of AHR forty years ago initiated many important contributions to our understanding of asthma and other airway diseases. However, our understanding of AHR in asthma remains complicated by the multitude of potential underlying mechanisms which in reality are likely to have different contributions amongst individual patients. Therefore the present review will discuss the current state of understanding of the major mechanisms proposed to contribute to AHR and highlight the way in which AHR testing is beginning to highlight distinct abnormalities associated with clinically relevant patient populations. In doing so we aim to provide a foundation by which future research can begin to ascribe certain mechanisms to specific patterns of bronchoconstriction and subsequently match phenotypes of bronchoconstriction with clinical phenotypes. We believe that this approach is not only within our grasp but will lead to improved mechanistic understanding of asthma phenotypes and hopefully better inform the development of phenotype-targeted therapy.
PMCID: PMC4386586  PMID: 25651937
2.  Efficacy of Nasal Mometasone for the Treatment of Chronic Sinonasal Disease in Inadequately Controlled Asthma 
Chronic sinonasal disease is common in asthma and associated with poor asthma control; however there are no long term trials addressing whether chronic treatment of sinonasal disease improves asthma control.
To determine if treatment of chronic sinonasal disease with nasal corticosteroids improves asthma control as measured by the Childhood Asthma Control Test (cACT) and Asthma Control Test (ACT) in children and adults respectively.
A 24 week multi-center randomized placebo controlled double-blinded trial of placebo versus nasal mometasone in adults and children with inadequately controlled asthma. Treatments were randomly assigned with concealment of allocation.
237 adults and 151 children were randomized to nasal mometasone versus placebo, 319 participants completed the study. There was no difference in the cACT (difference in change with mometasone – change with placebo [ΔM - ΔP]: -0.38, CI: -2.19 to 1.44, p = 0.68 ages 6 to 11) or the ACT (ΔM - ΔP: 0.51, CI: -0.46 to 1.48, p = 0.30, ages 12 and older) in those assigned to mometasone versus placebo. In children and adolescents, ages 6 to 17, there was no difference in asthma or sinus symptoms, but a decrease in episodes of poorly controlled asthma defined by a drop in peak flow. In adults there was a small difference in asthma symptoms measured by the Asthma Symptom Utility Index (ΔM - ΔP: 0.06, CI: 0.01 to 0.11, p <0.01) and in nasal symptoms (sinus symptom score ΔM - ΔP: -3.82, CI: -7.19 to- 0.45, p =0.03), but no difference in asthma quality of life, lung function or episodes of poorly controlled asthma in adults assigned to mometasone versus placebo.
Treatment of chronic sinonasal disease with nasal corticosteroids for 24 weeks does not improve asthma control. Treatment of sinonasal disease in asthma should be determined by the need to treat sinonasal disease rather than to improve asthma control.
PMCID: PMC4344935  PMID: 25174863
Asthma; rhinitis; sinusitis; sinonasal; asthma control; lung function; asthma exacerbation
3.  Animal Models of Allergic Airways Disease: Where Are We and Where to Next? 
Journal of cellular biochemistry  2014;115(12):2055-2064.
In a complex inflammatory airways disease such as asthma, abnormalities in a plethora of molecular and cellular pathways ultimately culminate in characteristic impairments in respiratory function. The ability to study disease pathophysiology in the setting of a functioning immune and respiratory system therefore makes mouse models an invaluable tool in translational research. Despite the vast understanding of inflammatory airways diseases gained from mouse models to date, concern over the validity of mouse models continues to grow. Therefore the aim of this review is two-fold; firstly, to evaluate mouse models of asthma in light of current clinical definitions, and secondly, to provide a framework by which mouse models can be continually refined so that they continue to stand at the forefront of translational science. Indeed, it is in viewing mouse models as a continual work in progress that we will be able to target our research to those patient populations in whom current therapies are insufficient.
PMCID: PMC4199895  PMID: 25043224
4.  Genome-Wide Association Study Identifies Novel Pharmacogenomic Loci For Therapeutic Response to Montelukast in Asthma 
PLoS ONE  2015;10(6):e0129385.
Genome-wide association study (GWAS) is a powerful tool to identify novel pharmacogenetic single nucleotide polymorphisms (SNPs). Leukotriene receptor antagonists (LTRAs) are a major class of asthma medications, and genetic factors contribute to variable responses to these drugs. We used GWAS to identify novel SNPs associated with the response to the LTRA, montelukast, in asthmatics.
Using genome-wide genotype and phenotypic data available from American Lung Association - Asthma Clinical Research Center (ALA-ACRC) cohorts, we evaluated 8-week change in FEV1 related to montelukast administration in a discovery population of 133 asthmatics. The top 200 SNPs from the discovery GWAS were then tested in 184 additional samples from two independent cohorts.
Twenty-eight SNP associations from the discovery GWAS were replicated. Of these, rs6475448 achieved genome-wide significance (combined P = 1.97 x 10-09), and subjects from all four studies who were homozygous for rs6475448 showed increased ΔFEV1 from baseline in response to montelukast.
Through GWAS, we identified a novel pharmacogenomic locus related to improved montelukast response in asthmatics.
PMCID: PMC4470685  PMID: 26083242
5.  The Nonallergic Asthma of Obesity. A Matter of Distal Lung Compliance 
Rationale: The pathogenesis of asthma in obesity is poorly understood, but may be related to breathing at low lung volumes.
Objectives: To determine if lung function in obese patients with asthma and control subjects would respond differently to weight loss.
Methods: Lung function was evaluated by conventional clinical tests and by impulse oscillometry in female late-onset, nonallergic patients with asthma and control subjects before, and 12 months after, bariatric surgery.
Measurements and Main Results: Patients with asthma (n = 10) had significantly lower FEV1 (79.8 ± 10.6 vs. 95.5 ± 7.0%) and FVC (82.4 ± 13.2 vs. 93.7 ± 8.9%) compared with control subjects (n = 13). There were no significant differences in FRC or TLC at baseline. Twelve months after surgery, control subjects had significant increases in FEV1 (95.5 ± 7.0 to 100.7 ± 5.9), FVC (93.6 ± 8.9 to 98.6 ± 8.3%), FRC (45.4 ± 18.5 to 62.1 ± 15.3%), and TLC (84.8 ± 15.0 to 103.1 ± 15.3%), whereas patients with asthma had improvement only in FEV1 (79.8 ± 10.6 to 87.2 ± 11.5). Control subjects and patients with asthma had a significantly different change in respiratory system resistance with weight loss: control subjects exhibited a uniform decrease in respiratory system resistance at all frequencies, whereas patients with asthma exhibited a decrease in frequency dependence of resistance. Fits of a mathematical model of lung mechanics to these impedance spectra suggest that the lung periphery was more collapsed by obesity in patients with asthma compared with control subjects.
Conclusions: Weight loss decompresses the lung in both obese control subjects and patients with asthma, but the more pronounced effects of weight loss on lung elastance suggest that the distal lung is inherently more collapsible in people with asthma.
PMCID: PMC4226017  PMID: 24821412
bariatric surgery; forced oscillation technique; impedance; lung volume
6.  Variability of methacholine bronchoprovocation and the effect of inhaled corticosteroids in mild asthma 
The methacholine challenge test quantifies airway hyper-responsiveness, which is measured by the provocative concentration of methacholine causing a 20% decrease in forced expiration volume in 1 second (PC20). The dose–response effect of inhaled corticosteroids (ICS) on PC20 has been inconsistent and within-patient variability of PC20 is not well established.
To determine the effect of high- vs low-dose ICS on PC20 and within-patient variability in those with repeated measurements of PC20.
A randomized, double-masked, crossover trial was conducted in patients with asthma on controller medications with PC20 of 8 mg/mL or lower (n = 64) to evaluate the effect of high-dose (1,000 μg/d) vs low-dose (250 μg/d) fluticasone for 4 weeks on PC20. In addition, the variability of PC20 was assessed in participants who underwent 2 or 3 PC20 measurements on the same dose of ICS (n = 27) over a 4-week interval.
Because there was a significant period effect, dose comparison of the change in PC20 was assessed in the first treatment period. There was no significant difference in the change in PC20 for high- vs low-dose ICS (39% vs 30% increase, respectively; P = .87). The within- and between-participant variances for log PC20 were 0.84 and 0.96, respectively, with an intra-class correlation of 0.53, and 37% of participants had more than 2 doubling dose changes in PC20 in those with repeated measurements.
The effect of ICS on PC20 is not dose dependent at fluticasone levels of 250 and 1,000 μg/d. Interpersonal variability for PC20 is large. A lack of precise measurements should be taken into account when interpreting any change in PC20.
PMCID: PMC3987862  PMID: 24507830
8.  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
9.  Epithelial Nuclear Factor- kappa B orchestrates house dust mite-induced airway inflammation, hyperresponsiveness, and fibrotic remodeling 
Journal of immunology (Baltimore, Md. : 1950)  2013;191(12):10.4049/jimmunol.1301329.
NF-κB activation within the epithelium has been implicated in the pathogenesis of asthma, yet the exact role of epithelial NF-κB in allergen-induced inflammation and airway remodeling remains unclear. In the present study, we utilized an intranasal House Dust Mite (HDM) extract exposure regimen time course in BALB/c mice to evaluate inflammation, NF-κB activation, airway hyperresponsiveness (AHR), and airway remodeling. We utilized CC10-IκBαSR transgenic mice to evaluate the functional importance of epithelial NF-κB in response to HDM. After a single exposure of HDM, mRNA expression of pro-inflammatory mediators was significantly elevated in lung tissue of WT mice, in association with increases in nuclear RelA and RelB, components of the classical and alternative NF-κB pathway, respectively, in the bronchiolar epithelium. In contrast, CC10-IκBαSR mice displayed marked decreases in nuclear RelA and RelB and mRNA expression of pro-inflammatory mediators compared to WT mice. After 15 challenges with HDM, WT mice exhibited increases in inflammation, airway hyperresponsiveness, mucus metaplasia and peri-bronchiolar fibrosis. CC10-IκBαSR transgenic mice displayed marked decreases in neutrophilic infiltration, tissue damping, and elastance parameters, in association will less peri-bronchiolar fibrosis and decreases in nuclear RelB in lung tissue. However, central airway resistance and mucus metaplasia remained elevated in CC10-IκBαSR transgenic mice, in association with continued presence of lymphocytes, and partial decreases in eosinophils and IL-13. The current study demonstrates that following airway exposure with an asthma-relevant allergen, activation of classical and alternative NF-κB pathways occur within the airway epithelium and may coordinately contribute to allergic inflammation, AHR and fibrotic airway remodeling.
PMCID: PMC3858534  PMID: 24227776
10.  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
11.  Cys-Leukotrienes Promote Fibrosis in a Mouse Model of Eosinophil-Mediated Respiratory Inflammation 
Leukotrienes (i.e., products of the 5-lipoxygenase pathway) are thought to be contributors to lung pathologies. Moreover, eosinophils have been linked with pulmonary leukotriene activities both as potential sources of these mediators and as responding effector cells. The objective of the present study was to define the role(s) of leukotrienes in the lung pathologies accompanying eosinophil-associated chronic respiratory inflammation. A transgenic mouse model of chronic T helper (Th) 2–driven inflammation expressing IL-5 from T cells and human eotaxin-2 locally in the lung (I5/hE2) was used to define potential in vivo relationships among eosinophils, leukotrienes, and chronic Th2-polarized pulmonary inflammation. Airway levels of cys-leukotrienes and leukotriene B4 (LTB4) are both significantly elevated in I5/hE2 mice. The eosinophil-mediated airway hyperresponsiveness (AHR) characteristic of these mice was abolished in the absence of leukotrienes (i.e., 5-lipoxygenase–deficient I5/hE2). More importantly, the loss of leukotrienes led to an unexpectedly significant decrease in collagen deposition (i.e., pulmonary fibrosis) that accompanied elevated levels of IL-4/-13 and TGF-β in the lungs of I5/hE2 mice. Further studies using mice deficient for the LTB4 receptor (BLT-1−/−/I5/hE2) and I5/hE2 animals administered a cys-leukotriene receptor antagonist (montelukast) demonstrated that the AHR and the enhanced pulmonary fibrosis characteristic of the I5/hE2 model were uniquely cys-leukotriene–mediated events. These data demonstrate that, similar to allergen challenge models of wild-type mice, cys-leukotrienes underlie AHR in this transgenic model of severe pulmonary Th2 inflammation. These data also suggest that an underappreciated link exists among eosinophils, cys-leukotriene–mediated events, and fibrotic remodeling associated with elevated levels of IL-4/-13 and TGF-β.
PMCID: PMC3931112  PMID: 23859654
5-lipoxygenase; asthma; eosinophils; montelukast; lung
12.  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
13.  Polygenic Heritability Estimates in Pharmacogenetics: Focus on Asthma and Related Phenotypes 
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
15.  Endoplasmic reticulum stress mediates house dust mite-induced airway epithelial apoptosis and fibrosis 
Respiratory Research  2013;14(1):141.
The endoplasmic reticulum (ER) stress response participates in many chronic inflammatory and autoimmune diseases. In the current study, we sought to examine the contribution of ER stress transducers in the pathogenesis of three principal facets of allergic asthma: inflammation, airway fibrosis, and airways hyperresponsiveness.
House Dust Mite (HDM) was used as an allergen for in vitro and in vivo challenge of primary human and murine airway epithelial cells. ER stress transducers were modulated using specific small interfering RNAs (siRNAs) in vivo. Inflammation, airway remodeling, and hyperresponsiveness were measured by total bronchoalveolar lavage (BAL) cell counts, determination of collagen, and methacholine responsiveness in mice, respectively.
Challenge of human bronchiolar and nasal epithelial cells with HDM extract induced the ER stress transducer, activating transcription factor 6 α (ATF6α) as well as protein disulfide isomerase, ERp57, in association with activation of caspase-3. SiRNA-mediated knockdown of ATF6α and ERp57 during HDM administration in mice resulted in a decrease in components of HDM-induced ER stress, disulfide mediated oligomerization of Bak, and activation of caspase-3. Furthermore, siRNA-mediated knockdown of ATF6α and ERp57 led to decreased inflammation, airway hyperresponsiveness and airway fibrosis.
Collectively, our work indicates that HDM induces ER stress in airway epithelial cells and that ATF6α and ERp57 play a significant role in the development of cardinal features of allergic airways disease. Inhibition of ER stress responses may provide a potential therapeutic avenue in chronic asthma and sub-epithelial fibrosis associated with loss of lung function.
PMCID: PMC3877992  PMID: 24364984
Allergen; HDM; Unfolded protein response; ER stress; Apoptosis; Asthma; Airway fibrosis
16.  Physiologic Dysfunction of the Asthmatic Lung 
Asthma is a syndrome of lung dysfunction characterized by airflow obstruction, reversibility to bronchodilators, and airways hyperresponsiveness (AHR). There is a growing body of evidence that suggests that the principle defect in asthma is the occlusion of the airway lumen by liquid, fibrin, and mucus. The fall in FEV1 observed in asthma is best explained by a loss of communicating airspaces and the rise in residual lung volume. Imaging studies in both human patients and experimental animals support this hypothesis. An increased propensity for the airways to close can be a cause of AHR. We conclude that loss of lung volume plays a central role in determining the dysfunction of the asthmatic lung as measured by FEV1. Together, these recent findings provide a better understanding of the causes of airflow obstruction and AHR, suggesting new avenues for the development of more effective asthma therapies.
PMCID: PMC2677406  PMID: 19387035
lung volume; peripheral resistance; FEV1; airways hyperresponsiveness; airway closure
17.  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
18.  Obesity and Asthma 
Rationale: Obesity is a major risk factor for asthma; the reasons for this are poorly understood, although it is thought that inflammatory changes in adipose tissue in obesity could contribute to airway inflammation and airway reactivity in individuals who are obese.
Objectives: To determine if inflammation in adipose tissue in obesity is related to late-onset asthma, and associated with increased markers of airway inflammation and reactivity.
Methods: We recruited a cohort of obese women with asthma and obese control women. We followed subjects with asthma for 12 months after bariatric surgery. We compared markers in adipose tissue and the airway from subjects with asthma and control subjects, and changes in subjects with asthma over time.
Measurements and Main Results: Subjects with asthma had increased macrophage infiltration of visceral adipose tissue (P < 0.01), with increased expression of leptin (P < 0.01) and decreased adiponectin (p < 0.001) when controlled for body mass index. Similar trends were observed in subcutaneous adipose tissue. Airway epithelial cells expressed receptors for leptin and adiponectin, and airway reactivity was significantly related to visceral fat leptin expression (rho = −0.8; P < 0.01). Bronchoalveolar lavage cytokines and cytokine production from alveolar macrophages were similar in subjects with asthma and control subjects at baseline, and tended to increase 12 months after surgery.
Conclusions: Obesity is associated with increased markers of inflammation in serum and adipose tissue, and yet decreased airway inflammation in obese people with asthma; these patterns reverse with bariatric surgery. Leptin and other adipokines may be important mediators of airway disease in obesity through direct effects on the airway rather than by enhancing airway inflammation.
PMCID: PMC3480522  PMID: 22837379
asthma; obesity; adipokine; airway hyperreactivity
19.  Association of corticotropin releasing hormone receptor 2 (CRHR2) genetic variants with acute bronchodilator response in asthma 
Pharmacogenetics and genomics  2008;18(5):373-382.
Corticotropin - releasing hormone receptor 2 (CRHR2) participates in smooth muscle relaxation response and may influence acute airway bronchodilator response to short – acting β2 agonist treatment of asthma. We aim to assess associations between genetic variants of CRHR2 and acute bronchodilator response in asthma.
We investigated 28 single nucleotide polymorphisms in CRHR2 for associations with acute bronchodilator response to albuterol in 607 Caucasian asthmatic subjects recruited as part of the Childhood Asthma Management Program (CAMP). Replication was conducted in two Caucasian adult asthma cohorts – a cohort of 427 subjects enrolled in a completed clinical trial conducted by Sepracor Inc. (MA, USA) and a cohort of 152 subjects enrolled in the Clinical Trial of Low-Dose Theopylline and Montelukast (LODO) conducted by the American Lung Association Asthma Clinical Research Centers.
Five variants were significantly associated with acute bronchodilator response in at least one cohort (p-value ≤ 0.05). Variant rs7793837 was associated in CAMP and LODO (p-value = 0.05 and 0.03, respectively) and haplotype blocks residing at the 5’ end of CRHR2 were associated with response in all three cohorts.
We report for the first time, at the gene level, replicated associations between CRHR2 and acute bronchodilator response. While no single variant was significantly associated in all three cohorts, the findings that variants at the 5’ end of CRHR2 are associated in each of three cohorts strongly suggest that the causative variants reside in this region and its genetic effect, although present, is likely to be weak.
PMCID: PMC3208318  PMID: 18408560
Asthma; genetics; corticotrophin releasing hormone receptor 2; CRHR2; bronchodilator response; polymorphism; β2 adrenergic receptor agonist
20.  Symposium on obesity and asthma –November 2, 2006 
Asthma and obesity are frequently associated, and obesity has been considered a factor contributing to both an increase in severity of asthma and to its development. The present document summarizes the proceedings of a symposium held in Montreal, Quebec, on November 2, 2006, under the auspices of the Réseau en santé respiratoire du Fonds de la recherche en santé du Québec in collaboration with the McGill University – Strauss Severe Asthma Program, Université Laval (Quebec City) and Université de Montréal. It includes an overview of the various aspects of the relationships between asthma and obesity with regard to animal models; genetic, hormonal and physiological determinants; influence of comorbidities (eg, sleep apnea syndrome); epidemiology; clinical and psychological features; and management of asthma in the obese population.
PMCID: PMC2676363  PMID: 17551594
Airway inflammation; Asthma; Body mass index; Lung function; Obesity; Sleep apnea syndrome
21.  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
22.  Airway Hyperresponsiveness and Inflammation: Causation, Correlation, or No Relation? 
Journal of allergy & therapy  2012;2012(Suppl 1):008.
Asthma represents a growing problem in the developing world, affecting millions of children and adults. Features of the disease are reversible airflow obstruction, airway hyperresponsiveness and airway inflammation leading to tissue damage and remodeling. Many studies have attempted to address whether inflammation and airway hyperresponsiveness are mechanistically linked. In this study, data are presented from several mouse models that illustrate that a clear link between these features of asthma remains elusive. The impact of altering inflammatory signaling (NF-κB or JNK1) on inflammation and airway hyperresponsiveness was examined. In addition, the effect of antigen sensitization and the route of antigen delivery were investigated. The data herein show that in many cases, inflammation and airway hyperresponsiveness do not directly correlate. In conclusion, the need for mechanistic studies in mouse models is highlighted to address the interplay between these components thought to be critical to asthma pathogenesis.
PMCID: PMC3613782  PMID: 23560246
23.  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
24.  Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control and inflammation 
Asthma in obese individuals is poorly understood, these patients are often refractory to standard therapy.
To gain insights into the pathogenesis and treatment of asthma in obese individuals by determining how obesity and bariatric surgery affect asthma control, airway hyperresponsiveness and markers of asthmatic inflammation.
A prospective study of (i) asthmatic and non-asthmatic bariatric surgery patients compared at baseline, and (ii) asthmatic patients followed for 12 months after bariatric surgery.
We studied 23 asthmatic and 21 non-asthmatic patients undergoing bariatric surgery. At baseline, asthmatics had lower FEV1 and FVC, and lower levels of lymphocytes in bronchoalveolar lavage.
Following surgery, asthmatic participants experienced significant improvements in asthma control (asthma control score 1.55 to 0.74, p < 0.0001) and asthma quality of life (4.87 to 5.87, p < 0.0001). Airways responsiveness to methacholine improved significantly (PC20 3.9 to 7.28, p = 0.03). There was a statistically significant interaction between IgE status and change in airways responsiveness (p for interaction term = 0.01), improvement in AHR was significantly related to change in BMI in those with normal IgE (p = 0.02, R2 = 0.46). The proportion of lymphocytes in bronchoalveolar lavage and production of cytokines from activated peripheral blood CD4+ T cells increased significantly.
Bariatric surgery improves airway hyperresponsiveness in obese asthmatics with normal serum IgE. Weight loss has dichotomous effects on airway physiology and T cell function typically involved in the pathogenesis of asthma, suggesting that obesity produces a unique phenotype of asthma that will require a distinct therapeutic approach.
PMCID: PMC3164923  PMID: 21782230
Obesity; asthma; bariatric surgery; weight loss; airway hyperreactivity; CD4 T cell
25.  Asthma in the Elderly: Current Understanding and Future Research Needs 
Asthma in the elderly (AIE) is under diagnosed and under treated and there is a paucity of knowledge. The National Institute on Aging convened this workshop to identify what is known, what gaps in knowledge remain and suggest research directions needed to improve the understanding and care of AIE. Asthma presenting at an advanced age often has similar clinical and physiologic consequences as seen with younger individuals but co-morbid illnesses and the psychosocial effects of aging may affect the diagnosis, clinical presentation and care of asthma in this population. At least two phenotypes exist among elderly asthma; those with long-standing asthma have more severe airflow limitation and less complete reversibility than those with late-onset asthma. Many challenges exist in the recognition and treatment of asthma in the elderly. Furthermore, the pathophysiological mechanisms of AIE are likely to be different from those seen in young asthmatics and these differences may influence the clinical course and outcomes of asthma in this population.
PMCID: PMC3164961  PMID: 21872730
Aging; airway; allergy; asthma; elderly; immune mechanisms; immunosenescence

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