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1.  P2X7-Regulated Protection from Exacerbations and Loss of Control Is Independent of Asthma Maintenance Therapy 
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.
doi:10.1164/rccm.201204-0750OC
PMCID: PMC3570642  PMID: 23144325
asthma; P2X7; exacerbation; Asthma Clinical Research Network; corticosteroids
2.  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.
doi:10.1164/rccm.201107-1317PP
PMCID: PMC3297096  PMID: 22095547
asthma; remodeling; inflammation; bronchoscopy; imaging
3.  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 www.clinicaltrials.gov (NCT00156819, NCT00046644, and NCT00073840).
doi:10.1164/rccm.201005-0758OC
PMCID: PMC3056223  PMID: 20851928
pharmacogenetics; asthma; β2-agonist
4.  Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program 
Rationale: The Severe Asthma Research Program cohort includes subjects with persistent asthma who have undergone detailed phenotypic characterization. Previous univariate methods compared features of mild, moderate, and severe asthma.
Objectives: To identify novel asthma phenotypes using an unsupervised hierarchical cluster analysis.
Methods: Reduction of the initial 628 variables to 34 core variables was achieved by elimination of redundant data and transformation of categorical variables into ranked ordinal composite variables. Cluster analysis was performed on 726 subjects.
Measurements and Main Results: Five groups were identified. Subjects in Cluster 1 (n = 110) have early onset atopic asthma with normal lung function treated with two or fewer controller medications (82%) and minimal health care utilization. Cluster 2 (n = 321) consists of subjects with early-onset atopic asthma and preserved lung function but increased medication requirements (29% on three or more medications) and health care utilization. Cluster 3 (n = 59) is a unique group of mostly older obese women with late-onset nonatopic asthma, moderate reductions in FEV1, and frequent oral corticosteroid use to manage exacerbations. Subjects in Clusters 4 (n = 120) and 5 (n = 116) have severe airflow obstruction with bronchodilator responsiveness but differ in to their ability to attain normal lung function, age of asthma onset, atopic status, and use of oral corticosteroids.
Conclusions: Five distinct clinical phenotypes of asthma have been identified using unsupervised hierarchical cluster analysis. All clusters contain subjects who meet the American Thoracic Society definition of severe asthma, which supports clinical heterogeneity in asthma and the need for new approaches for the classification of disease severity in asthma.
doi:10.1164/rccm.200906-0896OC
PMCID: PMC2822971  PMID: 19892860
asthma phenotype; definition; cluster analysis; severe asthma
5.  Identification of PCDH1 as a Novel Susceptibility Gene for Bronchial Hyperresponsiveness 
Rationale: Asthma is a chronic inflammatory airway disease that affects more than 300 million individuals worldwide. Asthma is caused by interaction of genetic and environmental factors. Bronchial hyperresponsiveness (BHR) is a hallmark of asthma and results from increased sensitivity of the airways to physical or chemical stimulants. BHR and asthma are linked to chromosome 5q31-q33.
Objectives: To identify a gene for BHR on chromosome 5q31-q33.
Methods: In 200 Dutch families with asthma, linkage analysis and fine mapping were performed, and the Protocadherin 1 gene (PCDH1) was identified. PCDH1 was resequenced in 96 subjects from ethnically diverse populations to identify novel sequence variants. Subsequent replication studies were undertaken in seven populations from The Netherlands, the United Kingdom, and the United States, including two general population samples, two family samples, and three case-control samples. PCDH1 mRNA and protein expression was investigated using polymerase chain reaction, Western blotting, and immunohistochemistry.
Measurements and Main Results: In seven out of eight populations (n = 6,168) from The Netherlands, United Kingdom, and United States, PCHD1 gene variants were significantly associated with BHR (P values, 0.005–0.05) This association was present in both families with asthma and general populations. PCDH1 mRNA and protein were expressed in airway epithelial cells and in macrophages.
Conclusions: PCDH1 is a novel gene for BHR in adults and children. The identification of PCDH1 as a BHR susceptibility gene may suggest that a structural defect in the integrity of the airway epithelium, the first line of defense against inhaled substances, contributes to the development of BHR.
doi:10.1164/rccm.200810-1621OC
PMCID: PMC2778155  PMID: 19729670
bronchial hyperresponsiveness; asthma genetics; protocadherin-1; cell adhesion; airway epithelium
6.  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.
doi:10.1164/rccm.200709-1363OC
PMCID: PMC2556451  PMID: 18617639
pharmacogenetics; asthma; bronchodilator agents
7.  IL4Rα Mutations Are Associated with Asthma Exacerbations and Mast Cell/IgE Expression 
Background: Severe asthma has been associated with severe exacerbations, lower lung function and greater tissue inflammation. Previous studies have suggested that mutations in interleukin-4 receptor α (IL4Rα) are associated with lower lung function, higher IgE, and a gain in receptor function. However, an effect on exacerbations and tissue inflammation has not been shown.
Hypothesis: Allelic substitutions in IL4Rα are associated with asthma exacerbations, lower lung function, and tissue inflammation, in particular to mast cells and IgE.
Methods: Two well-characterized cohorts of subjects with severe asthma were analyzed for five single nucleotide polymorphisms (SNPs) in IL4Rα. These polymorphisms were compared with the history of severe asthma exacerbations and lung function. In the primary (National Jewish) cohort, these polymorphisms were also compared with endobronchial tissue inflammatory cells and local IgE.
Results: In both cohorts, the presence of the minor alleles at E375A and Q551R, which were more common in African Americans, was associated with a history of severe exacerbations and lower lung function. In the National Jewish cohort, the C allele at E375A was associated with higher tissue mast cells and higher levels of IgE bound to mast cells. The significance for most of these associations remained when whites (the larger racial subgroup) were analyzed separately.
Conclusions: SNPs in IL4Rα, which are more common in African Americans, are associated with severe asthma exacerbations, lower lung function, and increased mast cell–related tissue inflammation. Further studies of the impact of these mutations in African Americans and on receptor function are indicated.
doi:10.1164/rccm.200607-909OC
PMCID: PMC1899282  PMID: 17170387
asthma; genetics; IL4Rα; exacerbations; mast cells; IgE
8.  Sequence, Haplotype, and Association Analysis of ADRβ2 in a Multiethnic Asthma Case-Control Study 
Rationale: The comprehensive evaluation of gene variation, haplotype structure, and linkage disequilibrium is important in understanding the function of β2-adrenergic receptor gene (ADRβ2) on disease susceptibility, pulmonary function, and therapeutic responses in different ethnic groups with asthma.
Objectives: To identify ADRβ2 polymorphisms and haplotype structure in white and African American subjects and to test for genotype and haplotype association with asthma phenotypes.
Methods: A 5.3-kb region of ADRβ2 was resequenced in 669 individuals from 429 whites and 240 African Americans. A total of 12 polymorphisms, representing an optimal haplotype tagging set, were genotyped in whites (338 patients and 326 control subjects) and African Americans (222 patients and 299 control subjects).
Results: A total of 49 polymorphisms were identified, 21 of which are novel; 31 polymorphisms (frequency > 0.03) were used to identify 24 haplotypes (frequency > 0.01) and assess linkage disequilibrium. Association with ratio (FEV1/FVC)2 for single-nucleotide polymorphism +79 (p < 0.05) was observed in African Americans. Significant haplotype association for (FEV1/FVC)2 was also observed in African Americans.
Conclusions: There are additional genetic variants besides +46 (Gly16Arg) that are important in determining asthma phenotypes. These data suggest that the length of a poly-C repeat (+1269) in the 3′ untranslated region of ADRβ2 may influence lung function, and may be important in delineating variation in β-agonist responses, especially in African Americans.
doi:10.1164/rccm.200509-1405OC
PMCID: PMC2648111  PMID: 16931635
asthma; β2-adrenergic receptor; β-agonist therapy; DNA polymorphisms; pharmacogenomics
9.  Genomewide Screen for Pulmonary Function in 200 Families Ascertained for Asthma 
Changes in pulmonary function are important in determining asthma outcome. Genetic factors may influence airway obstruction in asthma. We performed a genomewide screen in 200 families of probands objectively diagnosed with asthma in the 1960s to identify chromosomal regions related to changes in pre- and postbronchodilator lung function (FEV1, VC, and FEV1%VC) and assess influences of early-life smoke exposure. Smoking (pack-years), age, sex, and height were covariates in variance component analyses. Significant evidence for linkage of pre- and postbronchodilator FEV1%VC was obtained for chromosome 2q32 (LOD,4.9, increasing to 6.03 with additional fine-mapping markers, and 3.2, respectively). Linkage existed for chromosome 5q for pre- and postbronchodilator VC (likelihood of disease [LOD], 1.8 and 2.6, respectively). Results for pre- and postbronchodilator FEV1 were less significant (LOD, 1.5 and 1.6, chromosomes 11p and 10q, respectively). Results were not affected by passive smoke exposure. There is significant evidence for linkage of FEV1%VC to chromosome 2q32 in families of probands with asthma, 35 cM proximal from linkage previously observed in families of probands with early-onset chronic obstructive pulmonary disease. Thus, there may be multiple genes on chromosome 2q that are important in determining presence and degree of airflow limitation in families ascertained for obstructive airway disease.
doi:10.1164/rccm.200407-864OC
PMCID: PMC2718527  PMID: 15901612
asthma; function; genes; linkage; lung
10.  Differential Desensitization of Homozygous Haplotypes of the β2-Adrenergic Receptor in Lymphocytes 
Single-nucleotide polymorphisms of the β2-adrenergic receptor gene and its 5′ promoter have been associated with differences in receptor function and desensitization. Linkage disequilibrium may account for inconsistencies in reported effects of isolated polymorphisms. Therefore, we have investigated the three most common homozygous haplotypes of the β2-adrenergic receptor (position 19 [Cys/Arg] of the 5′ leader cistron and positions 16 [Arg/Gly] and 27 [Gln/Glu] of the receptor) for putative differences in agonist-induced desensitization. Lymphocytes of well defined nonasthmatic, nonallergic subjects homozygous for the haplotype CysGlyGln, ArgGlyGlu, or CysArgGln were isolated. Desensitization of (−)-isoproterenol–induced cyclic adenosine monophosphate (cAMP) accumulation and β2-adrenergic receptor sequestration and downregulation were measured in relation to β2-adrenergic receptor-mediated inhibition of IFN-γ and interleukin-5 production. We observed that lymphocytes of individuals bearing the CysGlyGln haplotype were more susceptible to desensitization of the β-agonist–induced cAMP response than those of individuals with the ArgGlyGlu or CysArgGln haplotype. The haplotype-dependent desensitization of β-agonist–induced cAMP response was not associated with haplotype-dependent β2-adrenergic receptor sequestration or downregulation. In addition, our data suggest reduced inhibition, in lymphocytes of subjects with the CysGlyGln haplotype, of interleukin-5 production induced by treatment with antibodies to the T-cell receptor–CD3 complex and to costimulatory molecule CD28 (αCD3/αCD28). This is the first study demonstrating haplotype-related differences in agonist-induced β2-adrenergic receptor desensitization in primary human cells. This haplotype-related desensitization of the β2-adrenergic receptor in lymphocytes might have consequences regarding the regulation of helper T-cell type 2 inflammatory responses.
doi:10.1164/rccm.200409-1162OC
PMCID: PMC2718471  PMID: 15879418
5′ leader cistron; cAMP; cytokine production; sequestration and downregulation; single-nucleotide polymorphism

Results 1-10 (10)