H A Boushey

University of California, San Francisco, San Francisco, California, United States

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Publications (220)1984.79 Total impact

  • Journal of Allergy and Clinical Immunology 02/2015; 135(2):AB109. DOI:10.1016/j.jaci.2014.12.1291 · 11.25 Impact Factor
  • Yvonne J Huang, Homer A Boushey
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    ABSTRACT: The application of recently developed sensitive, specific, culture-independent tools for identification of microbes is transforming concepts of microbial ecology, including concepts of the relationships between the vast complex populations of microbes associated with ourselves and with states of health and disease. Although most work initially focused on the community of microbes (microbiome) in the gastrointestinal tract and its relationship to gastrointestinal disease, interest has expanded to include study of the relationships of the airway microbiome to asthma and its phenotypes and to the relationships between the gastrointestinal microbiome, development of immune function, and predisposition to allergic sensitization and asthma. Here we provide our perspective on the findings of studies of differences in the airway microbiome between asthmatic patients and healthy subjects and of studies of relationships between environmental microbiota, gut microbiota, immune function, and asthma development. In addition, we provide our perspective on how these findings suggest the broad outline of a rationale for approaches involving directed manipulation of the gut and airway microbiome for the treatment and prevention of allergic asthma. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
    Journal of Allergy and Clinical Immunology 01/2015; 135(1):25-30. DOI:10.1016/j.jaci.2014.11.011 · 11.25 Impact Factor
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    ABSTRACT: Asthma is a chronic lung disease that has a high prevalence. The therapeutic intervention of this disease can be made more effective if genetic variability in patients' response to medications is implemented. However, a clear picture of the genetic architecture of asthma intervention response remains elusive. We conducted a genome-wide association study (GWAS) to identify drug response-associated genes for asthma, in which 909 622 SNPs were genotyped for 120 randomized participants who inhaled multiple doses of glucocorticoids. By integrating pharmacodynamic properties of drug reactions, we implemented a mechanistic model to analyze the GWAS data, enhancing the scope of inference about the genetic architecture of asthma intervention. Our pharmacodynamic model observed associations of genome-wide significance between dose-dependent response to inhaled glucocorticoids (measured as %FEV1) and five loci (P=5.315 × 10(-7) to 3.924 × 10(-9)), many of which map to metabolic genes related to lung function and asthma risk. All significant SNPs detected indicate a recessive effect, at which the homozygotes for the mutant alleles drive variability in %FEV1. Significant associations were well replicated in three additional independent GWAS studies. Pooled together over these three trials, two SNPs, chr6 rs6924808 and chr11 rs1353649, display an increased significance level (P=6.661 × 10(-16) and 5.670 × 10(-11)). Our study reveals a general picture of pharmacogenomic control for asthma intervention. The results obtained help to tailor an optimal dose for individual patients to treat asthma based on their genetic makeup.The Pharmacogenomics Journal advance online publication, 20 January 2015; doi:10.1038/tpj.2014.83.
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    ABSTRACT: ß2-agonists are the most common form of treatment of asthma but there is significant variability in response to these medications. A significant proportion of this responsiveness may be heritable. To investigate whether a genome-wide association study (GWAS) could identify novel pharmacogenetic loci in asthma. We performed a GWAS of acute bronchodilator response (BDR) to inhaled ß2-agonists. 444,088 single nucleotide polymorphisms (SNPs) were examined in 724 individuals from the SNP Health Association Resource (SHARe) Asthma Resource Project (SHARP). The top 50 SNPs were carried forward to replication in a population of 444 individuals. The combined p-value for 4 SNPs reached statistical genome-wide significance after correcting for multiple comparisons. Combined p-values for rs350729, rs1840321, rs1384918, rs1319797 were 2.21x10-10, 5.75 x10-8, 9.3x10-8, and 3.95x10-8 respectively. The significant variants all map to a novel genetic region on chromosome 2 near the ASB3 gene, a region associated with smooth muscle proliferation. As compared to the wild-type the presence of the mutant alleles reduced the degree of bronchodilator response by 20% in the original population and by a similar percentage in the confirmatory population. These GWAS findings for bronchodilator response in asthmatics suggest that a gene associated with smooth muscle proliferation may influence a proportion of the smooth muscle relaxation that occurs in asthma.
    American Journal of Respiratory and Critical Care Medicine 01/2015; DOI:10.1164/rccm.201408-1426OC · 11.99 Impact Factor
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    ABSTRACT: Background: Wheezing illnesses cause major morbidity in infants and are frequent precursors to asthma. Objective: We sought to examine environmental factors associated with recurrent wheezing in inner-city environments. Methods: The Urban Environment and Childhood Asthma study examined a birth cohort at high risk for asthma (n = 560) in Baltimore, Boston, New York, and St Louis. Environmental assessments included allergen exposure and, in a nested case-control study of 104 children, the bacterial content of house dust collected in the first year of life. Associations were determined among environmental factors, aeroallergen sensitization, and recurrent wheezing at age 3 years. Results: Cumulative allergen exposure over the first 3 years was associated with allergic sensitization, and sensitization at age 3 years was related to recurrent wheeze. In contrast, first-year exposure to cockroach, mouse, and cat allergens was negatively associated with recurrent wheeze (odds ratio, 0.60, 0.65, and 0.75, respectively; P <= .01). Differences in house dust bacterial content in the first year, especially reduced exposure to specific Firmicutes and Bacteriodetes, was associated with atopy and atopic wheeze. Exposure to high levels of both allergens and this subset of bacteria in the first year of life was most common among children without atopy or wheeze. Conclusions: In inner-city environments children with the highest exposure to specific allergens and bacteria during their first year were least likely to have recurrent wheeze and allergic sensitization. These findings suggest that concomitant exposure to high levels of certain allergens and bacteria in early life might be beneficial and suggest new preventive strategies for wheezing and allergic diseases.
    Journal of Allergy and Clinical Immunology 05/2014; 134(3). DOI:10.1016/j.jaci.2014.04.018 · 11.25 Impact Factor
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    ABSTRACT: Specific bacterial species are implicated in the pathogenesis of exacerbations of chronic obstructive pulmonary disease (COPD). However, recent studies of clinically stable COPD patients have demonstrated a greater diversity of airway microbiota, whose role in acute exacerbations is unclear. In this study temporal changes in the airway microbiome before, at the onset of, and after an acute exacerbation were examined in 60 sputum samples collected from subjects enrolled in a longitudinal study of bacterial infection in COPD. Microbiome composition and predicted functions were examined using 16S rRNA-based culture-independent profiling methods. Shifts in the abundance (≥2-fold, p<0.05) of many taxa at exacerbation and after treatment were observed. Microbiota members increased at exacerbation were primarily of the Proteobacteria phylum, including non-typical COPD pathogens. Changes in bacterial composition after treatment for exacerbation differed significantly among the therapy regimens clinically prescribed (antibiotics only, oral corticosteroids only, or both). Treatment with antibiotics alone primarily decreased the abundance of Proteobacteria, with prolonged suppression of some microbiota members observed. In contrast, treatment with corticosteroids alone led to enrichment for Proteobacteria and members of other phyla. Predicted metagenomes of particular microbiota members involved in these compositional shifts, indicated exacerbation-associated loss of functions involved in the synthesis of antimicrobial and anti-inflammatory products, alongside enrichment in functions related to pathogen-elicited inflammation. These trends reversed upon clinical recovery. Further larger studies will be necessary to determine whether specific compositional or functional changes detected in the airway microbiome could be useful indicators of exacerbation development or outcome.
    Journal of Clinical Microbiology 05/2014; 52(8). DOI:10.1128/JCM.00035-14 · 4.23 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2014; 133(2):AB400. DOI:10.1016/j.jaci.2013.12.1056 · 11.25 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2014; 133(2):AB240. DOI:10.1016/j.jaci.2013.12.853 · 11.25 Impact Factor
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    ABSTRACT: Acute respiratory illness (ARI) is the leading cause of asthma exacerbations yet the mechanisms underlying this association remain unclear. To address the deficiencies in our understanding of the molecular events characterizing ARI-induced asthma exacerbations, we undertook a transcriptional profiling study of the nasal mucosa over the course of ARI amongst individuals with a history of asthma, allergic rhinitis and no underlying respiratory disease. Transcriptional profiling experiments were performed using the Agilent Whole Human Genome 4X44K array platform. Time point-based microarray and principal component analyses were conducted to identify and distinguish ARI-associated transcriptional profiles over the course of our study. Gene enrichment analysis was conducted to identify biological processes over represented within each ARI-associated profile and gene expression subsequently confirmed by quantitative PCR. We found that ARI is characterized by dynamic, time-specific transcriptional profiles whose magnitudes of expression are influenced by underlying respiratory disease and the mucosal repair signature evoked during ARI. Most strikingly, we report that asthmatics that experience ARI-induced exacerbations are characterized by a reduced but prolonged inflammatory immune response, inadequate activation of mucosal repair and the expression of a newly described exacerbation-specific transcriptional signature. Findings from our study represent a significant contribution towards clarifying the complex molecular interactions which typify ARI-induced asthma exacerbations.
    Genome Medicine 01/2014; 6(1):1. DOI:10.1186/gm520 · 4.94 Impact Factor
  • Yvonne J Huang, Homer A Boushey
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    ABSTRACT: That the subglottic airways are not sterile, as was once believed, but are populated by a distinct "bronchial microbiome," is now accepted. Also accepted is the concept that asthma is associated with differences in the composition of this microbiome. What is not clear is whether the differences in microbial community composition themselves mediate pathologic changes in the airways or whether they reflect differences in systemic immune function driven by differences in the development of the gastrointestinal microbiome in early life, when the immune system is most malleable. Recognition of the probable existence of a "common mucosal immune system" allowed synthesis of these apparently opposing ideas into a single conceptual model. Gastrointestinal microbiome-driven differences in systemic immune function predispose to sensitization to allergens deposited on mucosal surfaces, whereas possibly similar, but not identical, differences in immune function predispose to less effective responses to microbial infection of the airways, resulting in persistence of the inflammation underlying the structural and functional abnormalities of asthma. In this model, allergic sensitization and asthma are thus seen as commonly overlapping but not necessarily coincident consequences of abnormalities in microbial colonization, development of immune function, and encounter with agents infecting the respiratory tract.
    01/2014; 11(Supplement_1):S48-S51. DOI:10.1513/AnnalsATS.201306-187MG
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    ABSTRACT: Background: Differences in pathophysiology may underlie asthma heterogeneity, and bronchial microbiota composition has been associated with the degree of airway hyperresponsiveness among patients with mild to moderate asthma. In this study, we investigated relationships between the bronchial airway microbiome and disease features in severe asthma. Methods: Bacterial microbiota represented in protected bronchial brushings from 30 severe asthma subjects were profiled using a 16S rRNA-based phylogenetic microarray (PhyloChip; Second Genome Inc., San Bruno, CA). Clinical, physiologic, and airway inflammation measures were analyzed for relationships to airway bacterial community structure and composition. Results: Airway bacterial community structure was associated with between-visit differences in Asthma Control Questionnaire (ACQ) scores (P < 0.01), sputum neutrophilia (P < 0.08), and body mass index (BMI) (P < 0.03). The specific microbiota associated with change in ACQ score and with sputum neutrophilia differed markedly from those associated with BMI. Proteobacteria composed more than 70% of bacterial taxa correlated with sputum neutrophilia (Benjamini-Hochberg-adjusted P < 0.05), including such bacterial families as Bacillaceae, Helicobacteraceae, and Moraxellaceae. Proteobacteria constituted 93% of taxa positively correlated with ACQ score difference, whereas Actinobacteria composed 80% of taxa negatively correlated with this variable. In contrast, Bacteroidetes accounted for 54% of the taxa strongly associated with BMI, including a greater relative abundance of Prevotellaceae and Porphyromonadaceae among subjects with BMI greater than or equal to 30. Conclusions: Distinct airway bacterial community composition was associated with specific clinical and inflammatory features of severe asthma in this group of patients. We speculate that particular microbiota members may be involved in the induction or modulation of specific inflammatory processes that contribute to severe asthma and corresponding clinical phenotype.
    01/2014; 11(Supplement_1):S78. DOI:10.1513/AnnalsATS.201306-163MG
  • The Journal of allergy and clinical immunology 12/2013; 133(5). DOI:10.1016/j.jaci.2013.11.009 · 11.25 Impact Factor
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    ABSTRACT: Exposure to dogs in early infancy has been shown to reduce the risk of childhood allergic disease development, and dog ownership is associated with a distinct house dust microbial exposure. Here, we demonstrate, using murine models, that exposure of mice to dog-associated house dust protects against ovalbumin or cockroach allergen-mediated airway pathology. Protected animals exhibited significant reduction in the total number of airway T cells, down-regulation of Th2-related airway responses, as well as mucin secretion. Following dog-associated dust exposure, the cecal microbiome of protected animals was extensively restructured with significant enrichment of, amongst others, Lactobacillus johnsonii. Supplementation of wild-type animals with L. johnsonii protected them against both airway allergen challenge or infection with respiratory syncytial virus. L. johnsonii-mediated protection was associated with significant reductions in the total number and proportion of activated CD11c(+)/CD11b(+) and CD11c(+)/CD8(+) cells, as well as significantly reduced airway Th2 cytokine expression. Our results reveal that exposure to dog-associated household dust results in protection against airway allergen challenge and a distinct gastrointestinal microbiome composition. Moreover, the study identifies L. johnsonii as a pivotal species within the gastrointestinal tract capable of influencing adaptive immunity at remote mucosal surfaces in a manner that is protective against a variety of respiratory insults.
    Proceedings of the National Academy of Sciences 12/2013; 111(2). DOI:10.1073/pnas.1310750111 · 9.81 Impact Factor
  • Yvonne J Huang, Homer A Boushey
    American Journal of Respiratory and Critical Care Medicine 11/2013; 188(10):1178-80. DOI:10.1164/rccm.201309-1702ED · 11.99 Impact Factor
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    ABSTRACT: Tiotropium has activity as an asthma controller. However, predictors of a positive response to tiotropium have not been described. We sought to describe individual and differential responses of asthmatic patients to salmeterol and tiotropium when added to an inhaled corticosteroid, as well as predictors of a positive clinical response. Data from the double-blind, 3-way, crossover National Heart, Lung, and Blood Institute's Asthma Clinical Research Network's Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (ClinicalTrials.gov number, NCT00565266) trial were analyzed for individual and differential treatment responses to salmeterol and tiotropium and predictors of a positive response to the end points FEV1, morning peak expiratory flow (PEF), and asthma control days (ACDs). Although approximately equal numbers of patients showed a differential response to salmeterol and tiotropium in terms of morning PEF (n = 90 and 78, respectively) and ACDs (n = 49 and 53, respectively), more showed a differential response to tiotropium for FEV1 (n = 104) than salmeterol (n = 62). An acute response to a short-acting bronchodilator, especially albuterol, predicted a positive clinical response to tiotropium for FEV1 (odds ratio, 4.08; 95% CI, 2.00-8.31; P < .001) and morning PEF (odds ratio, 2.12; 95% CI, 1.12-4.01; P = 0.021), as did a decreased FEV1/forced vital capacity ratio (FEV1 response increased 0.39% of baseline for every 1% decrease in FEV1/forced vital capacity ratio). Higher cholinergic tone was also a predictor, whereas ethnicity, sex, atopy, IgE level, sputum eosinophil count, fraction of exhaled nitric oxide, asthma duration, and body mass index were not. Although these results require confirmation, predictors of a positive clinical response to tiotropium include a positive response to albuterol and airway obstruction, factors that could help identify appropriate patients for this therapy.
    The Journal of allergy and clinical immunology 09/2013; 132(5). DOI:10.1016/j.jaci.2013.08.003 · 11.25 Impact Factor
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    ABSTRACT: Airway hyperresponsiveness (AHR), a primary characteristic of asthma, involves increased airway smooth muscle contractility in response to certain exposures. We sought to determine whether common genetic variants were associated with AHR severity. A genome-wide association study (GWAS) of AHR, quantified as the natural log of the dosage of methacholine causing a 20% drop in FEV1, was performed with 994 non-Hispanic white asthmatic subjects from three drug clinical trials: CAMP, CARE, and ACRN. Genotyping was performed on Affymetrix 6.0 arrays, and imputed data based on HapMap Phase 2, was used to measure the association of SNPs with AHR using a linear regression model. Replication of primary findings was attempted in 650 white subjects from DAG, and 3,354 white subjects from LHS. Evidence that the top SNPs were eQTL of their respective genes was sought using expression data available for 419 white CAMP subjects. The top primary GWAS associations were in rs848788 (P-value 7.2E-07) and rs6731443 (P-value 2.5E-06), located within the ITGB5 and AGFG1 genes, respectively. The AGFG1 result replicated at a nominally significant level in one independent population (LHS P-value 0.012), and the SNP had a nominally significant unadjusted P-value (0.0067) for being an eQTL of AGFG1. Based on current knowledge of ITGB5 and AGFG1, our results suggest that variants within these genes may be involved in modulating AHR. Future functional studies are required to confirm that our associations represent true biologically significant findings.
    BMC Medical Genetics 08/2013; 14(1):86. DOI:10.1186/1471-2350-14-86 · 2.45 Impact Factor
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    ABSTRACT: BACKGROUND: Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function. OBJECTIVE: We sought to identify novel lung function loci specifically for asthma and to confirm lung function loci identified in general populations. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
    The Journal of allergy and clinical immunology 03/2013; 132(2). DOI:10.1016/j.jaci.2013.01.051 · 11.25 Impact Factor
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    ABSTRACT: 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 () gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest 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 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.
    PLoS ONE 02/2013; 8(2):e56179. DOI:10.1371/journal.pone.0056179 · 3.53 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2013; 131(2):AB60. DOI:10.1016/j.jaci.2012.12.1536 · 11.25 Impact Factor
  • JAMA The Journal of the American Medical Association 01/2013; 309(2):136-7. DOI:10.1001/jama.2012.73385 · 30.39 Impact Factor

Publication Stats

11k Citations
1,984.79 Total Impact Points


  • 1984–2015
    • University of California, San Francisco
      • • Department of Medicine
      • • Division of Pulmonary, Critical Care & Allergy/Immunology
      • • Division of Hospital Medicine
      • • Cardiovascular Research Institute
      San Francisco, California, United States
  • 2012
    • University of Texas Medical Branch at Galveston
      • Department of Internal Medicine
      Galveston, TX, United States
  • 2009
    • San Francisco VA Medical Center
      San Francisco, California, United States
  • 2007
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1996–2007
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2006
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2001–2004
    • CSU Mentor
      • Department of Nursing
      Long Beach, California, United States
  • 1997–2001
    • Thomas Jefferson University
      Philadelphia, Pennsylvania, United States
  • 2000
    • San Francisco State University
      San Francisco, California, United States
  • 1998
    • ASTHMA, Inc. Clinical Research Center
      Seattle, Washington, United States
  • 1991
    • Cardiovascular Research Foundation
      New York, New York, United States