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Minal Calışkan,
Yury A Bochkov,
Eskil Kreiner-Møller,
Klaus Bønnelykke,
Michelle M Stein,
Gaixin Du,
Hans Bisgaard,
Daniel J Jackson,
James E Gern, Robert F Lemanske,
Dan L Nicolae,
Carole Ober
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ABSTRACT: Background Both genetic variation at the 17q21 locus and virus-induced respiratory wheezing illnesses are associated with the development of asthma. Our aim was to determine the effects of these two factors on the risk of asthma in the Childhood Origins of Asthma (COAST) and the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohorts. Methods We tested genotypes at the 17q21 locus for associations with asthma and with human rhinovirus (HRV) and respiratory syncytial virus (RSV) wheezing illnesses and tested for interactions between 17q21 genotypes and HRV and RSV wheezing illnesses with respect to the risk of asthma. Finally, we examined genotype-specific expression of 17q21 genes in unstimulated and HRV-stimulated peripheral-blood mononuclear cells (PBMCs). Results The 17q21 variants were associated with HRV wheezing illnesses in early life, but not with RSV wheezing illnesses. The associations of 17q21 variants with asthma were restricted to children who had had HRV wheezing illnesses, resulting in a significant interaction effect with respect to the risk of asthma. Moreover, the expression levels of ORMDL3 and of GSDMB were significantly increased in HRV-stimulated PBMCs, as compared with unstimulated PBMCs. The expression of these genes was associated with 17q21 variants in both conditions, although the increase with exposure to HRV was not genotype-specific. Conclusions Variants at the 17q21 locus were associated with asthma in children who had had HRV wheezing illnesses and with expression of two genes at this locus. The expression levels of both genes increased in response to HRV stimulation, although the relative increase was not associated with the 17q21 genotypes. (Funded by the National Institutes of Health.).
New England Journal of Medicine 03/2013; · 53.30 Impact Factor
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Xingnan Li,
Gregory A Hawkins,
Elizabeth J Ampleford,
Wendy C Moore,
Huashi Li,
Annette T Hastie,
Timothy D Howard,
Homer A Boushey,
William W Busse,
William J Calhoun,
Mario Castro,
Serpil C Erzurum,
Elliot Israel, Robert F Lemanske,
Stanley J Szefler,
Stephen I Wasserman,
Sally E Wenzel,
Stephen P Peters,
Deborah A Meyers,
Eugene R Bleecker
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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; · 9.17 Impact Factor
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Avraham Beigelman,
Tonya S King,
David Mauger,
Robert S Zeiger,
Robert C Strunk,
H William Kelly,
Fernando D Martinez, Robert F Lemanske,
Katherine Rivera-Spoljaric,
Daniel J Jackson,
Theresa Guilbert,
Ronina Covar,
Leonard B Bacharier
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ABSTRACT: BACKGROUND: Oral corticosteroids (OCSs) are recommended for severe wheezing episodes in children. However, limited evidence supports this intervention in preschool children with outpatient wheezing illnesses. OBJECTIVE: We sought to investigate whether OCSs reduce symptom scores during acute lower respiratory tract illnesses (LRTIs) in preschool children with recurrent wheeze. METHODS: We performed post hoc and replication analyses in 2 outpatient cohorts of children aged 1 to 5 years with episodic wheezing participating in clinical trials. We compared symptom scores during LRTIs that were or were not treated with OCSs, adjusting for differences in disease and episode severity covariates. We stratified episodes by severity by using a propensity model. The primary outcome was the area under the curve (AUC) of total symptom scores among the more severe episodes. RESULTS: Two hundred fifteen participants from the Acute Intervention Management Strategies trial experienced 798 acute LRTIs, 112 of which were defined as severe based on propensity scores. The AUCs of total symptom scores did not differ between the episodes that were (n = 70) and were not (n = 42) treated with OCSs (P = .46) nor was there an OCS treatment effect on individual symptom scores. Similar analyses of the Maintenance Versus Intermittent Inhaled Corticosteroids in Wheezing Toddlers trial, involving 278 participants with 133 severe LRTIs, confirmed the above findings (P = .46 for AUC of total symptoms score comparison). CONCLUSION: In 2 separate cohorts of preschool children with episodic wheezing, OCS treatment during clinically significant LRTIs did not reduce symptom severity during acute LRTIs, despite asthma controller medication use during most episodes. These findings need to be confirmed in a prospective randomized controlled trial.
The Journal of allergy and clinical immunology 03/2013; · 9.17 Impact Factor
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Emma E Thompson,
Rachel A Myers,
Gaixin Du,
Tessa M Aydelotte,
Christopher J Tisler,
Debra A Stern,
Michael D Evans,
Penelope E Graves,
Daniel J Jackson,
Fernando D Martinez,
James E Gern,
Anne L Wright, Robert F Lemanske,
Carole Ober
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ABSTRACT: BACKGROUND: Maternal asthma and child's sex are among the most significant and reproducible risk factors for the development of asthma. Although the mechanisms for these effects are unknown, they likely involve nonclassical genetic mechanisms. One such mechanism could involve the transfer and persistence of maternal cells to her offspring, a common occurrence known as maternal microchimerism (MMc). MMc has been associated with many autoimmune diseases but has not been investigated for a role in asthma or allergic disease. OBJECTIVE: We hypothesized that some of the observed risks for asthma may be due to different rates of transmission or persistence of maternal cells to children of mothers with asthma compared with children of mothers without asthma, or to sons compared with daughters. We further hypothesized that rates of MMc differ between children with and without asthma. METHODS: We tested these hypotheses in 317 subjects from 3 independent cohorts by using a real-time quantitative PCR assay to detect a noninherited HLA allele in the child. RESULTS: MMc was detected in 20.5% of the subjects (range 16.8%-27.1% in the 3 cohorts). We observed lower rates of asthma among MMc-positive subjects than among MMc-negative subjects (odds ratio, 0.38; 95% CI, 0.19-0.79; P = .029). Neither maternal asthma nor sex of the child was a significant predictor of MMc in the child (P = .81 and .15, respectively). CONCLUSIONS: Our results suggest for the first time that MMc may protect against the development of asthma.
The Journal of allergy and clinical immunology 02/2013; · 9.17 Impact Factor
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Anne Marie Singh,
Paul Dahlberg,
Kristjan Burmeister,
Michael D Evans,
Ronald Gangnon,
Kathy A Roberg,
Christopher Tisler,
Douglas Dasilva,
Tressa Pappas,
Lisa Salazar, Robert F Lemanske,
James E Gern,
Christine M Seroogy
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ABSTRACT: BACKGROUND: T regulatory (Treg) cells are important in balancing immune responses and dysregulation of Treg cells has been implicated in the pathogenesis of multiple disease states including asthma. In this study, our primary aim was to determine Treg cell frequency in the peripheral blood of children with and without asthma. The secondary aim was to explore the association between Treg cell frequency with allergen sensitization, disease severity and medication use. METHODS: Peripheral blood mononuclear cells from healthy control subjects (N = 93) and asthmatic children of varying disease severity (N = 66) were characterized by multi-parameter flow cytometry. RESULTS: Our findings demonstrate that children with asthma had a significantly increased frequency of Treg cells compared to children without asthma. Using a multivariate model, increased Treg cell frequency in children with asthma was most directly associated with inhaled corticosteroid use, and not asthma severity, allergic sensitization, or atopic status of the asthma. CONCLUSION: We conclude that low dose, local airway administration of corticosteroids is sufficient to impact the frequency of Treg cells in the peripheral blood. These data highlight the importance of considering medication exposure when studying Treg cells and suggest inhaled corticosteroid use in asthmatics may improve disease control through increased Treg cell frequency.
Clinical and Molecular Allergy 01/2013; 11(1):1. · 1.39 Impact Factor
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ABSTRACT: ABSTRACT BACKGROUND: Presently, there is insufficient information to compare the value of daily diaries versus retrospective questionnaires for assessing symptoms in relationship to asthma control in clinical trials. Daily symptom diaries are often burdensome to gather, incomplete, susceptible to fabrication and of questionable reliability. There is also concern that retrospective symptom questionnaires may be subject to poor recall, and may be insensitive. METHODS: To compare these two methods of assessing symptoms reporting, we analyzed data collected during the Best Add-on Therapy Giving Effective Responses (BADGER) trial. Asthma control in 182 children (6-17 years of age) during the trial was assessed in two ways: first, by asthma control days (ACDs) determined by manually recorded daily diary symptom and rescue medication use scores; and second, by monthly retrospective report of symptoms embedded within the age-appropriate version of the Asthma Control Test (ACT©). Correlations between ACDs and ACT© scores were analyzed, and the sensitivity of each method for measuring asthma control and determining the differential response among the three BADGER treatments was evaluated. RESULTS: Although validated using a 4-week recall period, ACT© correlated better with daily diary information from the last two weeks of the 4-week recall (r=0.46) than from the first two weeks (r=0.34). In addition, clinically significant differential treatment responses were detected using ACDs but not ACT© scores.
Chest 01/2013; · 5.25 Impact Factor
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Blanca E Himes,
Keith Sheppard,
Annerose Berndt,
Adriana S Leme,
Rachel A Myers,
Christopher R Gignoux,
Albert M Levin,
W James Gauderman,
James J Yang,
Rasika A Mathias, [......],
L Keoki Williams,
Esteban G Burchard,
Dan L Nicolae,
Carole Ober,
Dawn L Demeo,
Edwin K Silverman,
Beverly Paigen,
Gary Churchill,
Steve D Shapiro,
Scott T Weiss
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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 01/2013; 8(2):e56179. · 4.09 Impact Factor
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Loren C Denlinger,
David M Manthei,
Max A Seibold,
Kwangmi Ahn,
Eugene Bleecker,
Homer A Boushey,
William J Calhoun,
Mario Castro,
Vernon M Chinchili,
John V Fahy, [......],
Richard J Martin,
Deborah A Meyers,
Stephen P Peters,
Dagna Sheerar,
Lei Shi,
E Rand Sutherland,
Stanley J Szefler,
Michael E Wechsler,
Christine A Sorkness, Robert F Lemanske
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ABSTRACT: RATIONALE: The function of the P2X7 nucleotide receptor protects against exacerbation in mild-intermittent asthmatics 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 ACRN 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: One hundred eighty-seven exacerbations were studied in 742 subjects, and the change in asthma symptom burden was studied in an additional 110 subjects during a trial of ICS dose optimization. African American carriers of the minor G allele of the rs2230911 loss-of-function SNP were more likely to have a history of prednisone use in the previous 12 months, with adjustment for ICS and LABA use (OR = 2.7, 95% CI 1.2 - 6.2, p = 0.018). Despite medium dose ICS, attenuated pore function predicted earlier exacerbations in incompletely controlled patients with moderate asthma (HR = 3.2, CI 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.
American Journal of Respiratory and Critical Care Medicine 11/2012; · 11.08 Impact Factor
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The Journal of allergy and clinical immunology 10/2012; · 9.17 Impact Factor
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Rachel A Myers,
Blanca E Himes,
Christopher R Gignoux,
James J Yang,
W James Gauderman,
Cristina Rebordosa,
Jianming Xie,
Dara G Torgerson,
Albert M Levin,
James Baurley, [......],
Stephanie J London,
Kathleen C Barnes,
Benjamin A Raby,
Fernando D Martinez,
Frank D Gilliland,
L Keoki Williams,
Esteban G Burchard,
Scott T Weiss,
Dan L Nicolae,
Carole Ober
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ABSTRACT: BACKGROUND: Genome-wide association studies of asthma have implicated many genetic risk factors, with well-replicated associations at approximately 10 loci that account for only a small proportion of the genetic risk. OBJECTIVES: We aimed to identify additional asthma risk loci by performing an extensive replication study of the results from the EVE Consortium meta-analysis. METHODS: We selected 3186 single nucleotide polymorphisms for replication based on the P values from the EVE Consortium meta-analysis. These single nucleotide polymorphisms were genotyped in ethnically diverse replication samples from 9 different studies, totaling 7202 cases, 6426 controls, and 507 case-parent trios. Association analyses were conducted within each participating study, and the resulting test statistics were combined in a meta-analysis. RESULTS: Two novel associations were replicated in European Americans: rs1061477 in the KLK3 gene on chromosome 19 (combined odds ratio = 1.18; 95% CI, 1.10-1.25) and rs9570077 (combined odds ratio =1.20; 95% CI, 1.12-1.29) on chromosome 13q21. We could not replicate any additional associations in the African Americans or Latinos. CONCLUSIONS: This extended replication study identified 2 additional asthma risk loci in populations of European descent. The absence of additional loci for African Americans and Latinos highlights the difficulty in replicating associations in admixed populations.
The Journal of allergy and clinical immunology 10/2012; · 9.17 Impact Factor
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James E Gern,
Tressa Pappas,
Cynthia M Visness,
Katy F Jaffee, Robert F Lemanske,
Alkis Togias,
Gordon R Bloomberg,
William W Cruikshank,
Carin Lamm,
Marina Tuzova,
Robert A Wood,
Wai Ming Lee
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ABSTRACT: Background. The risk of developing childhood asthma has been linked to the severity and etiology of viral respiratory illnesses in early childhood. Since inner-city infants have unique environmental exposures, we hypothesized that patterns of respiratory viral infections would also be distinct. Methods. We compared the viral etiology of respiratory illnesses in 2 groups: a cohort of 515 infants from 4 inner-city areas and a cohort of 285 infants from mainly suburban Madison, Wisconsin. Nasal secretions were sampled during periods of respiratory illness and at 1 year of age and were analyzed for viral pathogens by multiplex polymerase chain reaction. Results. Overall, inner-city infants had lower rates of viral detection. Considering specific viruses, sick urban infants had lower rates of detectable rhinovirus or respiratory syncytial virus infection and higher rates of adenovirus infection. Every urban site had a higher proportion of adenovirus-positive samples associated with illnesses (10%-21%), compared with Madison (6%). Conclusions. These findings provide evidence that inner-city babies have different patterns of viral respiratory illnesses than babies who grow up in a more suburban location. These findings raise important questions about the etiology of virus-negative illnesses in urban infants and the possibility of long-term consequences of early life infections with adenovirus in this population.
The Journal of Infectious Diseases 09/2012; 206(9):1342-9. · 6.41 Impact Factor
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William J Calhoun,
Bill T Ameredes,
Tonya S King,
Nikolina Icitovic,
Eugene R Bleecker,
Mario Castro,
Reuben M Cherniack,
Vernon M Chinchilli,
Timothy Craig,
Loren Denlinger, [......],
Rodolfo Pascual,
Stephen P Peters,
Joe Ramsdell,
Christine A Sorkness,
E Rand Sutherland,
Stanley J Szefler,
Stephen I Wasserman,
Michael J Walter,
Michael E Wechsler,
Homer A Boushey
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ABSTRACT: 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.
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.
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.
clinicaltrials.gov Identifier: NCT00495157.
JAMA The Journal of the American Medical Association 09/2012; 308(10):987-97. · 30.03 Impact Factor
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ABSTRACT: RATIONALE: Human rhinoviruses (HRVs) consist of approximately 160 types that cause a wide range of clinical outcomes including asymptomatic infections, common colds, and severe lower respiratory illnesses. OBJECTIVE: To identify factors which influence the severity of HRV illnesses. METHODS: HRV species and types were determined in 1445 nasal lavages that were prospectively collected from 209 infants participating in a birth cohort who had at least one HRV infection. Questionnaires were used during each illness to identify moderate-to-severe illnesses (MSI). Measurements & MAIN RESULTS: Altogether, 670 HRV infections were identified and 519 of them were solitary infections (only one HRV type). These 519 viruses belonged to 93 different types of 3 species: 49 A, 9 B and 35 C. HRV-A (OR 8.2 [2.7, 25]) and HRV-C (OR 7.6 [2.6, 23]) were more likely to cause MSI compared to HRV-B. In addition, HRV infections were 5-10-fold more likely to cause MSI in the winter months (p<0.0001) compared to summer, in contrast to peak seasonal prevalence in spring and fall. When significant differences in host susceptibility to MSI (p=0.004) were considered, strain-specific rates of HRV MSI ranged from <1% to over 20%. CONCLUSIONS: Factors related to HRV species and type, season, and host susceptibility determine the risk of more severe HRV illness in infancy. These findings suggest that anti-HRV strategies should focus on HRV-A and -C species, and identify the need for additional studies to determine mechanisms for seasonal increases of HRV severity, independent of viral prevalence, in cold weather months.
American Journal of Respiratory and Critical Care Medicine 08/2012; · 11.08 Impact Factor
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Sandy R Durrani,
Daniel J Montville,
Allison S Pratt,
Sanjukta Sahu,
Mark K DeVries,
Victoria Rajamanickam,
Ronald E Gangnon,
Michelle A Gill,
James E Gern, Robert F Lemanske,
Daniel J Jackson
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ABSTRACT: Children with allergic asthma have more frequent and severe human rhinovirus (HRV)-induced wheezing and asthma exacerbations through unclear mechanisms.
We sought to determine whether increased high-affinity IgE receptor (FcεRI) expression and cross-linking impairs innate immune responses to HRV, particularly in allergic asthmatic children.
PBMCs were obtained from 44 children, and surface expression of FcεRI on plasmacytoid dendritic cells (pDCs), myeloid dendritic cells, monocytes, and basophils was assessed by using flow cytometry. Cells were also incubated with rabbit anti-human IgE to cross-link FcεRI, followed by stimulation with HRV-16, and IFN-α and IFN-λ1 production was measured by Luminex. The relationships among FcεRI expression and cross-linking, HRV-induced IFN-α and IFN-λ1 production, and childhood allergy and asthma were subsequently analyzed.
FcεRIα expression on pDCs was inversely associated with HRV-induced IFN-α and IFN-λ1 production. Cross-linking FcεRI before HRV stimulation further reduced PBMC IFN-α (47% relative reduction; 95% CI, 32% to 62%; P< .0001) and IFN-λ1 (81% relative reduction; 95% CI, 69% to 93%; P< .0001) secretion. Allergic asthmatic children had higher surface expression of FcεRIα on pDCs and myeloid dendritic cells when compared with that seen in nonallergic nonasthmatic children. Furthermore, after FcεRI cross-linking, allergic asthmatic children had significantly lower HRV-induced IFN responses than allergic nonasthmatic children (IFN-α, P= .004; IFN-λ1, P= .02) and nonallergic nonasthmatic children (IFN-α, P= .002; IFN-λ1, P= .01).
Allergic asthmatic children have impaired innate immune responses to HRV that correlate with increased FcεRI expression on pDCs and are reduced by FcεRI cross-linking. These effects likely increase susceptibility to HRV-induced wheezing and asthma exacerbations.
The Journal of allergy and clinical immunology 07/2012; 130(2):489-95. · 9.17 Impact Factor
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Blanca E Himes,
Xiaofeng Jiang,
Ruoxi Hu,
Ann C Wu,
Jessica A Lasky-Su,
Barbara J Klanderman,
John Ziniti,
Jody Senter-Sylvia,
John J Lima,
Charles G Irvin, [......],
Maartje A E Nieuwenhuis,
Judith M Vonk,
Reynold A Panettieri,
Amy Markezich,
Elliot Israel,
Vincent J Carey,
Kelan G Tantisira,
Augusto A Litonjua,
Quan Lu,
Scott T Weiss
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ABSTRACT: Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. FEV(1)) before and after the administration of a short-acting β(2)-agonist, the most common rescue medications used for the treatment of asthma. BDR also serves as a test of β(2)-agonist efficacy. BDR is a complex trait that is partly under genetic control. A genome-wide association study (GWAS) of BDR, quantified as percent change in baseline FEV(1) after administration of a β(2)-agonist, was performed with 1,644 non-Hispanic white asthmatic subjects from six drug clinical trials: CAMP, LOCCS, LODO, a medication trial conducted by Sepracor, CARE, and ACRN. Data for 469,884 single-nucleotide polymorphisms (SNPs) were used to measure the association of SNPs with BDR using a linear regression model, while adjusting for age, sex, and height. Replication of primary P-values was attempted in 501 white subjects from SARP and 550 white subjects from DAG. Experimental evidence supporting the top gene was obtained via siRNA knockdown and Western blotting analyses. The lowest overall combined P-value was 9.7E-07 for SNP rs295137, near the SPATS2L gene. Among subjects in the primary analysis, those with rs295137 TT genotype had a median BDR of 16.0 (IQR = [6.2, 32.4]), while those with CC or TC genotypes had a median BDR of 10.9 (IQR = [5.0, 22.2]). SPATS2L mRNA knockdown resulted in increased β(2)-adrenergic receptor levels. Our results suggest that SPATS2L may be an important regulator of β(2)-adrenergic receptor down-regulation and that there is promise in gaining a better understanding of the biological mechanisms of differential response to β(2)-agonists through GWAS.
PLoS Genetics 07/2012; 8(7):e1002824. · 8.69 Impact Factor
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ABSTRACT: Viral illnesses are important factors in both asthma inception and exacerbations, and allergic sensitization in early life further enhances asthma risk through unclear mechanisms. Cellular damage caused by infection or allergen inhalation increases ATP levels in the airways with subsequent purinergic receptor activation. The purinergic receptor P2X(7) can enhance airway leukocyte recruitment to the airways, and P2X(7) knockout mice display a reduced asthma-like phenotype.
Based on the P2X(7) knockout mouse, we hypothesized that children with low P2X(7) function would have decreased rates of asthma.
We used a functional assay to determine P2X(7) pore-producing capacity in whole-blood samples in a birth cohort at high risk for asthma development. The P2X(7) assay was validated with known loss-of-function alleles in human subjects. P2X(7) pore status categorization was used to assess asthma and allergy status in the cohort.
Attenuated P2X(7) function was associated with lower asthma rates at ages 6 and 8 years, and the greatest effects were observed in boys. Children with asthma at age 11 years who had low P2X(7) capacity had less severe disease in the previous year. Attenuated P2X(7) function was also associated with sensitization to fewer aeroallergens.
P2X(7) functional capacity is associated with asthma risk or disease severity, and these relationships appear to be age related.
The Journal of allergy and clinical immunology 06/2012; 130(2):496-502. · 9.17 Impact Factor
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ABSTRACT: 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 (https://biolincc.nhlbi.nih.gov/studies/). 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.
Thorax 05/2012; 67(5):450-5. · 6.84 Impact Factor
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ABSTRACT: The 2009 H1N1 flu appeared to cause more severe cold symptoms during the 2009-2010 flu season.
We evaluated H1N1 infections during peak viral season in children with and without asthma to determine whether the H1N1 infectivity rate and illness severity were greater in subjects with asthma.
One hundred and eighty children, 4-12 years of age, provided eight consecutive weekly nasal mucus samples from September 5 through October 24, 2009, and scored cold and asthma symptoms daily. Viral diagnostics were performed for all nasal samples.
One hundred and sixty-one children (95 with asthma, 66 without asthma) completed at least 6 of the 8 nasal samples. The incidence of H1N1 infection was significantly higher in children with asthma (41%) than in children without asthma (24%; odds ratio, 4; 95% confidence interval, 1.8-9; P < 0.001), but rates of human rhinovirus infection (90% each) and other viral infections (47 vs. 41%) were similar. In children with asthma, there was a nonsignificant trend for increased loss of asthma control during H1N1 infections compared with human rhinovirus infections (38 vs. 21%; odds ratio, 2.6; 95% confidence interval, 0.9-7.2; P = 0.07).
During peak 2009 H1N1 flu season, children with asthma were infected almost twice as often with H1N1 compared with other respiratory viruses. H1N1 infection also caused increased severity of cold symptoms compared with other viral infections. Given the increased susceptibility of children with asthma to infection, these findings reinforce the need for yearly influenza vaccination to prevent infection, and raise new questions about the mechanism for enhanced susceptibility to influenza infection in asthma.
American Journal of Respiratory and Critical Care Medicine 02/2012; 185(12):1275-9. · 11.08 Impact Factor
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The Journal of allergy and clinical immunology 01/2012; 129(4):1162-4. · 9.17 Impact Factor
