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1.
Artigo em Inglês | MEDLINE | ID: mdl-34848210

RESUMO

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here we describe the Precision Interventions for Severe and/or Exacerbation Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the U.S. The PrecISE Network was designed to conduct phase II/proof of concept clinical trials of precision interventions in the severe asthma population, and is supported by the National Heart Lung and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the Network will evaluate up to six interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for of severe asthma.

2.
Lancet Child Adolesc Health ; 5(12): 862-872, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34762840

RESUMO

BACKGROUND: Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent. METHODS: We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 µg in children, 100 µg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV1. We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 µg twice daily in children and 500 µg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 µg twice daily in children, 250 µg twice daily in adolescents and adults), and 5 × ICS versus 100 µg fluticasone plus a LABA (salmeterol 50 µg twice daily). We used a genome-wide significance threshold of p<1·6 × 10-4, and tested for replication using independent cohorts of individuals of African descent with asthma. FINDINGS: We included 249 unrelated children and 267 unrelated adolescents and adults in the BARD pharmacogenetic analysis. In children, we identified a significant admixture mapping peak for superior responsiveness to 5 × ICS versus 100 µg fluticasone plus salmeterol on chromosome 12 (odds ratio [ORlocal African] 3·95, 95% CI 2·02-7·72, p=6·1 × 10-5) fine mapped to a locus adjacent to RNFT2 and NOS1 (rs73399224, ORallele dose 0·17, 95% CI 0·07-0·42, p=8·4 × 10-5). In adolescents and adults, we identified a peak for superior responsiveness to 5 × ICS versus 2·5 × ICS on chromosome 22 (ORlocal African 3·35, 1·98-5·67, p=6·8 × 10-6) containing a locus adjacent to TPST2 (rs5752429, ORallele dose 0·21, 0·09-0·52, p=5·7 × 10-4). We replicated rs5752429 and nominally replicated rs73399224 in independent African American cohorts. INTERPRETATION: BARD is the first genome-wide pharmacogenetic study of LABA and ICS response in clinical trials of individuals of African descent to detect and replicate genome-wide significant loci. Admixture mapping of the composite BARD trial outcome enabled the identification of novel pharmacogenetic variation accounting for differential therapeutic responses in people of African descent with asthma. FUNDING: National Institutes of Health, National Heart, Lung, and Blood Institute.

3.
Chest ; 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34767825

RESUMO

BACKGROUND: Small airways are known to be affected early in the course of chronic obstructive pulmonary disease (COPD); however, traditional spirometric indices may not accurately identify small airways disease. RESEARCH QUESTION: Can FEV3/FEV6 identify early airflow abnormalities and predict future clinically important respiratory-related outcomes, including development of COPD? STUDY DESIGN AND METHODS: We included eight hundred thirty-two current and former smokers with post-bronchodilator FEV1/FVC ≥0.7 from the SPIROMICS cohort. Participants were classified as having a reduced pre-bronchodilator FEV3/FEV6 based on lower limit of normal (LLN) values. Repeatability analysis was performed for FEV3 and FEV6. Regression modeling was used to evaluate the relationship between baseline FEV3/FEV6 and outcome measures including functional small airways disease on thoracic imaging and respiratory exacerbations. Interval censored analysis was used to assess progression to COPD. RESULTS: FEV3/FEV6

4.
PLoS Genet ; 17(11): e1009912, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34784346

RESUMO

α1-anti-trypsin (A1AT), encoded by SERPINA1, is a neutrophil elastase inhibitor that controls the inflammatory response in the lung. Severe A1AT deficiency increases risk for Chronic Obstructive Pulmonary Disease (COPD), however, the role of A1AT in COPD in non-deficient individuals is not well known. We identify a 2.1-fold increase (p = 2.5x10-6) in the use of a distal poly-adenylation site in primary lung tissue RNA-seq in 82 COPD cases when compared to 64 controls and replicate this in an independent study of 376 COPD and 267 controls. This alternative polyadenylation event involves two sites, a proximal and distal site, 61 and 1683 nucleotides downstream of the A1AT stop codon. To characterize this event, we measured the distal ratio in human primary tissue short read RNA-seq data and corroborated our results with long read RNA-seq data. Integrating these results with 3' end RNA-seq and nanoluciferase reporter assay experiments we show that use of the distal site yields mRNA transcripts with over 50-fold decreased translation efficiency and A1AT expression. We identified seven RNA binding proteins using enhanced CrossLinking and ImmunoPrecipitation precipitation (eCLIP) with one or more binding sites in the SERPINA1 3' UTR. We combined these data with measurements of the distal ratio in shRNA knockdown experiments, nuclear and cytoplasmic fractionation, and chemical RNA structure probing. We identify Quaking Homolog (QKI) as a modulator of SERPINA1 mRNA translation and confirm the role of QKI in SERPINA1 translation with luciferase reporter assays. Analysis of single-cell RNA-seq showed differences in the distribution of the SERPINA1 distal ratio among hepatocytes, macrophages, αß-Tcells and plasma cells in the liver. Alveolar Type 1,2, dendritic cells and macrophages also vary in their distal ratio in the lung. Our work reveals a complex post-transcriptional mechanism that regulates alternative polyadenylation and A1AT expression in COPD.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34523824

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome-wide association study approach. METHODS: Participants with COPD (N = 4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self-reported unintentional weight loss > 5% in the past year or low BMI (BMI < 20 kg/m2 ). In ECLIPSE and SPIROMICS, weight loss was calculated using available longitudinal visits. Stratified analyses were performed among African American (AA) and Non-Hispanic White (NHW) participants with COPD. Single variant and gene-based analyses were performed adjusting for confounders. Fine mapping was performed using a Bayesian approach integrating genetic association results with linkage disequilibrium and functional annotation. Significant gene networks were identified by integrating genetic regions associated with weight loss with skeletal muscle protein-protein interaction (PPI) data. RESULTS: At the single variant level, only the rs35368512 variant, intergenic to GRXCR1 and LINC02383, was associated with weight loss (odds ratio = 3.6, 95% confidence interval = 2.3-5.6, P = 3.2 × 10-8 ) among AA COPD participants in COPDGene. At the gene level in COPDGene, EFNA2 and BAIAP2 were significantly associated with weight loss in AA and NHW COPD participants, respectively. The EFNA2 association replicated among AA from SPIROMICS (P = 0.0014), whereas the BAIAP2 association replicated in NHW from ECLIPSE (P = 0.025). The EFNA2 gene encodes the membrane-bound protein ephrin-A2 involved in the regulation of developmental processes and adult tissue homeostasis such as skeletal muscle. The BAIAP2 gene encodes the insulin-responsive protein of mass 53 kD (IRSp53), a negative regulator of myogenic differentiation. Integration of the gene-based findings participants with PPI data revealed networks of genes involved in pathways such as Rho and synapse signalling. CONCLUSIONS: The EFNA2 and BAIAP2 genes were significantly associated with weight loss in COPD participants. Collectively, the integrative network analyses indicated genetic variation associated with weight loss in COPD may influence skeletal muscle regeneration and tissue remodelling.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34536413

RESUMO

BACKGROUND: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE. OBJECTIVE: We aimed to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum by leveraging data from the National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine program; the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA); and the Atopic Dermatitis Research Network (N = 21,901). METHODS: We performed genome-wide association within strata of study, disease, and ancestry groups, and we combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data. RESULTS: We identified 6 loci at genome-wide significance (P < 5 × 10-9), including 4 loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, which were also identified in prior genome-wide association studies of atopic dermatitis and asthma. In the HLA allele association study, HLA-A∗02:01 was associated with decreased tIgE level (Pdiscovery = 2 × 10-4; Preplication = 5 × 10-4; Pdiscovery+replication = 4 × 10-7), and HLA-DQB1∗03:02 was strongly associated with decreased tIgE level in Hispanic/Latino ancestry populations (PHispanic/Latino discovery+replication = 8 × 10-8). CONCLUSION: We performed the largest genome-wide association study and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.

7.
J Allergy Clin Immunol Pract ; 9(11): 3934-3940.e9, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34438103

RESUMO

BACKGROUND: Sites of entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly expressed in nasal epithelial cells; however, little is known about the impact of intranasal corticosteroids (INCS) on coronavirus disease 2019 (COVID-19)-related outcomes. OBJECTIVE: To determine the association between baseline INCS use and COVID-19-related outcomes. METHODS: Using the Cleveland Clinic COVID-19 Research Registry, we performed a propensity score matching for treatment with INCS before SARS-CoV-2 infection (April 1, 2020, to March 31, 2021). Of the 82,096 individuals who tested positive, 72,147 met inclusion criteria. Our endpoints included the need for hospitalization, admission to the intensive care unit (ICU), or in-hospital mortality. RESULTS: Of the 12,608 (17.5%) who were hospitalized, 2935 (4.1%) required ICU admission and 1880 (2.6%) died during hospitalization. A significant proportion (n = 10,187; 14.1%) were using INCS before SARS-CoV-2 infection. Compared with nonusers, INCS users demonstrated lower risk for hospitalization (adjusted odds ratio [OR] [95% confidence interval (CI)]: 0.78 [0.72; 0.85]), ICU admission (adjusted OR [95% CI]: 0.77 [0.65; 0.92]), and in-hospital mortality (adjusted OR [95% CI]: 0.76 [0.61; 0.94]). These findings were replicated in sensitivity analyses where patients on inhaled corticosteroids and those with allergic rhinitis were excluded. The beneficial effect of INCS was significant after adjustment for baseline blood eosinophil count (measured before SARS-CoV-2 testing) in a subset of 30,289 individuals. CONCLUSION: INCS therapy is associated with a lower risk for COVID-19-related hospitalization, ICU admission, or death. Future randomized control trials are needed to determine if INCS reduces the risk for severe outcomes related to COVID-19.


Assuntos
COVID-19 , Corticosteroides/uso terapêutico , Teste para COVID-19 , Humanos , Unidades de Terapia Intensiva , SARS-CoV-2
8.
Am J Respir Crit Care Med ; 204(5): 536-545, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33971109

RESUMO

Rationale: Racial residential segregation has been associated with worse health outcomes, but the link with chronic obstructive pulmonary disease (COPD) morbidity has not been established.Objectives: To investigate whether racial residential segregation is associated with COPD morbidity among urban Black adults with or at risk of COPD.Methods: Racial residential segregation was assessed using isolation index, based on 2010 decennial census and baseline address, for Black former and current smokers in the multicenter SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), a study of adults with or at risk for COPD. We tested the association between isolation index and respiratory symptoms, physiologic outcomes, imaging parameters, and exacerbation risk among urban Black residents, adjusting for established COPD risk factors, including smoking. Additional mediation analyses were conducted for factors that could lie on the pathway between segregation and COPD outcomes, including individual and neighborhood socioeconomic status, comorbidity burden, depression/anxiety, and ambient pollution.Measurements and Main Results: Among 515 Black participants, those residing in segregated neighborhoods (i.e., isolation index ⩾0.6) had worse COPD Assessment Test score (ß = 2.4; 95% confidence interval [CI], 0.7 to 4.0), dyspnea (modified Medical Research Council scale; ß = 0.29; 95% CI, 0.10 to 0.47), quality of life (St. George's Respiratory Questionnaire; ß = 6.1; 95% CI, 2.3 to 9.9), and cough and sputum (ß = 0.8; 95% CI, 0.1 to 1.5); lower FEV1% predicted (ß = -7.3; 95% CI, -10.9 to -3.6); higher rate of any and severe exacerbations; and higher percentage emphysema (ß = 2.3; 95% CI, 0.7 to 3.9) and air trapping (ß = 3.8; 95% CI, 0.6 to 7.1). Adverse associations attenuated with adjustment for potential mediators but remained robust for several outcomes, including dyspnea, FEV1% predicted, percentage emphysema, and air trapping.Conclusions: Racial residential segregation was adversely associated with COPD morbidity among urban Black participants and supports the hypothesis that racial segregation plays a role in explaining health inequities affecting Black communities.


Assuntos
Afro-Americanos/estatística & dados numéricos , Disparidades nos Níveis de Saúde , Doença Pulmonar Obstrutiva Crônica/etnologia , Doença Pulmonar Obstrutiva Crônica/mortalidade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Segregação Social , População Urbana/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Características de Residência , Classe Social , Inquéritos e Questionários , Estados Unidos/etnologia
9.
Metabolites ; 11(3)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799786

RESUMO

Susceptibility and progression of lung disease, as well as response to treatment, often differ by sex, yet the metabolic mechanisms driving these sex-specific differences are still poorly understood. Women with chronic obstructive pulmonary disease (COPD) have less emphysema and more small airway disease on average than men, though these differences become less pronounced with more severe airflow limitation. While small studies of targeted metabolites have identified compounds differing by sex and COPD status, the sex-specific effect of COPD on systemic metabolism has yet to be interrogated. Significant sex differences were observed in 9 of the 11 modules identified in COPDGene. Sex-specific associations by COPD status and emphysema were observed in 3 modules for each phenotype. Sex stratified individual metabolite associations with COPD demonstrated male-specific associations in sphingomyelins and female-specific associations in acyl carnitines and phosphatidylethanolamines. There was high preservation of module assignments in SPIROMICS (SubPopulations and InteRmediate Outcome Measures In COPD Study) and similar female-specific shift in acyl carnitines. Several COPD associated metabolites differed by sex. Acyl carnitines and sphingomyelins demonstrate sex-specific abundances and may represent important metabolic signatures of sex differences in COPD. Accurately characterizing the sex-specific molecular differences in COPD is vital for personalized diagnostics and therapeutics.

10.
Genome Med ; 13(1): 66, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33883027

RESUMO

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression. METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants. RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections. CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.


Assuntos
Brônquios , COVID-19/genética , Mucosa Respiratória , SARS-CoV-2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Enzima de Conversão de Angiotensina 2/genética , Asma/genética , COVID-19/imunologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/imunologia , Expressão Gênica , Variação Genética , Humanos , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/imunologia , Doença Pulmonar Obstrutiva Crônica/genética , Locos de Características Quantitativas , Fatores de Risco , Fumar/genética
11.
BMC Pulm Med ; 21(1): 139, 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33906617

RESUMO

BACKGROUND: Millions of Americans are living in food deserts in the United States, however the role of the local food environment on COPD has not been studied. The aim of this study is to determine the association between food deserts and COPD-related outcomes. METHOD: In this cross-sectional analysis we linked data collected from SPIROMICS (SubPopulations and InteRmediate Outcome Measures in COPD Study) between 2010 and 2015 and food desert data, defined as an underserved area that lacks access to affordable healthy foods, from the Food Access Research Atlas. COPD outcomes include percentage of predicted forced expiratory volume in one second (FEV1%), St. George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), 6-min walk distance test (6MWD), exacerbations, and air trapping. We used generalized linear mixed models to evaluate the association between living in food deserts and respiratory outcomes, adjusting for age, gender, race, education, income, marital status, BMI, smoking status, pack years, and urban status RESULTS: Among 2713 participants, 22% lived in food deserts. Participants living in food deserts were less likely to be white and more likely to have a lower income than those who did not live in food deserts. In the adjusted model controlling for demographics and individual income, living in food deserts was associated lower FEV1% (ß = - 2.51, P = 0.046), higher air trapping (ß = 2.47, P = 0.008), worse SGRQ (ß = 3.48, P = 0.001) and CAT (ß = 1.20, P = 0.003) scores, and 56% greater odds of severe exacerbations (P = 0.004). Results were consistent when looking at food access alone, regardless of whether participants lived in low income areas. CONCLUSIONS: Findings suggest an independent association between food desert and food access alone with COPD outcomes. Health program planning may benefit from addressing disparities in access to food.


Assuntos
Alimentos , Doença Pulmonar Obstrutiva Crônica , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
12.
Respir Res ; 22(1): 127, 2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33906653

RESUMO

BACKGROUND: Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes. METHODS: sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV1) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity). RESULTS: Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P < 0.001), reduced FEV1 (P < 0.001), and emphysema severity (P < 0.001). In an inverse-variance weighted meta-analysis, one SD lower log10-transformed sRAGE was associated with 105 ± 22 mL lower FEV1 and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV1 decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar. CONCLUSIONS: Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations.


Assuntos
Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/sangue , Enfisema Pulmonar/sangue , Receptor para Produtos Finais de Glicação Avançada/sangue , Idoso , Biomarcadores/sangue , Feminino , Volume Expiratório Forçado , Humanos , Estudos Longitudinais , Pulmão/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Fenótipo , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/fisiopatologia , Índice de Gravidade de Doença , Espirometria , Tomografia Computadorizada por Raios X , Capacidade Vital
13.
Artigo em Inglês | MEDLINE | ID: mdl-33713768

RESUMO

BACKGROUND: Genetic ancestry plays a role in asthma health disparities. OBJECTIVE: Our aim was to evaluate the impact of ancestry on and identify genetic variants associated with asthma, total serum IgE level, and lung function. METHODS: A total of 436 Peruvian children (aged 9-19 years) with asthma and 291 without asthma were genotyped by using the Illumina Multi-Ethnic Global Array. Genome-wide proportions of indigenous ancestry populations from continental America (NAT) and European ancestry from the Iberian populations in Spain (IBS) were estimated by using ADMIXTURE. We assessed the relationship between ancestry and the phenotypes and performed a genome-wide association study. RESULTS: The mean ancestry proportions were 84.7% NAT (case patients, 84.2%; controls, 85.4%) and 15.3% IBS (15.8%; 14.6%). With adjustment for asthma, NAT was associated with higher total serum IgE levels (P < .001) and IBS was associated with lower total serum IgE levels (P < .001). NAT was associated with higher FEV1 percent predicted values (P < .001), whereas IBS was associated with lower FEV1 values in the controls but not in the case patients. The HLA-DR/DQ region on chromosome 6 (Chr6) was strongly associated with total serum IgE (rs3135348; P = 3.438 × 10-10) and was independent of an association with the haplotype HLA-DQA1∼HLA-DQB1:04.01∼04.02 (P = 1.55 × 10-05). For lung function, we identified a locus (rs4410198; P = 5.536 × 10-11) mapping to Chr19, near a cluster of zinc finger interacting genes that colocalizes to the long noncoding RNA CTD-2537I9.5. This novel locus was replicated in an independent sample of pediatric case patients with asthma with similar admixture from Brazil (P = .005). CONCLUSION: This study confirms the role of HLA in atopy, and identifies a novel locus mapping to a long noncoding RNA for lung function that may be specific to children with NAT.

14.
Am J Respir Crit Care Med ; 204(3): 285-293, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33779531

RESUMO

Rationale: Androgens are potentially beneficial in asthma, but AR (androgen receptor) has not been studied in human airways.Objectives: To measure whether AR and its ligands are associated with human asthma outcomes.Methods: We compared the effects of AR expression on lung function, symptom scores, and fractional exhaled nitric oxide (FeNO) in adults enrolled in SARP (Severe Asthma Research Program). The impact of sex and of androgens on asthma outcomes was also evaluated in the SARP with validation studies in the Cleveland Clinic Health System and the NHANES (U.S. National Health and Nutrition Examination Survey).Measurements and Main Results: In SARP (n = 128), AR gene expression from bronchoscopic epithelial brushings was positively associated with both FEV1/FVC ratio (R2 = 0.135, P = 0.0002) and the total Asthma Quality of Life Questionnaire score (R2 = 0.056, P = 0.016) and was negatively associated with FeNO (R2 = 0.178, P = 9.8 × 10-6) and NOS2 (nitric oxide synthase gene) expression (R2 = 0.281, P = 1.2 × 10-10). In SARP (n = 1,659), the Cleveland Clinic Health System (n = 32,527), and the NHANES (n = 2,629), women had more asthma exacerbations and emergency department visits than men. The levels of the AR ligand precursor dehydroepiandrosterone sulfate correlated positively with the FEV1 in both women and men.Conclusions: Higher bronchial AR expression and higher androgen levels are associated with better lung function, fewer symptoms, and a lower FeNO in human asthma. The role of androgens should be considered in asthma management.


Assuntos
Asma/genética , Sulfato de Desidroepiandrosterona/sangue , RNA Mensageiro/metabolismo , Receptores Androgênicos/genética , Mucosa Respiratória/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/sangue , Asma/fisiopatologia , Testes Respiratórios , Broncoscopia , Feminino , Volume Expiratório Forçado , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Qualidade de Vida , Fatores Sexuais , Capacidade Vital , Adulto Jovem
15.
J Allergy Clin Immunol ; 147(5): 1594-1601, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33667479

RESUMO

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.


Assuntos
Asma , Biomarcadores , Medicina de Precisão , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Projetos de Pesquisa
16.
NPJ Biofilms Microbiomes ; 7(1): 14, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547327

RESUMO

Chronic obstructive pulmonary disease (COPD) is heterogeneous in development, progression, and phenotypes. Little is known about the lung microbiome, sampled by bronchoscopy, in milder COPD and its relationships to clinical features that reflect disease heterogeneity (lung function, symptom burden, and functional impairment). Using bronchoalveolar lavage fluid collected from 181 never-smokers and ever-smokers with or without COPD (GOLD 0-2) enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we find that lung bacterial composition associates with several clinical features, in particular bronchodilator responsiveness, peak expiratory flow rate, and forced expiratory flow rate between 25 and 75% of FVC (FEF25-75). Measures of symptom burden (COPD Assessment Test) and functional impairment (six-minute walk distance) also associate with disparate lung microbiota composition. Drivers of these relationships include members of the Streptococcus, Prevotella, Veillonella, Staphylococcus, and Pseudomonas genera. Thus, lung microbiota differences may contribute to airway dysfunction and airway disease in milder COPD.


Assuntos
Bactérias/classificação , Pulmão/microbiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , RNA Ribossômico 16S/genética , Análise de Sequência de RNA/métodos , Adulto , Idoso , Bactérias/isolamento & purificação , Líquido da Lavagem Broncoalveolar/microbiologia , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/microbiologia , Espirometria
18.
Chest ; 160(1): 94-103, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33539837

RESUMO

BACKGROUND: Mild expiratory flow limitation may not be recognized using traditional spirometric criteria based on the ratio of FEV1/FVC. RESEARCH QUESTION: Does slow vital capacity (SVC) instead of FVC increase the sensitivity of spirometry to identify patients with early or mild obstructive lung disease? STUDY DESIGN AND METHODS: We included 854 current and former smokers from the Subpopulations and Intermediate Outcome Measures in COPD Study cohort with a postbronchodilator FEV1/FVC ≥ 0.7 and FEV1 % predicted of ≥ 80% at enrollment. We compared baseline characteristics, chest CT scan features, exacerbations, and progression to COPD (postbronchodilator FEV1/FVC, < 0.7) during the follow-up period between 734 participants with postbronchodilator FEV1/SVC of ≥ 0.7 and 120 with postbronchodilator FEV1/SVC < 0.7 at the enrollment. We performed multivariate linear and logistic regression models and negative binomial and interval-censored proportion hazards regression models adjusted for demographics and smoking exposure to examine the association of FEV1/SVC < 0.7 with those characteristics and outcomes. RESULTS: Participants with FEV1/SVC < 0.7 were older and had lower FEV1 and more emphysema than those with FEV1/SVC ≥ 0.7. In adjusted analysis, individuals with postbronchodilator FEV1/SVC < 0.7 showed a greater percentage of emphysema by 0.45% (95% CI, 0.09%-0.82%), percentage of gas trapping by 2.52% (95% CI, 0.59%-4.44%), and percentage of functional small airways disease based on parametric response mapping by 2.78% (95% CI, 0.72%-4.83%) at baseline than those with FEV1/SVC ≥ 0.7. During a median follow-up time of 1,500 days, an FEV1/SVC < 0.7 was not associated with total exacerbations (incident rate ratio [IRR], 1.61; 95% CI, 0.97-2.64), but was associated with severe exacerbations (IRR, 2.60; 95% CI, 1.04-4.89). An FEV1/SVC < 0.7 was associated with progression to COPD during a 3-year follow-up even after adjustment for demographics and smoking exposure (hazard ratio, 3.93; 95% CI, 2.71-5.72). We found similar results when we examined the association of prebronchodilator FEV1/SVC < 0.7 or FEV1/SVC less than the lower limit of normal with chest CT scan features and progression to COPD. INTERPRETATION: Low FEV1 to SVC in current and former smokers with normal spirometry results can identify individuals with CT scan features of COPD who are at risk for severe exacerbations and is associated with progression to COPD in the future. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01969344T4; URL: www.clinicaltrials.gov.


Assuntos
Volume Expiratório Forçado/fisiologia , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fumantes , Tomografia Computadorizada por Raios X/métodos , Capacidade Vital/fisiologia , Progressão da Doença , Seguimentos , Humanos , Pulmão/diagnóstico por imagem , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Espirometria/métodos
19.
J Pers Med ; 11(1)2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33477890

RESUMO

An unaddressed and important issue is the role age plays in modulating response to short acting ß2-agonists in individuals with asthma. The objective of this study was to identify whether age modifies genetic associations of single nucleotide polymorphisms (SNPs) with bronchodilator response (BDR) to ß2-agonists. Using three cohorts with a total of 892 subjects, we ran a genome wide interaction study (GWIS) for each cohort to examine SNP by age interactions with BDR. A fixed effect meta-analysis was used to combine the results. In order to determine if previously identified BDR SNPs had an age interaction, we also examined 16 polymorphisms in candidate genes from two published genome wide association studies (GWAS) of BDR. There were no significant SNP by age interactions on BDR using the genome wide significance level of 5 × 10-8. Using a suggestive significance level of 5 × 10-6, three interactions, including one for a SNP within PRAG1 (rs4840337), were significant and replicated at the significance level of 0.05. Considering candidate genes from two previous GWAS of BDR, three SNPs (rs10476900 (near ADRB2) [p-value = 0.009], rs10827492 (CREM) [p-value = 0.02], and rs72646209 (NCOA3) [p-value = 0.02]) had a marginally significant interaction with age on BDR (p < 0.05). Our results suggest age may be an important modifier of genetic associations for BDR in asthma.

20.
Indoor Air ; 31(3): 702-716, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33037695

RESUMO

Increased outdoor concentrations of fine particulate matter (PM2.5 ) and oxides of nitrogen (NO2 , NOx ) are associated with respiratory and cardiovascular morbidity in adults and children. However, people spend most of their time indoors and this is particularly true for individuals with chronic obstructive pulmonary disease (COPD). Both outdoor and indoor air pollution may accelerate lung function loss in individuals with COPD, but it is not feasible to measure indoor pollutant concentrations in all participants in large cohort studies. We aimed to understand indoor exposures in a cohort of adults (SPIROMICS Air, the SubPopulations and Intermediate Outcome Measures in COPD Study of Air pollution). We developed models for the entire cohort based on monitoring in a subset of homes, to predict mean 2-week-measured concentrations of PM2.5 , NO2 , NOx , and nicotine, using home and behavioral questionnaire responses available in the full cohort. Models incorporating socioeconomic, meteorological, behavioral, and residential information together explained about 60% of the variation in indoor concentration of each pollutant. Cross-validated R2 for best indoor prediction models ranged from 0.43 (NOx ) to 0.51 (NO2 ). Models based on questionnaire responses and estimated outdoor concentrations successfully explained most variation in indoor PM2.5 , NO2 , NOx , and nicotine concentrations.


Assuntos
Poluentes Atmosféricos , Poluição do Ar em Ambientes Fechados/estatística & dados numéricos , Exposição Ambiental/estatística & dados numéricos , Dióxido de Nitrogênio , Material Particulado , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Adulto , Poluição do Ar , Criança , Estudos de Coortes , Monitoramento Ambiental , Humanos , Avaliação de Resultados em Cuidados de Saúde , Projetos de Pesquisa , Poluição por Fumaça de Tabaco/estatística & dados numéricos
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