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BACKGROUND: Asthma is a heterogeneous common respiratory disease that remains poorly understood. The established genetic associations fail to explain the high estimated heritability, and the prevalence of asthma differs between populations and geographic regions. Robust association analyses incorporating different genetic ancestries and whole-genome sequencing data may identify novel genetic associations. METHODS: We performed family-based genome-wide association analyses of childhood-onset asthma based on whole-genome sequencing (WGS) data for the 'The Genetic Epidemiology of Asthma in Costa Rica' study (GACRS) and the Childhood Asthma Management Program (CAMP). Based on parent-child trios with children diagnosed with asthma, we performed a single variant analysis using an additive and a recessive genetic model and a region-based association analysis of low-frequency and rare variants. RESULTS: Based on 1180 asthmatic trios (894 GACRS trios and 286 CAMP trios, a total of 3540 samples with WGS data), we identified three novel genetic loci associated with childhood-onset asthma: rs4832738 on 4p14 ($P=1.72\ast{10}^{-9}$, recessive model), rs1581479 on 8p22 ($P=1.47\ast{10}^{-8}$, additive model) and rs73367537 on 10q26 ($P=1.21\ast{10}^{-8}$, additive model in GACRS only). Integrative analyses suggested potential novel candidate genes underlying these associations: PGM2 on 4p14 and FGF20 on 8p22. CONCLUSION: Our family-based whole-genome sequencing analysis identified three novel genetic loci for childhood-onset asthma. Gene expression data and integrative analyses point to PGM2 on 4p14 and FGF20 on 8p22 as linked genes. Furthermore, region-based analyses suggest independent potential low-frequency/rare variant associations on 8p22. Follow-up analyses are needed to understand the functional mechanisms and generalizability of these associations.
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Asma , Estudo de Associação Genômica Ampla , Humanos , Predisposição Genética para Doença , Asma/genética , Loci Gênicos , Sequenciamento Completo do Genoma , Polimorfismo de Nucleotídeo Único/genética , Fatores de Crescimento de Fibroblastos/genéticaRESUMO
The US Department of Health and Human Services has defined health literacy (HL) as the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions. Structural and social determinants of health lead to low HL in approximately 36% of adults in the United States, where this condition is most prevalent in racial and ethnic minorities, economically disadvantaged communities, and immigrants with limited English proficiency. In turn, low HL can worsen asthma outcomes through direct effects (eg, nonadherence to or incorrect use of medications) and indirect effects (eg, an unhealthy diet leading to obesity, a risk factor for asthma morbidity). The purpose of this update is to examine evidence from studies on low HL and health and asthma outcomes published in the last 12 years, identify approaches to improve HL and reduce health disparities in asthma, and discuss future directions for research in this area under the conceptual framework of a socioecological model that illustrates the multifactorial and interconnected complexity of this public health issue at different levels.
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Asma , Letramento em Saúde , Humanos , Asma/epidemiologia , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Little is known about nasal epithelial gene expression and total IgE in youth. OBJECTIVE: We aimed to identify genes whose nasal epithelial expression differs by total IgE in youth, and group them into modules that could be mapped to airway epithelial cell types. METHODS: We conducted a transcriptome-wide association study of total IgE in 469 Puerto Ricans aged 9 to 20 years who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study, separately in all subjects and in those with asthma. We then attempted to replicate top findings for each analysis using data from 3 cohorts. Genes with a Benjamini-Hochberg-adjusted P value of less than .05 in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study and a P value of less than .05 in the same direction of association in 1 or more replication cohort were considered differentially expressed genes (DEGs). DEGs for total IgE in subjects with asthma were further dissected into gene modules using coexpression analysis, and such modules were mapped to specific cell types in airway epithelia using public single-cell RNA-sequencing data. RESULTS: A higher number of DEGs for total IgE were identified in subjects with asthma (n = 1179 DEGs) than in all subjects (n = 631 DEGs). In subjects with asthma, DEGs were mapped to 11 gene modules. The top module for positive correlation with total IgE was mapped to myoepithelial and mucus secretory cells in lower airway epithelia and was regulated by IL-4, IL5, IL-13, and IL-33. Within this module, hub genes included CDH26, FETUB, NTRK2, CCBL1, CST1, and CST2. Furthermore, an enrichment analysis showed overrepresentation of genes in signaling pathways for synaptogenesis, IL-13, and ferroptosis, supporting interactions between interleukin- and acetylcholine-induced responses. CONCLUSIONS: Our findings for nasal epithelial gene expression support neuroimmune coregulation of total IgE in youth with asthma.
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Asma , Interleucina-13 , Criança , Humanos , Adolescente , Interleucina-13/genética , Nariz , Transcriptoma , Imunoglobulina ERESUMO
BACKGROUND: Piwi-interacting RNAs (piRNAs), comprising the largest noncoding RNA group, regulate transcriptional processes. Whether piRNAs are associated with type 2 (T2)-high asthma is unknown. OBJECTIVE: We sought to investigate the association between piRNAs and T2-high asthma in childhood asthma. METHODS: We sequenced plasma samples from 462 subjects in the Childhood Asthma Management Program (CAMP) as the discovery cohort and 1165 subjects in the Genetics of Asthma in Costa Rica Study (GACRS) as a replication cohort. Sequencing reads were filtered first, and piRNA reads were annotated and normalized. Linear regression was used for the association analysis of piRNAs and peripheral blood eosinophil count, total serum IgE level, and long-term asthma exacerbation in children with asthma. Mediation analysis was performed to investigate the effect direction. We then ascertained if the circulating piRNAs were present in asthmatic airway epithelial cells in a Gene Expression Omnibus (GEO; www.ncbi.nlm.nih.gov/geo) public data set. RESULTS: Fifteen piRNAs were significantly associated with eosinophil count in CAMP (P ≤ .05), and 3 were successfully replicated in GACRS. Eleven piRNAs were associated with total IgE in CAMP, and one of these was replicated in GACRS. All 22 significant piRNAs were identified in epithelial cells in vitro, and 6 of these were differentially expressed between subjects with asthma and healthy controls. Fourteen piRNAs were associated with long-term asthma exacerbation, and effect of piRNAs on long-term asthma exacerbation are mediated through eosinophil count and serum IgE level. CONCLUSION: piRNAs are associated with peripheral blood eosinophils and total serum IgE in childhood asthma and may play important roles in T2-high asthma.
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Asma , RNA de Interação com Piwi , Criança , Humanos , RNA Interferente Pequeno/genética , Asma/genética , Imunoglobulina E/genética , FenótipoRESUMO
BACKGROUND: Black adults are disproportionately affected by asthma and are often considered a homogeneous group in research studies despite cultural and ancestral differences. OBJECTIVE: We sought to determine if asthma morbidity differs across adults in Black ethnic subgroups. METHODS: Adults with moderate-severe asthma were recruited across the continental United States and Puerto Rico for the PREPARE (PeRson EmPowered Asthma RElief) trial. Using self-identifications, we categorized multiethnic Black (ME/B) participants (n = 226) as Black Latinx participants (n = 146) or Caribbean, continental African, or other Black participants (n = 80). African American (AA/B) participants (n = 518) were categorized as Black participants who identified their ethnicity as being American. Baseline characteristics and retrospective asthma morbidity measures (self-reported exacerbations requiring systemic corticosteroids [SCs], emergency department/urgent care [ED/UC] visits, hospitalizations) were compared across subgroups using multivariable regression. RESULTS: Compared with AA/B participants, ME/B participants were more likely to be younger, residing in the US Northeast, and Spanish speaking and to have lower body mass index, health literacy, and <1 comorbidity, but higher blood eosinophil counts. In a multivariable analysis, ME/B participants were significantly more likely to have ED/UC visits (incidence rate ratio [IRR] = 1.34, 95% CI = 1.04-1.72) and SC use (IRR = 1.27, 95% CI = 1.00-1.62) for asthma than AA/B participants. Of the ME/B subgroups, Puerto Rican Black Latinx participants (n = 120) were significantly more likely to have ED/UC visits (IRR = 1.64, 95% CI = 1.22-2.21) and SC use for asthma (IRR = 1.43, 95% CI = 1.06-1.92) than AA/B participants. There were no significant differences in hospitalizations for asthma among subgroups. CONCLUSIONS: ME/B adults, specifically Puerto Rican Black Latinx adults, have higher risk of ED/UC visits and SC use for asthma than other Black subgroups.
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Asma , População Negra , Adulto , Humanos , Asma/complicações , Asma/epidemiologia , Asma/etnologia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Etnicidade/estatística & dados numéricos , Hispânico ou Latino/etnologia , Hispânico ou Latino/estatística & dados numéricos , Morbidade , Estudos Retrospectivos , Estados Unidos/epidemiologia , Porto Rico/etnologia , Negro ou Afro-Americano/etnologia , Negro ou Afro-Americano/estatística & dados numéricos , População do Caribe/estatística & dados numéricos , África/etnologia , População Negra/etnologia , População Negra/estatística & dados numéricosRESUMO
Elexacaftor/tezacaftor/ivacaftor (ETI) has made a substantial positive impact for people living with CF (pwCF). However, there can be substantial variability in efficacy, and we lack adequate biomarkers to predict individual response. We thus aimed to identify transcriptomic profiles in nasal respiratory epithelium that predict clinical response to ETI treatment. We obtained nasal epithelial samples from pwCF prior to ETI initiation and performed a transcriptome-wide analysis of baseline gene expression to predict changes in FEV1 (∆FEV1), year's best FEV1 (∆ybFEV1), and body mass index (∆BMI). Using the top differentially expressed genes (DEGs), we generated transcriptomic risk scores (TRS) and evaluated their predictive performance. The study included 40 pwCF aged ≥6 years (mean 27.7 [SD=15.1] years; 40% female). After ETI initiation, FEV1 improved ≥5% in 22 (61.1%) participants and ybFEV1 improved ≥5% in 19 (50%). TRS were constructed using top over-expressed and under-expressed genes for each. Adding the ∆FEV1 TRS for to a model with age, sex, and baseline FEV1 increased the AUC from 0.41 to 0.88; the ∆ybFEV1 TRS increased the AUC from 0.51 to 0.88; and the ∆BMI TRS increased the AUC from 0.46 to 0.92. Average accuracy was thus ~85% in predicting the response to the three outcomes. Results were similar in models further adjusted for F508del zygosity and previous CFTR modulator use. In conclusion, we identified nasal epithelial transcriptomic profiles that help accurately predict changes in FEV1 and BMI with ETI treatment. These novel TRS could serve as predictive biomarkers for clinical response to modulator treatment in pwCF.
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In the United States, people living in deprived urban areas and persons in certain minoritized groups are often exposed to violence and affected with asthma, and epidemiologic studies have shown a link between exposure to violence (ETV) and asthma throughout the lifespan. Indeed, ETV at the individual, intrafamilial and community levels has been linked to asthma in children and adults. In this review, we discuss the evidence for a causal relation between ETV and asthma, emphasizing findings published in the last five years. Interpretation of the available evidence is limited by variable quality of the assessment of ETV or asthma, potential recall and selection bias, inability to estimate the relative contribution of various types of violence to the observed associations, lack of objective biomarkers of asthma or asthma endotypes, and inconsistent consideration of potential confounders or modifiers of the ETV-asthma link. Despite such limitations, the aggregate evidence from studies conducted in different locations and populations suggests that ETV affects asthma and asthma outcomes, and that this is explained by direct physiologic effects of violence-related distress and indirect effects (e.g., through risky health behaviors or co-morbidities). Thus, large prospective studies with careful assessment of specific types of ETV, key covariates and comorbidities (including mental illness), and asthma are needed to advance this field. Such research efforts should not preclude screening for maltreatment in children with asthma and ETV-related depression and anxiety in adolescents and adults with asthma. Further, vigorous policies are needed to curtail violence, as such policies could benefit patients with asthma while saving lives.
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BACKGROUND: Epidemiologic studies have reported conflicting findings for cat or dog exposure and childhood asthma. No study has evaluated whether persistent pet exposure from early life to school age is associated with asthma or allergic sensitization in youth. OBJECTIVE: To evaluate whether persistent ownership of a cat or a dog throughout childhood is associated with asthma in Puerto Rican youth, a group disproportionately affected with asthma. METHODS: Prospective study of 384 youth who completed a baseline visit at ages 6 to 14 years and a second visit at ages 9 to 20 years. Persistent cat or dog ownership was defined as ownership of a cat or a dog in early life (during pregnancy or the first year of life) at either study visit (at school age). An allergen-specific IgE result was considered positive if more than or equal to 0.35 IU/mL. Logistic regression was used for the multivariable analysis of asthma and allergic sensitization. RESULTS: In an analysis adjusting for household income, family history of atopy, persistent overweight or obesity, a persistent unhealthy diet, the time interval between study visits, and other covariates, persistent cat ownership was significantly associated with 68% reduced odds of asthma (95% CI for odds ratio = 0.11-0.92) but not with any allergic sensitization or sensitization to cat allergen. In contrast, persistent dog ownership was not significantly associated with asthma or allergic sensitization. CONCLUSION: Among school-aged Puerto Rican youth followed for an average of 5 years, persistent cat ownership from early life to school age was inversely associated with asthma.
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Background: Lung nodules are common incidental findings, and timely evaluation is critical to ensure diagnosis of localized-stage and potentially curable lung cancers. Rates of guideline-concordant lung nodule evaluation are low, and the risk of delayed evaluation is higher for minoritized groups. Objectives: To summarize the existing evidence, identify knowledge gaps, and prioritize research questions related to interventions to reduce disparities in lung nodule evaluation. Methods: A multidisciplinary committee was convened to review the evidence and identify key knowledge gaps in four domains: 1) research methodology, 2) patient-level interventions, 3) clinician-level interventions, and 4) health system-level interventions. A modified Delphi approach was used to identify research priorities. Results: Key knowledge gaps included 1) a lack of standardized approaches to identify factors associated with lung nodule management disparities, 2) limited data evaluating the role of social determinants of health on disparities in lung nodule management, 3) a lack of certainty regarding the optimal strategy to improve patient-clinician communication and information transmission and/or retention, and 4) a paucity of information on the impact of patient navigators and culturally trained multidisciplinary teams. Conclusions: This statement outlines a research agenda intended to stimulate high-impact studies of interventions to mitigate disparities in lung nodule evaluation. Research questions were prioritized around the following domains: 1) need for methodologic guidelines for conducting research related to disparities in nodule management, 2) evaluating how social determinants of health influence lung nodule evaluation, 3) studying approaches to improve patient-clinician communication, and 4) evaluating the utility of patient navigators and culturally enriched multidisciplinary teams to reduce disparities.
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Neoplasias Pulmonares , Humanos , Comunicação , Pulmão , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/diagnóstico , Pesquisa , Sociedades Médicas , Estados UnidosRESUMO
BACKGROUND: Expression quantitative trait methylation (eQTM) analyses uncover associations between DNA methylation markers and gene expression. Most eQTM analyses of complex diseases have focused on cis-eQTM pairs (within 1 megabase). OBJECTIVES: This study sought to identify cis- and trans-methylation markers associated with gene expression in airway epithelium from youth with and without atopic asthma. METHODS: In this study, the investigators conducted both cis- and trans-eQTM analyses in nasal (airway) epithelial samples from 158 Puerto Rican youth with atopic asthma and 100 control subjects without atopy or asthma. The investigators then attempted to replicate their findings in nasal epithelial samples from 2 studies of children, while also examining whether their results in nasal epithelium overlap with those from an eQTM analysis in white blood cells from the Puerto Rican subjects. RESULTS: This study identified 9,108 cis-eQTM pairs and 2,131,500 trans-eQTM pairs. Trans-associations were significantly enriched for transcription factor and microRNA target genes. Furthermore, significant cytosine-phosphate-guanine sites (CpGs) were differentially methylated in atopic asthma and significant genes were enriched for genes differentially expressed in atopic asthma. In this study, 50.7% to 62.6% of cis- and trans-eQTM pairs identified in Puerto Rican youth were replicated in 2 smaller cohorts at false discovery rate-adjusted P < .1. Replicated genes in the trans-eQTM analysis included biologically plausible asthma-susceptibility genes (eg, HDC, NLRP3, ITGAE, CDH26, and CST1) and are enriched in immune pathways. CONCLUSIONS: Studying both cis- and trans-epigenetic regulation of airway epithelial gene expression can identify potential causal and regulatory pathways or networks for childhood asthma. Trans-eQTM CpGs may regulate gene expression in airway epithelium through effects on transcription factor and microRNA target genes.
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Asma , MicroRNAs , Criança , Adolescente , Humanos , Transcriptoma , Epigênese Genética , Asma/metabolismo , Metilação de DNA , Epitélio/metabolismo , Marcadores Genéticos , Mucosa Nasal/metabolismo , Fatores de Transcrição/genética , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
BACKGROUND: Sex differences related to immune responses can influence atopic manifestations in childhood asthma. While genome-wide association studies have investigated a sex-specific genetic architecture of the immune response, gene-by-sex interactions have not been extensively analysed for atopy-related markers including allergy skin tests, IgE and eosinophils in asthmatic children. METHODS: We performed a genome-wide gene-by-sex interaction analysis for atopy-related markers using whole-genome sequencing data based on 889 trios from the Genetic Epidemiology of Asthma in Costa Rica Study (GACRS) and 284 trios from the Childhood Asthma Management Program (CAMP). We also tested the findings in UK Biobank participants with self-reported childhood asthma. Furthermore, downstream analyses in GACRS integrated gene expression to disentangle observed associations. RESULTS: Single nucleotide polymorphism (SNP) rs1255383 at 10q11.21 demonstrated a genome-wide significant gene-by-sex interaction (pinteraction=9.08×10-10) for atopy (positive skin test) with opposite direction of effects between females and males. In the UK Biobank participants with a history of childhood asthma, the signal was consistently observed with the same sex-specific effect directions for high eosinophil count (pinteraction=0.0058). Gene expression of ZNF33B (zinc finger protein 33B), located at 10q11.21, was moderately associated with atopy in girls, but not in boys. CONCLUSIONS: We report SNPs in/near a zinc finger gene as novel sex-differential loci for atopy-related markers with opposite effect directions in females and males. A potential role for ZNF33B should be studied further as an important driver of sex-divergent features of atopy in childhood asthma.
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Asma , Hipersensibilidade Imediata , Criança , Humanos , Masculino , Feminino , Estudo de Associação Genômica Ampla , Imunoglobulina E , Asma/epidemiologia , Hipersensibilidade Imediata/genética , Hipersensibilidade Imediata/epidemiologia , Eosinófilos , Polimorfismo de Nucleotídeo Único , Predisposição Genética para DoençaRESUMO
MOTIVATION: Tissue-level omics data such as transcriptomics and epigenomics are an average across diverse cell types. To extract cell-type-specific (CTS) signals, dozens of cellular deconvolution methods have been proposed to infer cell-type fractions from tissue-level data. However, these methods produce vastly different results under various real data settings. Simulation-based benchmarking studies showed no universally best deconvolution approaches. There have been attempts of ensemble methods, but they only aggregate multiple single-cell references or reference-free deconvolution methods. RESULTS: To achieve a robust estimation of cellular fractions, we proposed EnsDeconv (Ensemble Deconvolution), which adopts CTS robust regression to synthesize the results from 11 single deconvolution methods, 10 reference datasets, 5 marker gene selection procedures, 5 data normalizations and 2 transformations. Unlike most benchmarking studies based on simulations, we compiled four large real datasets of 4937 tissue samples in total with measured cellular fractions and bulk gene expression from different tissues. Comprehensive evaluations demonstrated that EnsDeconv yields more stable, robust and accurate fractions than existing methods. We illustrated that EnsDeconv estimated cellular fractions enable various CTS downstream analyses such as differential fractions associated with clinical variables. We further extended EnsDeconv to analyze bulk DNA methylation data. AVAILABILITY AND IMPLEMENTATION: EnsDeconv is freely available as an R-package from https://github.com/randel/EnsDeconv. The RNA microarray data from the TRAUMA study are available and can be accessed in GEO (GSE36809). The demographic and clinical phenotypes can be shared on reasonable request to the corresponding authors. The RNA-seq data from the EVAPR study cannot be shared publicly due to the privacy of individuals that participated in the clinical research in compliance with the IRB approval at the University of Pittsburgh. The RNA microarray data from the FHS study are available from dbGaP (phs000007.v32.p13). The RNA-seq data from ROS study is downloaded from AD Knowledge Portal. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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RNA , Transcriptoma , Análise de Sequência de RNA , RNA-Seq , Simulação por ComputadorRESUMO
BACKGROUND: Numeracy is the mathematical knowledge required to understand and act on instructions from health care providers. Whether persistently low parental numeracy is linked to childhood asthma exacerbations is unknown. OBJECTIVE: To evaluate whether low parental numeracy at 2 time points is associated with asthma exacerbations and worse lung function in Puerto Rican youth. METHODS: Prospective study of 225 youth with asthma in San Juan (PR) who participated in 2 visits approximately 5.3 years apart, with the first at ages 6 to 14 years and the second at ages 9 to 20 years. Parental numeracy was assessed with a modified version of the Asthma Numeracy Questionnaire (score range = 0-3 points), and persistently low parental numeracy was defined as a score less than or equal to 1 point at both visits. Asthma exacerbation outcomes included more than or equal to 1 emergency department (ED) visit, more than or equal to 1 hospitalization, and more than or equal to 1 severe exacerbation (≥1 ED visit or ≥1 hospitalization) for asthma in the year before the second visit. Spirometry was conducted using an EasyOne spirometer (NDD Medical Technologies, Andover, Massachusetts). RESULTS: In an analysis adjusting for age, sex, parental education, use of inhaled corticosteroids, and the time between study visits, persistently low parental numeracy was associated with more than or equal to 1 ED visit for asthma (odds ratio [ORs], 2.17; 95% confidence interval [CI], 1.10-4.26), more than or equal to 1 hospitalization for asthma (OR, 3.92; 95% CI, 1.42-10.84), and more than or equal to 1 severe asthma exacerbation (OR, 1.99; 95% CI, 1.01-3.87) in the year before the follow-up visit. Persistently low parental numeracy was not significantly associated with change in lung function measures. CONCLUSION: Persistently low parental numeracy is associated with asthma exacerbation outcomes in Puerto Rican youth.
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Asma , Adolescente , Criança , Humanos , Corticosteroides , Asma/epidemiologia , Asma/etnologia , Hispânico ou Latino , Pais , Estudos Prospectivos , Adulto Jovem , Progressão da Doença , Letramento em SaúdeRESUMO
BACKGROUND: Black and Latinx adults experience disproportionate asthma-related morbidity and limited specialty care access. The severe acute respiratory syndrome coronavirus 2 pandemic expanded telehealth use. OBJECTIVE: To evaluate visit type (telehealth [TH] vs in-person [IP]) preferences and the impact of visit type on asthma outcomes among Black and Latinx adults with moderate-to-severe asthma. METHODS: For this PREPARE trial ancillary study, visit type preference was surveyed by e-mail or telephone post-trial. Emergency medical record data on visit types and asthma outcomes were available for a subset (March 2020 to April 2021). Characteristics associated with visit type preferences, and relationships between visit type and asthma outcomes (control [Asthma Control Test] and asthma-related quality of life [Asthma Symptom Utility Index]), were tested using multivariable regression. RESULTS: A total of 866 participants consented to be surveyed, with 847 respondents. Among the participants with asthma care experience with both visit types, 42.0% preferred TH for regular checkups, which associated with employment (odds ratio [OR] = 1.61; 95% confidence interval [CI], 1.09-2.39; P = .02), lower asthma medication adherence (OR = 1.06; 95% CI, 1.01-1.11; P = .03), and having more historical emergency department and urgent care asthma visits (OR = 1.10 for each additional visit; 95% CI, 1.02-1.18; P = .02), after adjustment. Emergency medical record data were available for 98 participants (62 TH, 36 IP). Those with TH visits were more likely Latinx, from the Southwest, employed, using inhaled corticosteroid-only controller therapy, with lower body mass index, and lower self-reported asthma medication adherence vs those with IP visits only. Both groups had comparable Asthma Control Test (18.4 vs 18.9, P = .52) and Asthma Symptom Utility Index (0.79 vs 0.84, P = .16) scores after adjustment. CONCLUSION: TH may be similarly efficacious as and often preferred over IP among Black and Latinx adults with moderate-to-severe asthma, especially for regular checkups. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02995733.
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Asma , Preferência do Paciente , Telemedicina , Adulto , Humanos , Corticosteroides/uso terapêutico , Asma/tratamento farmacológico , Asma/diagnóstico , Hispânico ou Latino , Qualidade de Vida , Negro ou Afro-AmericanoRESUMO
INTRODUCTION: Reported associations between World Trade Center (WTC) occupational exposure and chronic obstructive pulmonary disease (COPD) or asthma COPD overlap (ACO) have been inconsistent. Using spirometric case definitions, we examined that association in the largest WTC occupational surveillance cohort. METHODS: We examined the relation between early arrival at the 2001 WTC disaster site (when dust and fumes exposures were most intense) and COPD and ACO in workers with at least one good quality spirometry with bronchodilator response testing between 2002 and 2019, and no physician-diagnosed COPD before 9/11/2001. COPD was defined spirometrically as fixed airflow obstruction and ACO as airflow obstruction plus an increase of ≥ 400 ml in FEV1 after bronchodilator administration. We used a nested 1:4 case-control design matching on age, sex and height using incidence density sampling. RESULTS: Of the 17,928 study participants, most were male (85.3%) and overweight or obese (84.9%). Further, 504 (2.8%) and 244 (1.4%) study participants met the COPD and ACO spirometric case definitions, respectively. In multivariable analyses adjusted for smoking, occupation, cohort entry period, high peripheral blood eosinophil count and other covariates, early arrival at the WTC site was associated with both COPD (adjusted odds ratio [ORadj] = 1.34, 95% confidence interval [CI] 1.01-1.78) and ACO (ORadj = 1.55, 95%CI 1.04-2.32). CONCLUSION: In this cohort of WTC workers, WTC exposure intensity was associated with spirometrically defined COPD and ACO. Our findings suggest that early arrival to the WTC site is a risk factor for the development of COPD or of fixed airway obstruction in workers with pre-existing asthma.
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Asma , Eosinofilia , Exposição Ocupacional , Doença Pulmonar Obstrutiva Crônica , Masculino , Humanos , Feminino , Broncodilatadores , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Asma/diagnóstico , Asma/epidemiologia , Pulmão , Exposição Ocupacional/efeitos adversos , Eosinofilia/complicaçõesRESUMO
Rationale: Current guidelines do not sufficiently capture the heterogeneous nature of asthma; a more detailed molecular classification is needed. Metabolomics represents a novel and compelling approach to derive asthma endotypes (i.e., subtypes defined by functional and/or pathobiological mechanisms). Objectives: To validate metabolomic-driven endotypes of asthma and explore their underlying biology. Methods: In the Genetics of Asthma in Costa Rica Study (GACRS), untargeted metabolomic profiling, similarity network fusion, and spectral clustering was used to identify metabo-endotypes of asthma, and differences in asthma-relevant phenotypes across these metabo-endotypes were explored. The metabo-endotypes were recapitulated in the Childhood Asthma Management Program (CAMP), and clinical differences were determined. Metabolomic drivers of metabo-endotype membership were investigated by meta-analyzing findings from GACRS and CAMP. Measurements and Main Results: Five metabo-endotypes were identified in GACRS with significant differences in asthma-relevant phenotypes, including prebronchodilator (p-ANOVA = 8.3 × 10-5) and postbronchodilator (p-ANOVA = 1.8 × 10-5) FEV1/FVC. These differences were validated in the recapitulated metabo-endotypes in CAMP. Cholesterol esters, trigylcerides, and fatty acids were among the most important drivers of metabo-endotype membership. The findings suggest dysregulation of pulmonary surfactant homeostasis may play a role in asthma severity. Conclusions: Clinically meaningful endotypes may be derived and validated using metabolomic data. Interrogating the drivers of these metabo-endotypes has the potential to help understand their pathophysiology.
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Asma/metabolismo , Asma/fisiopatologia , Pulmão/metabolismo , Pulmão/fisiopatologia , Metabolômica , Adolescente , Asma/diagnóstico , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Fenótipo , Reprodutibilidade dos TestesRESUMO
De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains <1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of CâA and TâC mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.
Assuntos
Amish/genética , Genoma Humano , Adulto , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Genética Populacional , Heterozigoto , Humanos , Masculino , Mutação , Linhagem , Sequenciamento Completo do Genoma , Adulto JovemRESUMO
BACKGROUND: Observational studies have yielded inconsistent findings for the relation between vitamin D level and total IgE or allergic sensitization. OBJECTIVE: To determine whether vitamin D supplementation reduces levels of total IgE and IgE to each of 2 common indoor allergens in children with asthma and low vitamin D levels. METHODS: Total IgE, IgE to Dermatophagoides pteronyssinus, and IgE to Blattella germanica were measured at the randomization and exit visits for 174 participants in the Vitamin D Kids Asthma Study, a multicenter, double-blind, randomized placebo-controlled trial of vitamin D3 supplementation (4000 IU/d) to prevent severe exacerbations in children with persistent asthma and vitamin D levels less than 30 ng/mL. Multivariable linear regression was used for the analysis of the effect of vitamin D supplementation on change in each IgE measure. RESULTS: Participants were followed for an average of 316 days. At the exit visit, more subjects in the vitamin D arm achieved a vitamin D level equal to or more than 30 ng/mL compared with those in the placebo arm (87% vs 30%; P < .001). In a multivariable analysis, vitamin D3 supplementation had no significant effect on change in total IgE, IgE to Dermatophagoides pteronyssinus, or IgE to Blattella germanica between the exit and randomization visits (eg, for log10 total IgE, ß = 0.007; 95% CI, -0.061 to 0.074; P = .85). CONCLUSIONS: Vitamin D supplementation, compared with placebo, has no significant effect on serum levels of total IgE, IgE to dust mite, or IgE to cockroach in children with asthma and low vitamin D levels.
Assuntos
Alérgenos/imunologia , Antígenos de Dermatophagoides/imunologia , Proteínas de Artrópodes/imunologia , Asma/tratamento farmacológico , Cisteína Endopeptidases/imunologia , Imunoglobulina E/sangue , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico , Animais , Asma/sangue , Asma/imunologia , Criança , Suplementos Nutricionais , Método Duplo-Cego , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Asthma disproportionately affects African American/Black (AA/B) and Hispanic/Latinx (H/L) patients and individuals with low socioeconomic status (SES), but the relationship between SES and asthma morbidity within these racial/ethnic groups is inadequately understood. OBJECTIVE: To determine the relationship between SES and asthma morbidity among AA/B and H/L adults with moderate to severe asthma using multidomain SES frameworks and mediation analyses. METHODS: We analyzed enrollment data from the PeRson EmPowered Asthma RElief randomized trial, evaluating inhaled corticosteroid supplementation to rescue therapy. We tested for direct and indirect relationships between SES and asthma morbidity using structural equation models. For SES, we used a latent variable defined by poverty, education, and unemployment. For asthma morbidity, we used self-reported asthma exacerbations in the year before enrollment (corticosteroid bursts, emergency room/urgent care visits, or hospitalizations), and Asthma Control Test scores. We tested for mediation via health literacy, perceived stress, and self-reported discrimination. All models adjusted for age, sex, body mass index, ethnicity, and comorbidities. RESULTS: Among 990 AA/B and H/L adults, low SES (latent variable) was directly associated with hospitalizations (ß = 0.24) and worse Asthma Control Test scores (ß = 0.20). Stress partially mediated the relationship between SES and increased emergency room/urgent care visits and worse asthma control (ß = 0.03 and = 0.05, respectively). Individual SES domains were directly associated with asthma morbidity. Stress mediated indirect associations between low educational attainment and unemployment with worse asthma control (ß = 0.05 and = 0.06, respectively). CONCLUSIONS: Lower SES is directly, and indirectly through stress, associated with asthma morbidity among AA/B and H/L adults. Identification of stressors and relevant management strategies may lessen asthma-related morbidity among these populations.
Assuntos
Asma , Classe Social , Corticosteroides , Adulto , Negro ou Afro-Americano , Asma/tratamento farmacológico , Asma/epidemiologia , Humanos , MorbidadeRESUMO
BACKGROUND: Hispanic/Latinx (HL) ethnicity encompasses racially and culturally diverse subgroups. Studies suggest that Puerto Ricans (PR) may bear greater asthma-related morbidity than Mexicans, but these were conducted in children or had limited clinical characterization. OBJECTIVES: This study sought to determine whether disparities in asthma morbidity exist among HL adult subgroups. METHODS: Adults with moderate-severe asthma were recruited from US clinics, including from Puerto Rico, for the Person Empowered Asthma Relief (PREPARE) trial. Considering the shared heritage between PR and other Caribbean HL (Cubans and Dominicans [C&D]), the investigators compared baseline self-reported clinical characteristics between Caribbean HL (CHL) (PR and C&D: n = 457) and other HLs (OHL) (Mexicans, Spaniards, Central/South Americans; n = 141), and between CHL subgroups (C&D [n = 56] and PR [n = 401]). This study compared asthma morbidity measures (self-reported exacerbations requiring systemic corticosteroids, emergency department/urgent care (ED/UC) visits, hospitalizations, health care utilization) through negative binomial regression. RESULTS: CHL compared to OHL were similar in age, body mass index, poverty status, blood eosinophils, and fractional exhaled nitric oxide but were prescribed more asthma controller therapies. Relative to OHL, CHL had significantly increased odds of asthma exacerbations (odds ratio [OR]: 1.84; 95% CI: 1.4-2.4), ED/UC visits (OR: 1.88; 95% CI: 1.4-2.5), hospitalization (OR: 1.98; 95% CI: 1.06-3.7), and health care utilization (OR: 1.91; 95% CI: 1.44-2.53). Of the CHL subgroups, PR had significantly increased odds of asthma exacerbations, ED/UC visits, hospitalizations, and health care utilization compared to OHL, whereas C&D only had increased odds of exacerbations compared to OHL. PR compared to C&D had greater odds of ED/UC and health care utilization. CONCLUSIONS: CHL adults, compared with OHL, adults reported nearly twice the asthma morbidity; these differences are primarily driven by PR. Novel interventions are needed to reduce morbidity in this highly impacted population.