Publications by authors named "Juan C Celedón"

287 Publications

Metabo-Endotypes of Asthma Reveal Differences in Lung Function: Discovery and Validation in two TOPMed Cohorts.

Am J Respir Crit Care Med 2021 Nov 12. Epub 2021 Nov 12.

Brigham and Women's Hospital and Harvard Medical School, Channing Division of Network Medicine, Boston, Massachusetts, United States.

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/pathobiological mechanisms.

Objective: 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 determined. Metabolomic drivers of metabo-endotype membership were investigated 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 pre-bronchodilator (p-ANOVA=8.3x10-5) and post-bronchodilator (p-ANOVA=1.8x10-5) forced expiratory volume/forced vital capacity (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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http://dx.doi.org/10.1164/rccm.202105-1268OCDOI Listing
November 2021

Accurately assessing children's asthma study.

Authors:
Juan C Celedón

Science 2021 10 21;374(6566):413-414. Epub 2021 Oct 21.

Department of Pediatrics and Departments of Medicine, Epidemiology, and Human Genetics, University of Pittsburgh, Pittsburgh, PA 15261, USA, and Division of Pulmonary Medicine, University of Pittsburgh Medical Center Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.

[Figure: see text].
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http://dx.doi.org/10.1126/science.abm1147DOI Listing
October 2021

Lymph node-resident dendritic cells drive T2 cell development involving MARCH1.

Sci Immunol 2021 Oct 15;6(64):eabh0707. Epub 2021 Oct 15.

Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA.

[Figure: see text].
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http://dx.doi.org/10.1126/sciimmunol.abh0707DOI Listing
October 2021

Urinary caffeine and caffeine metabolites, asthma, and lung function in a nationwide study of U.S. adults.

J Asthma 2021 Oct 27:1-8. Epub 2021 Oct 27.

Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA.

Objective: Coffee intake has been inversely associated with asthma in adults. We examined the relation between urinary levels of caffeine or caffeine metabolites and asthma, lung function, and fractional exhaled nitric oxide (FeNO) in adults.

Methods: Cross-sectional study of 2,832 adults aged 18-79 years in the US National Health and Nutrition Examination Survey (NHANES). Multivariable logistic or linear regression was used for the analysis of urinary levels of caffeine or each of its three major metabolites (paraxanthine, theobromine, and theophylline) and current asthma, lung function, and FeNO.

Results: Subjects with urinary paraxanthine levels in the fourth quartile (Q4) had 53% lower odds of current asthma than those whose urinary paraxanthine levels were in the first quartile (Q1; 95% confidence = 0.22 to 1.00). Among never and former smokers, subjects with urinary theophylline levels above Q1 had 49% lower odds of current asthma than those whose urinary theophylline level was in Q1 (95% CI = 0.31 to 0.85). Among subjects without current asthma, each log-unit increment in paraxanthine level was associated with a 0.83% increment in percent predicted (%pred) FEV and a 1.27% increment in %pred FVC, while each log-unit in theophylline was associated with a 1.24% increment in %pred FVC. Neither urinary caffeine nor any urinary caffeine metabolite was associated with bronchodilator response or FeNO.

Conclusions: Our findings suggest that two caffeine metabolites (theophylline and paraxanthine) may contribute to the previously reported inverse association between coffee intake and asthma in adults.
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http://dx.doi.org/10.1080/02770903.2021.1993250DOI Listing
October 2021

Multi-omics colocalization with genome-wide association studies reveals a context-specific genetic mechanism at a childhood onset asthma risk locus.

Genome Med 2021 10 10;13(1):157. Epub 2021 Oct 10.

Departments of Human Genetics, University of Chicago, Chicago, IL, USA.

Background: Genome-wide association studies (GWASs) have identified thousands of variants associated with asthma and other complex diseases. However, the functional effects of most of these variants are unknown. Moreover, GWASs do not provide context-specific information on cell types or environmental factors that affect specific disease risks and outcomes. To address these limitations, we used an upper airway epithelial cell (AEC) culture model to assess transcriptional and epigenetic responses to rhinovirus (RV), an asthma-promoting pathogen, and provide context-specific functional annotations to variants discovered in GWASs of asthma.

Methods: Genome-wide genetic, gene expression, and DNA methylation data in vehicle- and RV-treated upper AECs were collected from 104 individuals who had a diagnosis of airway disease (n=66) or were healthy participants (n=38). We mapped cis expression and methylation quantitative trait loci (cis-eQTLs and cis-meQTLs, respectively) in each treatment condition (RV and vehicle) in AECs from these individuals. A Bayesian test for colocalization between AEC molecular QTLs and adult onset asthma and childhood onset asthma GWAS SNPs, and a multi-ethnic GWAS of asthma, was used to assign the function to variants associated with asthma. We used Mendelian randomization to demonstrate DNA methylation effects on gene expression at asthma colocalized loci.

Results: Asthma and allergic disease-associated GWAS SNPs were specifically enriched among molecular QTLs in AECs, but not in GWASs from non-immune diseases, and in AEC eQTLs, but not among eQTLs from other tissues. Colocalization analyses of AEC QTLs with asthma GWAS variants revealed potential molecular mechanisms of asthma, including QTLs at the TSLP locus that were common to both the RV and vehicle treatments and to both childhood onset and adult onset asthma, as well as QTLs at the 17q12-21 asthma locus that were specific to RV exposure and childhood onset asthma, consistent with clinical and epidemiological studies of these loci.

Conclusions: This study provides evidence of functional effects for asthma risk variants in AECs and insight into RV-mediated transcriptional and epigenetic response mechanisms that modulate genetic effects in the airway and risk for asthma.
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http://dx.doi.org/10.1186/s13073-021-00967-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504130PMC
October 2021

Violence-related distress and lung function in two longitudinal studies of youth.

Eur Respir J 2021 Sep 29. Epub 2021 Sep 29.

Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA

Increasing violence-related distress over time was associated with worse lung function and worse asthma-related quality of life in youth with asthma despite treatment with low-dose inhaled corticosteroids.Exposure to violence has been associated with lower lung function in cross-sectional studies. We examined whether increasing violence-related distress over time is associated with worse lung function and worse asthma control or quality of life in a secondary analysis of a 48-week randomized clinical trial in 98 youth with asthma (ages 9-16 years) treated with low-dose inhaled corticosteroids (the Vitamin D Kids Asthma Study [VDKA]). We then replicated our findings for lung function in a prospective study of 232 Puerto Rican youth followed for an average of 5·4 years. Violence-related distress was assessed using the Checklist of Children's Distress Symptoms (CCDS) scale. Our outcomes of interest were percent predicted (%pred) lung function measures and (in VDKA only) asthma control (assessed using the Asthma Control Test) and asthma-related quality of life (assessed using the Pediatric Asthma Quality of Life questionnaire). In a multivariable analysis in VDKA, each 1-point increment in the CCDS score was associated with decrements of 3.27% in %predFEV (95% confidence interval [CI]=-6.44% to -0.22%, p=0.04) and a 2.65% decrement in percent predicted FVC (95% CI=-4.86% to -0.45%, p=0.02), and 0.30 points in the overall PAQLQ score (95% CI=-0.50 to -0.10, p<0.01). Similar findings for FEV and FVC were obtained in the prospective study of Puerto Rican youth. Our findings suggest that violence-related distress may worsen lung function and quality of life in youth with asthma (even those treated with low-dose inhaled corticosteroids) and further support policies to reduce exposure to violence among children in the U.S. and Puerto Rico.
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http://dx.doi.org/10.1183/13993003.02329-2021DOI Listing
September 2021

Building a Diverse Workforce in Pulmonary, Critical Care, and Sleep Medicine.

Authors:
Juan C Celedón

ATS Sch 2021 Jun 30;2(2):145-148. Epub 2021 Jun 30.

Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania.

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http://dx.doi.org/10.34197/ats-scholar.2021-0038EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357065PMC
June 2021

Enhancing Recruitment and Retention of Minority Populations for Clinical Research in Pulmonary, Critical Care, and Sleep Medicine: An Official American Thoracic Society Research Statement.

Am J Respir Crit Care Med 2021 08;204(3):e26-e50

Well-designed clinical research needs to obtain information that is applicable to the general population. However, most current studies fail to include substantial cohorts of racial/ethnic minority populations. Such underrepresentation may lead to delayed diagnosis or misdiagnosis of disease, wide application of approved interventions without appropriate knowledge of their usefulness in certain populations, and development of recommendations that are not broadly applicable. To develop best practices for recruitment and retention of racial/ethnic minorities for clinical research in pulmonary, critical care, and sleep medicine. The American Thoracic Society convened a workshop in May of 2019. This included an international interprofessional group from academia, industry, the NIH, and the U.S. Food and Drug Administration, with expertise ranging from clinical and biomedical research to community-based participatory research methods and patient advocacy. Workshop participants addressed historical and current mistrust of scientific research, systemic bias, and social and structural barriers to minority participation in clinical research. A literature search of PubMed and Google Scholar was performed to support conclusions. The search was not a systematic review of the literature. Barriers at the individual, interpersonal, institutional, and federal/policy levels were identified as limiting to minority participation in clinical research. Through the use of a multilevel framework, workshop participants proposed evidence-based solutions to the identified barriers. To date, minority participation in clinical research is not representative of the U.S. and global populations. This American Thoracic Society research statement identifies potential evidence-based solutions by applying a multilevel framework that is anchored in community engagement methods and patient advocacy.
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http://dx.doi.org/10.1164/rccm.202105-1210STDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513588PMC
August 2021

CHIT: an allele-specific method for testing the association between molecular quantitative traits and phenotype-genotype interaction.

Bioinformatics 2021 Jul 29. Epub 2021 Jul 29.

Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA.

Motivation: Allele specific differences in molecular traits can be obtained from next generation sequencing data and could potentially improve testing power, but such information is usually overlooked in association studies. Furthermore, the variation of molecular quantitative traits (e.g., gene expression) could result from the interaction effect of genotypes and phenotypes, but it is challenging to identify such interaction signals in complex disease studies in humans due to small genetic effect sizes and/or small sample sizes.

Results: We develop a novel statistical method, the combined haplotype interaction test (CHIT), which tests for association between molecular quantitative traits and phenotype-genotype interactions by modeling the total read counts and allele-specific reads in a target region. CHIT can be used as a supplementary analysis to the regular linear interaction regression. In our simulations, CHIT obtains non-inflated type I error rates, and it has higher power than a standard interaction quantitative trait locus approach based on linear regression models. Finally, we illustrate CHIT by testing associations between gene expression obtained by RNA-seq and the interaction of SNPs and atopy status from a study of childhood asthma in Puerto Ricans, and results demonstrate that CHIT could be more powerful than a standard linear interaction expression quantitative trait loci (eQTL) approach.

Availability: The CHIT algorithm has been implemented in Python. The source code and documentation are available and can be downloaded from https://github.com/QiYanPitt/CHIT.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btab554DOI Listing
July 2021

Effect of vitamin D supplementation on total and allergen-specific IgE in children with asthma and low vitamin D levels.

J Allergy Clin Immunol 2021 Jun 9. Epub 2021 Jun 9.

Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pa. Electronic address:

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 D 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 D 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 log total IgE, β = 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.
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http://dx.doi.org/10.1016/j.jaci.2021.05.037DOI Listing
June 2021

COVID-19 vaccination: Helping the latinx community to come forward.

EClinicalMedicine 2021 May 15;35:100860. Epub 2021 May 15.

Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States.

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http://dx.doi.org/10.1016/j.eclinm.2021.100860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123372PMC
May 2021

Diet and asthma: Is the sum more important than the parts?

J Allergy Clin Immunol 2021 09 6;148(3):706-707. Epub 2021 May 6.

Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pa. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2021.04.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443165PMC
September 2021

Pharmacogenetic Polygenic Risk Score for Bronchodilator Response in Children and Adolescents with Asthma: Proof-of-Concept.

J Pers Med 2021 Apr 20;11(4). Epub 2021 Apr 20.

PRecisiOn Medicine Translational Research (PROMoTeR) Center, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA 02215, USA.

Genome-wide association studies (GWAS) of response to asthma medications have primarily focused on Caucasian populations, with findings that may not be generalizable to minority populations. We derived a polygenic risk score (PRS) for response to albuterol as measured by bronchodilator response (BDR), and examined the PRS in a cohort of Hispanic school-aged children with asthma. We leveraged a published GWAS of BDR to identify relevant genetic variants, and ranked the top variants according to their Combined Annotation Dependent Depletion (CADD) scores. Variants with CADD scores greater than 10 were used to compute the PRS. Once we derived the PRS, we determined the association of the PRS with BDR in a cohort of Hispanic children with asthma (the Genetics of Asthma in Costa Rica Study (GACRS)) in adjusted linear regression models. Mean BDR in GACRS participants was5.6% with a standard deviation of 10.2%. We observed a 0.63% decrease in BDR in response to albuterol for a standard deviation increase in the PRS ( = 0.05). We also observed decreased odds of a BDR response at or above the 12% threshold for a one standard deviation increase in the PRS (OR = 0.80 (95% CI 0.67 to 0.95)). Our findings show that combining variants from a pharmacogenetic GWAS into a PRS may be useful for predicting medication response in asthma.
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http://dx.doi.org/10.3390/jpm11040319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073919PMC
April 2021

Testosterone-to-estradiol ratio and lung function in a prospective study of Puerto Rican youth.

Ann Allergy Asthma Immunol 2021 08 20;127(2):236-242.e1. Epub 2021 Apr 20.

Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address:

Background: Age- and sex-related differences in asthma may be due to changes in sex hormone levels.

Objective: To evaluate whether a change in free testosterone or free testosterone-to-estradiol ratio is associated with changes in lung function and eosinophils in the Puerto Rican youth.

Methods: We tested for the association between the change in sex hormone levels and change in lung function or change in eosinophils in a prospective study of 317 children (with and without asthma) followed up from ages 6 to 14 years to ages 10 to 20 years (146 females, 171 males) in San Juan, Puerto Rico. Serum levels of testosterone, estradiol, sex hormone-binding globulin, and progesterone were measured at 2 study visits, approximately 4.9 years apart. Using testosterone and sex hormone-binding globulin levels, we derived free testosterone and the free testosterone-to-estradiol ratio. Multivariable linear regression was used for the analysis of change in lung function and eosinophils, conducted separately by sex.

Results: In girls, each quartile increment in the free testosterone-to-estradiol ratio was associated with a 2.03% increment in percent predicted forced expiratory volume in 1 second (FEV)/forced vital capacity (FVC) between study visits. In males, each quartile increment in the free testosterone-to-estradiol ratio was associated with a 3.27% increment in percent predicted FEV and a 1.81% increment in percent predicted FEV/FVC between study visits. In girls with asthma, an increased free testosterone-to-estradiol ratio was significantly associated with decreased eosinophils between visits (P=0.03).

Conclusion: In Puerto Rican youth, increased free testosterone-to-estradiol ratio over time was associated with an increased FEV/FVC in both sexes, and with an increased FEV in males.
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http://dx.doi.org/10.1016/j.anai.2021.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349830PMC
August 2021

Predicting Severe Asthma Exacerbations in Children: Blueprint for Today and Tomorrow.

J Allergy Clin Immunol Pract 2021 07 5;9(7):2619-2626. Epub 2021 Apr 5.

Pediatric Pulmonary and Sleep Medicine, Breathing Institute, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colo.

Severe asthma exacerbations are the primary cause of morbidity and mortality in children with asthma. Accurate prediction of children at risk for severe exacerbations, defined as those requiring systemic corticosteroids, emergency department visit, and/or hospitalization, would considerably reduce health care utilization and improve symptoms and quality of life. Substantial progress has been made in identifying high-risk exacerbation-prone children. Known risk factors for exacerbations include demographic characteristics (ie, low income, minority race/ethnicity), poor asthma control, environmental exposures (ie, aeroallergen exposure/sensitization, concomitant viral infection), inflammatory biomarkers, genetic polymorphisms, and markers from other "omic" technologies. The strongest risk factor for a future severe exacerbation remains having had one in the previous year. Combining risk factors into composite scores and use of advanced predictive analytic techniques such as machine learning are recent methods used to achieve stronger prediction of severe exacerbations. However, these methods are limited in prediction efficiency and are currently unable to predict children at risk for impending (within days) severe exacerbations. Thus, we provide a commentary on strategies that have potential to allow for accurate and reliable prediction of children at risk for impending exacerbations. These approaches include implementation of passive, real-time monitoring of impending exacerbation predictors, use of population health strategies, prediction of severe exacerbation responders versus nonresponders to conventional exacerbation management, and considerations for preschool-age children who can be especially high risk. Rigorous prediction and prevention of severe asthma exacerbations is needed to advance asthma management and improve the associated morbidity and mortality.
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http://dx.doi.org/10.1016/j.jaip.2021.03.039DOI Listing
July 2021

A region-based method for causal mediation analysis of DNA methylation data.

Epigenetics 2021 03 23:1-11. Epub 2021 Mar 23.

Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Exposure to environmental factors can affect DNA methylation at a 5'-cytosine-phosphate-guanine-3' (CpG) site or a genomic region, which can then affect an outcome. In other words, environmental effects on an outcome could be mediated by DNA methylation. To date, single CpG-site-based mediation analysis has been employed extensively. More recently, however, there has been considerable interest in studying differentially methylated regions (DMRs), both because DMRs are more likely to have functional effects than single CpG sites and because testing DMRs reduces multiple testing. In this report, we propose a novel causal mediation approach under the counterfactual framework to test the significance of total (TE), direct (DE), and indirect effects (IE) of predictors on response variable with a methylated region (MR) as the mediator (denoted as MR-Mediation). Functional linear transformation is used to reduce the possible high dimension of the CpG sites in a predefined MR and to account for their location information. In our simulation studies, MR-Mediation retained the desired Type I error rates for TE, DE, and IE tests. Furthermore, MR-Mediation had better power performance than testing mean methylation level as the mediator in most considered scenarios, especially for IE (i.e., mediated effect) test, which could be more interesting than the other two effect tests. We further illustrate our proposed method by analysing the methylation mediated effect of exposure to gun violence on total immunoglobulin E or atopic asthma among participants in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study.
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http://dx.doi.org/10.1080/15592294.2021.1900026DOI Listing
March 2021

Exposure to violence, chronic stress, nasal DNA methylation, and atopic asthma in children.

Pediatr Pulmonol 2021 07 22;56(7):1896-1905. Epub 2021 Mar 22.

Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Background: Exposure to violence (ETV) or chronic stress may influence asthma through unclear mechanisms.

Methods: Epigenome-wide association study (EWAS) of ETV or chronic stress measures and DNA methylation in nasal epithelium from 487 Puerto Ricans aged 9-20 years who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study [EVA-PR]). We assessed four measures of ETV and chronic stress in children (ETV scale, gun violence, and perceived stress) and their mothers (perceived stress). Each EWAS was conducted using linear regression, with CpGs as dependent variables and the stress/violence measure as a predictor, adjusting for age, sex, the top five principal components, and SVA latent factors. We then selected the top 100 CpGs (by p value) associated with each stress/violence measure in EVA-PR and conducted a meta-analysis of the selected CpGs and atopic asthma using data from EVA-PR and two additional cohorts (Project Viva and PIAMA).

Results: Three CpGs (in SNN, PTPRN2, and LINC01164) were associated with maternal perceived stress or gun violence (p = 1.28-3.36 × 10 ), but not with atopic asthma, in EVA-PR. In a meta-analysis of three cohorts, which included the top CpGs associated with stress/violence measures in EVA-PR, 12 CpGs (in STARD3NL, SLC35F4, TSR3, CDC42SE2, KLHL25, PLCB1, BUD13, OR2B3, GALR1, TMEM196, TEAD4, and ANAPC13) were associated with atopic asthma at FDR-p < .05.

Conclusions: Pending confirmation in longitudinal studies, our findings suggest that nasal epithelial methylation markers associated with measures of ETV and chronic stress may be linked to atopic asthma in children and adolescents.
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http://dx.doi.org/10.1002/ppul.25372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217314PMC
July 2021

The American Thoracic Society Leadership in a Year Like No Other.

Authors:
Juan C Celedón

Am J Respir Crit Care Med 2021 05;203(9):1068-1069

Division of Pediatric Pulmonary Medicine University of Pittsburgh Medical Center Children's Hospital of Pittsburgh and University of Pittsburgh Pittsburgh, Pennsylvania.

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http://dx.doi.org/10.1164/rccm.202103-0640EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314906PMC
May 2021

Integrated associations of nasopharyngeal and serum metabolome with bronchiolitis severity and asthma: A multicenter prospective cohort study.

Pediatr Allergy Immunol 2021 07 4;32(5):905-916. Epub 2021 Mar 4.

Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: While infant bronchiolitis contributes to substantial acute (eg, severity) and chronic (eg, asthma development) morbidities, its pathobiology remains uncertain. We examined the integrated relationships of local (nasopharyngeal) and systemic (serum) responses with bronchiolitis morbidities.

Methods: In a multicenter prospective cohort study of infants hospitalized for bronchiolitis, we applied a network analysis approach to identify distinct networks (modules)-clusters of densely interconnected metabolites-of the nasopharyngeal and serum metabolome. We examined their individual and integrated relationships with acute severity (defined by positive pressure ventilation [PPV] use) and asthma development by age 5 years.

Results: In 140 infants, we identified 285 nasopharyngeal and 639 serum metabolites. Network analysis revealed 7 nasopharyngeal and 8 serum modules. At the individual module level, nasopharyngeal-amino acid, tricarboxylic acid (TCA) cycle, and carnitine modules were associated with higher risk of PPV use (r > .20; P < .001), while serum-carnitine, amino acid, and glycerophosphorylcholine (GPC)/glycerophosphorylethanolamine (GPE) modules were associated with lower risk (all r < -.20; P < .05). The integrated analysis for PPV use revealed consistent findings-for example, nasopharyngeal-TCA (adjOR: 2.87, 95% CI: 1.68-12.2) and serum-GPC/GPE (adjOR: 0.54, 95% CI: 0.38-0.80) modules-and an additional module-serum-glucose-alanine cycle module (adjOR: 0.69, 95% CI: 0.56-0.86). With asthma risk, there were no individual associations, but there were integrated associations (eg, nasopharyngeal-carnitine module; adjOR: 1.48, 95% CI: 1.11-1.99).

Conclusion: In infants with bronchiolitis, we found integrated relationships of local and systemic metabolome networks with acute and chronic morbidity. Our findings advance research into the complex interplay among respiratory viruses, local and systemic response, and disease pathobiology in infants with bronchiolitis.
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http://dx.doi.org/10.1111/pai.13466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269431PMC
July 2021

Serum insulin-like growth factor-1, asthma, and lung function among British adults.

Ann Allergy Asthma Immunol 2021 03 11;126(3):284-291.e2. Epub 2020 Dec 11.

Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address:

Background: Insulin-like growth factor-1 (IGF-1) plays a key role in the pathogenesis of metabolic syndrome, which is in turn associated with asthma. Whether IGF-1 contributes to asthma causation or asthma severity is largely unknown.

Objective: To evaluate the relation between serum IGF-1 and asthma, asthma outcomes, and lung function in adults.

Methods: Cross-sectional study of 297,590 adults (aged 40-69 years) who participated in the United Kingdom Biobank, had no diagnosis of diabetes, and were not on insulin. Multivariable logistic or linear regression was used to analyze serum IGF-1 and physician-diagnosed asthma, current wheezing, asthma hospitalizations, and lung function measures (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and FEV1 to FVC ratio).

Results: Serum IGF-1 levels above the lowest quartile (Q1) were significantly associated with lower odds of asthma (adjusted odds ratio for fourth quartile [Q4] vs Q1 = 0.88; 95% confidence interval [CI], 0.85-0.91). Among the participants with asthma, IGF-1 levels above Q1 were significantly associated with lower odds of current wheezing (adjusted odds ratio for Q4 vs Q1 = 0.89; 95% CI, 0.83-0.96), but not with asthma hospitalizations. Serum IGF-1 was significantly and positively associated with FEV1 (b = 20.9 mL; 95% CI, 19.1-22.7) and FVC (b = 25.6 mL; 95% CI, 23.4-27.7), regardless of an asthma diagnosis; these associations were significant in men and women, with larger estimated effects in men.

Conclusion: In a large study of British adults, higher serum IGF-1 levels were associated with lower odds of asthma and current wheezing and higher FEV1 and FVC. Our findings suggest potential beneficial effects of circulating IGF-1 on asthma and asthma outcomes in adults.
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http://dx.doi.org/10.1016/j.anai.2020.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897263PMC
March 2021

Association of quantitative CT lung density measurements and lung function decline in World Trade Center workers.

Clin Respir J 2021 Jun 29;15(6):613-621. Epub 2020 Dec 29.

Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: Occupational exposures at the WTC site after 11 September 2001 have been associated with presumably inflammatory chronic lower airway diseases.

Aims: In this study, we describe the trajectories of expiratory air flow decline, identify subgroups with adverse progression, and investigate the association of those trajectories with quantitative computed tomography (QCT) imaging measurement of increased and decreased lung density.

Methods: We examined the trajectories of expiratory air flow decline in a group of 1,321 former WTC workers and volunteers with at least three periodic spirometries, and using QCT-measured low (LAV%, -950 HU) and high (HAV%, from -600 to -250 HU) attenuation volume percent. We calculated the individual regression line slopes for first-second forced expiratory volume (FEV slope), identified subjects with rapidly declining ("accelerated decliners") and increasing ("improved"), and compared them to subjects with "intermediate" (0 to -66.5 mL/year) FEV slope. We then used multinomial logistic regression to model those three trajectories, and the two lung attenuation metrics.

Results: The mean longitudinal FEV slopes for the entire study population, and its intermediate, decliner, and improved subgroups were, respectively, -40.4, -34.3, -106.5, and 37.6 mL/year. In unadjusted and adjusted analyses, LAV% and HAV% were both associated with "accelerated decliner" status (OR , 95% CI 2.37, 1.41-3.97, and 1.77, 1.08-2.89, respectively), compared to the intermediate decline.

Conclusions: Longitudinal FEV decline in this cohort, known to be associated with QCT proximal airway inflammation metric, is also associated with QCT indicators of increased and decreased lung density. The improved FEV trajectory did not seem to be associated with lung density metrics.
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http://dx.doi.org/10.1111/crj.13313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149480PMC
June 2021

Integrated-omics endotyping of infants with rhinovirus bronchiolitis and risk of childhood asthma.

J Allergy Clin Immunol 2021 06 13;147(6):2108-2117. Epub 2020 Nov 13.

Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.

Background: Young children with rhinovirus (RV) infection-particularly bronchiolitis-are at high risk for developing childhood asthma. Emerging evidence suggests clinical heterogeneity within RV bronchiolitis. However, little is known about these biologically distinct subgroups (endotypes) and their relations with asthma risk.

Objective: We aimed to identify RV bronchiolitis endotypes and examine their longitudinal relations with asthma risk.

Methods: As part of a multicenter prospective cohort study of infants (age <12 months) hospitalized for bronchiolitis, we integrated clinical, RV species (RV-A, RV-B, and RV-C), nasopharyngeal microbiome (16S rRNA gene sequencing), cytokine, and metabolome (liquid chromatography tandem mass spectrometry) data collected at hospitalization. We then applied network and clustering approaches to identify bronchiolitis endotypes. We also examined their longitudinal association with risks of developing recurrent wheeze by age 3 years and asthma by age 5 years.

Results: Of 122 infants hospitalized for RV bronchiolitis (median age, 4 months), we identified 4 distinct endotypes-mainly characterized by RV species, microbiome, and type 2 cytokine (T2) response: endotype A, virusmicrobiomeT2; endotype B, virusmicrobiomeT2; endotype C, virusmicrobiomeT2; and endotype D, virusmicrobiomeT2. Compared with endotype A infants, endotype D infants had a significantly higher rate of recurrent wheeze (33% vs 64%; hazard ratio, 2.23; 95% CI, 1.00-4.96; P = .049) and a higher risk for developing asthma (28% vs 59%; odds ratio, 3.74: 95% CI, 1.21-12.6; P = .03).

Conclusions: Integrated-omics analysis identified biologically meaningful RV bronchiolitis endotypes in infants, such as one characterized by RV-C infection, Moraxella-dominant microbiota, and high T2 cytokine response, at higher risk for developing recurrent wheeze and asthma. This study should facilitate further research toward validating our inferences.
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http://dx.doi.org/10.1016/j.jaci.2020.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116357PMC
June 2021

Exposure to violence, chronic stress, nasal DNA methylation, and atopic asthma in children.

medRxiv 2020 Nov 4. Epub 2020 Nov 4.

Background: Exposure to violence (ETV) or stress may cause asthma through unclear mechanisms.

Methods: Epigenome-wide association study (EWAS) of DNA methylation in nasal epithelium and four ETV or chronic stress measures in 487 Puerto Ricans aged 9-20 years who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study [EVA-PR]). We assessed measures of ETV or chronic stress in children (ETV scale, gun violence, and perceived stress) and their mothers (perceived stress). Each EWAS was conducted using linear regression, with CpGs as dependent variables and the stress/violence measure as a predictor, adjusting for age, sex, the top five principal components, and SVA latent factors. We then selected the top 100 CpGs (by P-value) associated with each stress/violence measure in EVA-PR and conducted a meta-analysis of the selected CpGs and atopic asthma using data from EVA-PR and two additional cohorts (Project Viva and PIAMA).

Results: In the EWAS of stress/violence in EVA-PR, gun violence was associated with methylation of cg18961589 in (β=0.03, =1.28×10 ), and maternal stress was associated with methylation of cg03402351 in (β=0.04, =1.69×10 ) and cg19064846 in (β=0.03, =3.36×10 ). In a meta-analysis of three cohorts, which included the top CpGs associated with stress/violence in EVA-PR, CpGs in and were associated with atopic asthma at FDR- < 0.05.

Conclusions: ETV and chronic stress may increase the risk of atopic asthma through DNA methylation in airway epithelium, though this needs confirmation in future longitudinal studies.
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http://dx.doi.org/10.1101/2020.11.03.20225250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654924PMC
November 2020

Maternal Depressive Symptoms, Lung Function, and Severe Asthma Exacerbations in Puerto Rican Children.

J Allergy Clin Immunol Pract 2021 03 28;9(3):1319-1326.e3. Epub 2020 Oct 28.

Division of Pulmonary Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pa. Electronic address:

Background: Maternal depression has been linked to health care use for asthma in cross-sectional or short-term follow-up studies of school-aged children.

Objective: To examine whether increased or persistent maternal depressive symptoms over approximately 5 years are associated with severe asthma exacerbations or worse lung function in youth.

Methods: A prospective study of 386 youth living in Puerto Rico, aged 6 to 14 years at a baseline visit and 9 to 20 years at a second visit, was performed. Our exposure of interest was change in persistence of maternal depressive symptoms, assessed at both visits using the Center for Epidemiologic Studies Depression Scale (CESD). Our outcomes of interest were change in percent predicted forced expiratory volume in 1 second (FEV) and FEV/forced vital capacity (FVC) between the first and second visits in all subjects, and ≥1 severe asthma exacerbation in the year before the second visit in subjects with asthma.

Results: In a multivariable analysis, each 1-point increment in the CESD score was associated with decrements of 0.15% in percent predicted FEV (95% confidence interval [CI] = -0.28% to -0.01%; P = .03) and 0.10% in percent predicted FEV/FVC (95% CI = -0.20% to 0.001%; P = .05) between visits, as well as with 1.03 times increased odds of ≥1 severe asthma exacerbation at the second visit (95% CI for odds ratio = 0.99 to 1.06, P = .09). In a multivariable analysis, the presence of maternal depressive symptoms (a CESD score ≥21 points) at the second visit or at both visits was significantly associated with 3.17 to 3.52 times increased odds of ≥1 severe asthma exacerbation in the year before the second visit.

Conclusions: Increasing or persistent maternal depressive symptoms over approximately 5 years are associated with worse lung function measures and severe asthma exacerbations among Puerto Rican youth, a high-risk population.
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http://dx.doi.org/10.1016/j.jaip.2020.10.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946650PMC
March 2021

A genome-wide association study of severe asthma exacerbations in Latino children and adolescents.

Eur Respir J 2021 04 1;57(4). Epub 2021 Apr 1.

Division of Pediatric Pulmonary Medicine, University of Pittsburgh Medical Centre, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA

Severe asthma exacerbations are a major cause of school absences and healthcare costs in children, particularly those in high-risk racial/ethnic groups.To identify susceptibility genes for severe asthma exacerbations in Latino children and adolescents, we conducted a meta-analysis of genome-wide association studies (GWAS) in 4010 Latino youth with asthma in four independent cohorts, including 1693 Puerto Ricans, 1019 Costa Ricans, 640 Mexicans, 256 Brazilians and 402 members of other Latino subgroups. We then conducted methylation quantitative trait locus, expression quantitative trait locus and expression quantitative trait methylation analyses to assess whether the top single nucleotide polymorphism (SNP) in the meta-analysis is linked to DNA methylation and gene expression in nasal (airway) epithelium in separate cohorts of Puerto Rican and Dutch children and adolescents.In the meta-analysis of GWAS, an SNP in (rs2253681) was significantly associated with 1.55 increased odds of severe asthma exacerbation (95% CI 1.34-1.79, p=6.3×10). This SNP was significantly associated with DNA methylation of a CpG site (cg25024579) at the locus, which was in turn associated with increased expression of in nasal airway epithelium from Puerto Rican children and adolescents (β=0.10, p=2.18×10).SNP rs2253681 was significantly associated with both DNA methylation of a cis-CpG in and severe asthma exacerbations in Latino youth. This may be partly explained by changes in airway epithelial expression of a gene recently implicated in atopic asthma in Puerto Rican children and adolescents ().
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http://dx.doi.org/10.1183/13993003.02693-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026735PMC
April 2021

An interaction of the 17q12-21 locus with mold exposure in childhood asthma.

Pediatr Allergy Immunol 2021 02 13;32(2):373-376. Epub 2020 Oct 13.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1111/pai.13376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277824PMC
February 2021

Indoor endotoxin, proximity to a major roadway, and severe asthma exacerbations among children in Puerto Rico.

Ann Allergy Asthma Immunol 2020 12 8;125(6):658-664.e2. Epub 2020 Sep 8.

Division of Pediatric Pulmonary Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address:

Background: Few studies have examined concurrent exposure to household endotoxin and traffic-related air pollution in relation to childhood asthma, yet both factors are associated with asthma outcomes.

Objective: To examine whether proximity to a major roadway (a traffic-related air pollution proxy) modifies the estimated effects of indoor endotoxin on asthma outcomes in children.

Methods: Cross-sectional study of 200 children with asthma (ages, 6-14 years) living in Puerto Rico. Residential distance to a major roadway was calculated as the distance from the participant's residential US census block centroid to the nearest major road. The outcomes of interest were severe asthma exacerbations, missed school days for asthma, atopy, lung function, and bronchodilator response (BDR). Logistic, linear, or negative binomial regression was used for the multivariable analysis.

Results: In the multivariable analysis, there was an interaction between indoor endotoxin and residential distance to a roadway on severe asthma exacerbations (P = .02) and BDR (P = .07). In an analysis stratified by distance to a roadway, each log-unit increase in endotoxin was associated with 4.21 times increased odds of severe asthma exacerbations among children living within 499 m (the lower 3 quartiles of residential distance) to a road (95% confidence interval, 1.5-12.0). Among subjects living further than 499 m away from a roadway, each log-unit increase in endotoxin was associated with reduced odds of severe asthma exacerbations (odds ratio, 0.03; 95% confidence interval, 0.001-0.67). Similar but less substantial findings were observed for BDR.

Conclusion: Our findings suggest that residential proximity to a major road modifies the estimated effect of endotoxin on severe asthma exacerbations in children.
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http://dx.doi.org/10.1016/j.anai.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680389PMC
December 2020

A genome-wide association study of asthma hospitalizations in adults.

J Allergy Clin Immunol 2021 03 2;147(3):933-940. Epub 2020 Sep 2.

Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pa. Electronic address:

Background: Little is known about the genetic determinants of severe asthma exacerbations.

Objectives: We aimed to identify genetic variants associated with asthma hospitalizations.

Methods: We conducted a genome-wide association study of asthma hospitalizations in 34,167 white British adults with asthma, 1,658 of whom had at least 1 asthma-related hospitalization. This analysis was conducted by using logistic regression under an additive genetic model with adjustment for age, sex, body mass index, smoking status, and the first 5 principal components derived from genotypic data. We then analyzed data from 2 cohorts of Latino children and adolescents for replication and conducted quantitative trait locus and functional annotation analyses.

Results: At the chromosome 6p21.3 locus, the single-nucleotide polymorphism (SNP) rs56151658 (8 kb from the promoter of HLA-DQB1) was most significantly associated with asthma hospitalizations (for test allele A, odds ratio = 1.36 [95% CI = 1.22-1.52]; P = 3.11 × 10); 21 additional SNPs in this locus were associated with asthma hospitalizations at a P value less than 1 × 10. In the replication cohorts, multiple SNPs in strong linkage disequilibrium with rs56151658 were associated with severe asthma exacerbations at a P value of .01 or less in the same direction of association as in the discovery cohort. Three HLA genes (HLA-DQA2, HLA-DRB6, and HLA-DOB) were also shown to mediate the estimated effects of the SNPs associated with asthma hospitalizations through effects on gene expression in lung tissue.

Conclusions: We identified strong candidate genes for asthma hospitalizations in adults in the region for class II HLA genes through genomic, quantitative trait locus, and summary data-based mendelian randomization analyses.
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http://dx.doi.org/10.1016/j.jaci.2020.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921212PMC
March 2021
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