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1.
Artigo em Inglês | MEDLINE | ID: mdl-31525075

RESUMO

RATIONALE: Women have a higher burden of asthma than men. Although sex hormones may explain sex differences in asthma, their role is unclear. OBJECTIVES: To examine sex hormone levels and asthma in adults. METHODS: Cross-sectional study of serum levels of free testosterone and estradiol and current asthma in 7,615 adults (3,953 men and 3,662 women) aged 18-79 years who participated in the 2013-2014 and 2015-2016 U.S. National Health and Nutrition Examination Survey. Logistic regression was used for the multivariable analysis of sex hormones and current asthma, which was conducted separately in women and men. MEASUREMENTS AND MAIN RESULTS: Free testosterone levels in the fourth quartile were associated with lower odds of current asthma in women (odds ratio [OR] for quartile 4 vs. 1=0.56, 95% confidence interval [CI]=0.39 to 0.80). Given an interaction between obesity and sex hormones on current asthma, we stratified the analysis by obesity. In this analysis, elevated free testosterone (OR for quartile 4 vs. 1= 0.59, 95% CI=0.37 to 0.91) and estradiol (OR for quartile 4 vs. 1= 0.44, 95% CI=0.23 to 0.78) levels were associated with reduced odds of current asthma in obese women, and an elevated serum estradiol was associated with lower odds of current asthma in non-obese men (OR for quartile 4 vs. 1=0.44, 95% CI=0.21 to 0.90). CONCLUSIONS: Our findings suggest that sex hormones play a role in known sex differences in asthma in adults. Moreover, our results suggest that obesity modifies the effects of sex hormones on asthma in adults.

3.
Chest ; 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31557467

RESUMO

BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to identify regions of common genetic variation contributing to lung function in individuals diagnosed with asthma, utilizing whole-genome sequencing (WGS) data. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based 'Genetic Epidemiology of Asthma in Costa Rica' study. Asthma affection status was defined through a doctor's diagnosis of asthma and the majority of asthma cases also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single-variants were performed to assess the associations with lung function phenotypes. RESULTS: A plausible association was identified between baseline FEV1/FVC-ratio and a SNP in our top hit CRISPLD2 (rs12051168, p=3.6x10-8 in unadjusted model) that retained suggestive significance in the covariate-adjusted model (p=5.6x10-6). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV1 (p=3.3x10-3), post-bronchodilator (PB) FEV1 (7.3x10-3), PB FEV1/FVC (p=5.1x10-5). The identified baseline FEV1/FVC-ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts where the majority of asthmatics also had confirmed AHR (combined weighted Z p-value=0.015) but not in cohorts without information on AHR. CONCLUSIONS: These findings suggest that utilizing specific asthma characteristics, such as AHR, can identify more genetically homogenous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 may also be important for baseline lung function in individuals with asthma that may also have AHR.

4.
Clin Respir J ; 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31347281

RESUMO

RATIONALE: Occupational exposures at the WTC site after September 11, 2001 have been associated with several presumably inflammatory lower airway diseases. Pulmonary arterial enlargement, as suggested by an increased ratio of the diameter of the pulmonary artery to the diameter of the aorta (PAAr) has been reported as a computed tomographic (CT) scan marker of adverse respiratory health outcomes, including WTC-related disease. In this study, we sought to utilize a novel quantitative CT (QCT) measurement of PAAr to test the hypothesis that an increased ratio is associated with FEV1 below each subject's statistically determined lower limit of normal (FEV1  < LLN). METHODS: In a group of 1,180 WTC workers and volunteers, we examined whether FEV1  < LLN was associated with an increased QCT-measured PAAr, adjusting for previously identified important covariates. RESULTS: Unadjusted analyses showed a statistically significant association of FEV1  < LLN with PAAr (35.3% vs 24.7%, P = 0.0001), as well as with height, body mass index, early arrival at the WTC disaster site, shorter WTC exposure duration, post-traumatic stress disorder checklist (PCL) score, wall area percent and evidence of bronchodilator response. The multivariate logistic regression model confirmed the association of FEV1  < LLN with PAAr (OR 1.63, 95% CI 1.21, 2.20, P = 0.0015) and all the unadjusted associations, except for PCL score. CONCLUSIONS: In WTC workers, FEV1  < LLN is associated with elevated PAAr which, although likely multifactorial, may be related to distal vasculopathy, as has been hypothesized for chronic obstructive pulmonary disease.

5.
Nat Commun ; 10(1): 3095, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300640

RESUMO

The nasal cellular epigenome may serve as biomarker of airway disease and environmental response. Here we collect nasal swabs from the anterior nares of 547 children (mean-age 12.9 y), and measure DNA methylation (DNAm) with the Infinium MethylationEPIC BeadChip. We perform nasal Epigenome-Wide Association analyses (EWAS) of current asthma, allergen sensitization, allergic rhinitis, fractional exhaled nitric oxide (FeNO) and lung function. We find multiple differentially methylated CpGs (FDR < 0.05) and Regions (DMRs; ≥ 5-CpGs and FDR < 0.05) for asthma (285-CpGs), FeNO (8,372-CpGs; 191-DMRs), total IgE (3-CpGs; 3-DMRs), environment IgE (17-CpGs; 4-DMRs), allergic asthma (1,235-CpGs; 7-DMRs) and bronchodilator response (130-CpGs). Discovered DMRs annotated to genes implicated in allergic asthma, Th2 activation and eosinophilia (EPX, IL4, IL13) and genes previously associated with asthma and IgE in EWAS of blood (ACOT7, SLC25A25). Asthma, IgE and FeNO were associated with nasal epigenetic age acceleration. The nasal epigenome is a sensitive biomarker of asthma, allergy and airway inflammation.

6.
Clin Exp Allergy ; 49(9): 1225-1234, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31187518

RESUMO

BACKGROUND: Response to inhaled corticosteroids is highly variable, and the association between DNA methylation and treatment response is not known. OBJECTIVE: To examine the association between peripheral blood DNA methylation and inhaled corticosteroid response in children with persistent asthma. METHODS: Epigenome-wide DNA methylation was analysed in individuals on inhaled corticosteroids in three independent and ethnically diverse cohorts-Childhood Asthma Management Program (CAMP); Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE); and Genetic Epidemiology of Asthma in Costa Rica Study (GACRS). Treatment response was evaluated using two definitions, the absence of emergency department visits and/or hospitalizations and the absence oral corticosteroid use while on inhaled corticosteroid therapy. CpG sites meeting nominal significance (P < 0.05) for each outcome were combined in a three-cohort meta-analysis with adjustment for multiple testing. DNA methylation was correlated with gene expression using Pearson and partial correlations. RESULTS: In 154 subjects from CAMP, 72 from BAMSE, and 168 from GACRS, relative hypomethylation of cg00066816 (171 bases upstream of IL12B) was associated with the absence of emergency department visits and/or hospitalizations (Q = 0.03) in all cohorts and lower IL12B expression (ρ = 0.34, P = 0.01) in BAMSE. Relative hypermethylation of cg04256470 (688 bases upstream of CORT) was associated with the absence of oral corticosteroid use (Q = 0.04) in all cohorts and higher CORT expression (ρ = 0.20, P = 0.045) in CAMP. CONCLUSION AND CLINICAL RELEVANCE: Differential DNA methylation of IL12B and CORT are associated with inhaled corticosteroid treatment response in persistent childhood asthmatics. Pharmaco-methylation can identify novel markers of treatment sensitivity in asthma.

7.
Lung ; 197(4): 517-522, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31254057

RESUMO

BACKGROUND: We previously reported that wall area percent (WAP), a quantitative CT (QCT) indicator of airway wall thickness and, presumably, inflammation, is associated with adverse longitudinal expiratory flow trajectories in WTC workers, but that obesity and weight gain also seemed to be independently predictive of the latter. Previous studies have reported no association between WAP and obesity, so we investigated that association in nonsmoking WTC-exposed individuals and healthy unexposed controls. METHODS: We assessed WAP using the Chest Imaging Platform QCT system in a segmental bronchus in 118 former WTC workers, and 89 COPDGene® WTC-unexposed and asymptomatic subjects. We used multiple regression to model WAP vs. body mass index (BMI) in the two groups, adjusting for important subject and CT image characteristics. RESULTS: Unadjusted analyses revealed significant differences between the two groups with regards to WAP, age, gender, scan pixel spacing and slice interval, but not BMI or total lung capacity. In adjusted analysis, there was a significant interaction between BMI and WTC exposure on WAP. BMI was significantly and positively associated with WAP in the WTC group, but not in the COPDGene® group, but stratified analyses revealed that the effect was significant in WTC subjects with clinical evidence of lower airway disease (LAD). DISCUSSION: Unlike non-diseased subjects, BMI was significantly associated with WAP in WTC workers and, in stratified analyses, the association was significant only among those with LAD. Our findings suggest that this adverse effect of obesity on airway structure and inflammation may be confined to already diseased individuals.

9.
Epigenetics ; 14(9): 844-849, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31122150

RESUMO

Vitamin D is a nutrient and a hormone with multiple effects on immune regulation and respiratory viral infections, which can worsen asthma and lead to severe asthma exacerbations. We set up a complete experimental and analytical pipeline for ATAC-Seq and RNA-Seq to study genome-wide epigenetic changes in human bronchial epithelial cells of asthmatic subjects, following treatment of these cells with calcitriol (vitamin D3) and Poly (I:C)(a viral analogue). This approach led to the identification of biologically plausible candidate genes for viral infections and asthma, such as DUSP10 and SLC44A1.

10.
PLoS Genet ; 15(5): e1008142, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31063461

RESUMO

The development of high-throughput biotechnologies allows the collection of omics data to study the biological mechanisms underlying complex diseases at different levels, such as genomics, epigenomics, and transcriptomics. However, each technology is designed to collect a specific type of omics data. Thus, the association between a disease and one type of omics data is usually tested individually, but this strategy is suboptimal. To better articulate biological processes and increase the consistency of variant identification, omics data from various platforms need to be integrated. In this report, we introduce an approach that uses a modified Fisher's method (denoted as Omnibus-Fisher) to combine separate p-values of association testing for a trait and SNPs, DNA methylation markers, and RNA sequencing, calculated by kernel machine regression into an overall gene-level p-value to account for correlation between omics data. To consider all possible disease models, we extend Omnibus-Fisher to an optimal test by using perturbations. In our simulations, a usual Fisher's method has inflated type I error rates when directly applied to correlated omics data. In contrast, Omnibus-Fisher preserves the expected type I error rates. Moreover, Omnibus-Fisher has increased power compared to its optimal version when the true disease model involves all types of omics data. On the other hand, the optimal Omnibus-Fisher is more powerful than its regular version when only one type of data is causal. Finally, we illustrate our proposed method by analyzing whole-genome genotyping, DNA methylation data, and RNA sequencing data from a study of childhood asthma in Puerto Ricans.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31146018

RESUMO

BACKGROUND: Cadmium and lead are hazardous pollutants. OBJECTIVE: We examined the relation between serum levels of cadmium and lead and current wheeze, current asthma, and lung function in US adults. METHODS: A cross-sectional study of 13,888 adults aged 20 to 79 years in 2007-2012 National Health and Nutrition Examination Survey (NHANES) was considered. Multivariable logistic or linear regression was used for the analyses of current wheeze, current asthma, and lung function measures (forced expiratory volume in 1 second [FEV1]% predicted, forced vital capacity [FVC]% predicted, FEV1/FVC% predicted, and fractional exhaled nitric oxide [FeNO]), which were conducted first in all participants, and then separately in never/former smokers and current smokers. RESULTS: High levels of serum cadmium were significantly associated with current wheeze in all participants and in current smokers (odds ratio for fourth vs first quartile = 2.84, 95% confidence interval = 2.07-3.90, Pfor linear trend < .01), as well as with current asthma in current smokers. Serum lead was not significantly associated with current wheeze or current asthma, regardless of smoking status. Serum cadmium was significantly associated with lower FEV1% predicted, FEV1/FVC% predicted, and FeNO in all participants and in never/former smokers, and serum lead was significantly associated with lower FEV1/FVC% predicted in all participants, with similar findings in never/former smokers and in current smokers. CONCLUSIONS: Our findings suggest that exposure to cadmium is associated with an increased risk of wheeze and asthma in US adults who currently smoke. Moreover, our results suggest that exposure to cadmium or lead has negative effects on lung function in nonsmoking US adults.

13.
Eur Respir J ; 53(5)2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30923181

RESUMO

Early allergic sensitisation (atopy) is the first step in the development of allergic diseases such as atopic asthma later in life. Genes and pathways associated with atopy and atopic asthma in children and adolescents have not been well characterised.A transcriptome-wide association study (TWAS) of atopy and atopic asthma in white blood cells (WBCs) or whole blood was conducted in a cohort of 460 Puerto Ricans aged 9-20 years (EVA-PR study) and in a cohort of 250 Swedish adolescents (BAMSE study). Pathway enrichment and network analyses were conducted to further assess top findings, and classification models of atopy and atopic asthma were built using expression levels for the top differentially expressed genes (DEGs).In a meta-analysis of the study cohorts, both previously implicated genes (e.g. IL5RA and IL1RL1) and genes not previously reported in TWASs (novel) were significantly associated with atopy and/or atopic asthma. Top novel genes for atopy included SIGLEC8 (p=8.07×10-13), SLC29A1 (p=7.07×10-12) and SMPD3 (p=1.48×10-11). Expression quantitative trait locus analyses identified multiple asthma-relevant genotype-expression pairs, such as rs2255888/ALOX15 Pathway enrichment analysis uncovered 16 significantly enriched pathways at adjusted p<0.01, including those relevant to T-helper cell type 1 (Th1) and Th2 immune responses. Classification models built using the top DEGs and a few demographic/parental history variables accurately differentiated subjects with atopic asthma from nonatopic control subjects (area under the curve 0.84).We have identified genes and pathways for atopy and atopic asthma in children and adolescents, using transcriptome-wide data from WBCs and whole blood samples.

14.
J Allergy Clin Immunol ; 143(6): 2263-2270.e14, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30738172

RESUMO

BACKGROUND: Epigenetic clocks have been suggested to capture one feature of the complexity between aging and the epigenome. However, little is known about the epigenetic clock in childhood allergy and asthma. OBJECTIVE: We sought to examine associations of DNA methylation age (DNAmAge) and epigenetic age acceleration with childhood allergy and asthma. METHODS: We calculated DNAmAge and age acceleration at birth, early childhood, and midchildhood based on the IlluminaHumanMethylation450BeadChip in Project Viva. We evaluated epigenetic clock associations with allergy and asthma using covariate-adjusted linear and logistic regressions. We attempted to replicate our findings in the Genetics of Asthma in Costa Rica Study. RESULTS: At midchildhood (mean age, 7.8 years) in Project Viva, DNAmAge and age acceleration were cross-sectionally associated with greater total serum IgE levels and greater odds of atopic sensitization. Every 1-year increase in intrinsic epigenetic age acceleration was associated with a 1.22 (95% CI, 1.07-1.39), 1.17 (95% CI, 1.03-1.34), and 1.29 (95% CI, 1.12-1.49) greater odds of atopic sensitization and environmental and food allergen sensitization. DNAmAge and extrinsic epigenetic age acceleration were also cross-sectionally associated with current asthma at midchildhood. DNAmAge and age acceleration at birth and early childhood were not associated with midchildhood allergy or asthma. The midchildhood association between age acceleration and atopic sensitization were replicated in an independent data set. CONCLUSIONS: Because the epigenetic clock might reflect immune and developmental components of biological aging, our study suggests pathways through which molecular epigenetic mechanisms of immunity, development, and maturation can interact along the age axis and associate with childhood allergy and asthma by midchildhood.

17.
Clin Exp Allergy ; 49(6): 789-798, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30697902

RESUMO

BACKGROUND: Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome-wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response. OBJECTIVE: We aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings. METHODS: A meta-analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10-6 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations. RESULTS: A total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10-6 ). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10-3 ) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10-3 ). Additionally, the reported association of the L3MBTL4-ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified. CONCLUSIONS AND CLINICAL RELEVANCE: This study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment.

18.
Pediatr Pulmonol ; 54(3): 237-244, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30614209

RESUMO

BACKGROUND: Asthma may worsen during adolescence, due to both health risk behaviors and psychosocial stressors commonly encountered during this life stage. METHODS: Cross-sectional study of 24 612 high school students who participated in the 2009 and 2011 National Youth Risk Behavior Survey. Multivariable logistic regression was used to examine the relation between self-reported health risk behaviors or psychosocial stressors and current asthma. Mediation analysis was performed to assess whether depressive symptoms or suicidal behavior contribute to the link between psychosocial stressors and asthma. RESULTS: Current asthma was reported by 13.1% of the study participants. In a multivariable analysis, female sex, obesity, shorter sleep duration, frequent soda/pop consumption, and marijuana use were each significantly associated with 14-36% increased odds of asthma. Any violent behavior (adjusted odds ratio [OR] = 1.12, 95% confidence interval [CI] = 1.02-1.24), any victimization (OR = 1.43, 95%CI = 1.29-1.58), any suicidal behavior (OR = 1.41, 95%CI = 1.22-1.64) and having felt sad or hopeless in the past year (OR = 1.57, 95%CI = 1.40-1.75) were each associated with current asthma. In a mediation analyses, having felt sad/hopeless and suicidal behaviors accounted for 21% and 14%, respectively, of the victimization-asthma association. CONCLUSION: Potentially modifiable risk factors, including obesity, short sleep duration, frequent soda/pop consumption, and psychosocial stressors are associated with asthma in US adolescents. Promoting healthier lifestyles, as well as screening for violence exposure and treating depressive symptoms, could help reduce asthma burden in this population.

19.
Ann Am Thorac Soc ; 16(1): 1-16, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30592451

RESUMO

High-throughput, "next-generation" sequencing methods are now being broadly applied across all fields of biomedical research, including respiratory disease, critical care, and sleep medicine. Although there are numerous review articles and best practice guidelines related to sequencing methods and data analysis, there are fewer resources summarizing issues related to study design and interpretation, especially as applied to common, complex, nonmalignant diseases. To address these gaps, a single-day workshop was held at the American Thoracic Society meeting in May 2017, led by the American Thoracic Society Section on Genetics and Genomics. The aim of this workshop was to review the design, analysis, interpretation, and functional follow-up of high-throughput sequencing studies in respiratory, critical care, and sleep medicine research. This workshop brought together experts in multiple fields, including genetic epidemiology, biobanking, bioinformatics, and research ethics, along with physician-scientists with expertise in a range of relevant diseases. The workshop focused on application of DNA and RNA sequencing research in common chronic diseases and did not cover sequencing studies in lung cancer, monogenic diseases (e.g., cystic fibrosis), or microbiome sequencing. Participants reviewed and discussed study design, data analysis and presentation, interpretation, functional follow-up, and reporting of results. This report summarizes the main conclusions of the workshop, specifically addressing the application of these methods in respiratory, critical care, and sleep medicine research. This workshop report may serve as a resource for our research community as well as for journal editors and reviewers of sequencing-based manuscript submissions in our research field.

20.
Lancet Respir Med ; 7(4): 336-346, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30584054

RESUMO

BACKGROUND: Epigenetic mechanisms could alter the airway epithelial barrier and ultimately lead to atopic diseases such as asthma. We aimed to identify DNA methylation profiles that are associated with-and could accurately classify-atopy and atopic asthma in school-aged children. METHODS: We did a genome-wide study of DNA methylation in nasal epithelium and atopy or atopic asthma in 483 Puerto Rican children aged 9-20 years, recruited using multistage probability sampling. Atopy was defined as at least one positive IgE (≥0·35 IU/mL) to common aeroallergens, and asthma was defined as a physician's diagnosis plus wheeze in the previous year. Significant (false discovery rate p<0·01) methylation signals were correlated with gene expression, and top CpGs were validated by pyrosequencing. We then replicated our top methylation findings in a cohort of 72 predominantly African American children, and in 432 children from a European birth cohort. Next, we tested classification models based on nasal methylation for atopy or atopic asthma in all cohorts. FINDINGS: DNA methylation profiles were markedly different between children with (n=312) and without (n=171) atopy in the Puerto Rico discovery cohort, recruited from Feb 12, 2014, until May 8, 2017. After adjustment for covariates and multiple testing, we found 8664 differentially methylated CpGs by atopy, with false discovery rate-adjusted p values ranging from 9·58 × 10-17 to 2·18 × 10-22 for the top 30 CpGs. These CpGs were in or near genes relevant to epithelial barrier function, including CDHR3 and CDH26, and in other genes related to airway epithelial integrity and immune regulation, such as FBXL7, NTRK1, and SLC9A3. Moreover, 28 of the top 30 CpGs replicated in the same direction in both independent cohorts. Classification models of atopy based on nasal methylation performed well in the Puerto Rico cohort (area under the curve [AUC] 0·93-0·94 and accuracy 85-88%) and in both replication cohorts (AUC 0·74-0·92, accuracy 68-82%). The models also performed well for atopic asthma in the Puerto Rico cohort (AUC 0·95-1·00, accuracy 88%) and the replication cohorts (AUC 0·82-0·88, accuracy 86%). INTERPRETATION: We identified specific methylation profiles in airway epithelium that are associated with atopy and atopic asthma in children, and a nasal methylation panel that could classify children by atopy or atopic asthma. Our findings support the feasibility of using the nasal methylome for future clinical applications, such as predicting the development of asthma among wheezing infants. FUNDING: US National Institutes of Health.

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