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1.
Lancet Respir Med ; 8(10): 1045-1056, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32910899

RESUMO

Asthma is an inflammatory airway disease that is estimated to affect 339 million people globally. The symptoms of about 5-10% of patients with asthma are not adequately controlled with current therapy, and little success has been achieved in developing drugs that target the underlying mechanisms of asthma rather than suppressing symptoms. Over the past 3 years, well powered genetic studies of asthma have increased the number of independent asthma-associated genetic loci to 128. In this Series paper, we describe the immense progress in asthma genetics over the past 13 years and link asthma genetic variants to possible drug targets. Further studies are needed to establish the functional significance of gene variants associated with asthma in subgroups of patients and to describe the biological networks within which they function. The genomics-guided discovery of plausible drug targets for asthma could pave the way for the repurposing of existing drugs for asthma and the development of new treatments.


Assuntos
Asma/genética , Asma/terapia , Terapia de Alvo Molecular , Descoberta de Drogas , Estudo de Associação Genômica Ampla , Humanos
2.
Medicine (Baltimore) ; 99(34): e21732, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846793

RESUMO

BACKGROUND: We performed an updated meta-analysis to clarify the relationship between glutathione S-transferase Mu and theta (GSTM1 and GSTT1, respectively) null/positive genotypes and asthma. METHODS: We performed a literature search using PubMed and Web of Science databases in August 2019. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the role of GSTM1 and GSTT1 genotypes in the risk of asthma. RESULTS: Overall, we found a significant association with asthma risk in the general population for both the GSTM1 genotype (OR = 1.21; 95% CI: 1.07-1.35; P < .001; I = 69.5%) and the GSTT1 genotype (OR = 1.61; 95% CI: 1.30-2.00; P < .001; I = 83.6%). Moreover, significant associations between both genotypes and asthma risk were also found by age stratification. Furthermore, for GSTM1 we found significant associations in populations living in Asia, Europe, and Russia, but not in Africa. Conversely, for GSTT1, we found a significantly increased risk in populations living in Asia, Europe, Africa, and Russia. In addition, a significant association was found for both genotypes with a sample size <500, but not a sample size >2000. CONCLUSION: Our meta-analysis provides evidence that GSTM1 and GSTT1 genotypes could be used as asthma-associated biomarkers.


Assuntos
Asma/genética , Glutationa Transferase/genética , Fatores Etários , Grupos de Populações Continentais , Predisposição Genética para Doença , Genótipo , Humanos , Fatores de Risco , Fatores Sexuais
3.
Gene ; 763: 145073, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-32827684

RESUMO

BACKGROUND: The role of FoxP3, a master regulator of T regulatory cells, in allergic diseases such as asthma is of immense importance yet the effect of its gene variants on the disease predisposition is not fully understood. We studied the association of FoxP3 polymorphisms (-2383C/T and -3279C/A) in allergic asthma patients and their correlation with serum IL-4, IL-13, Total IgE, and Vitamin D levels. METHODS: In this study 350 individuals were enrolled, 150 allergic asthma patients and 200 healthy controls. SNP analyses were performed by RFLP. IL-4, IL-13 vitamin D and Total IgE were measured by ELISA. RESULTS: The AA homozygous mutant of -3279C/A posed a three-fold risk [P < 0.005; OR, 3.52] whereas the -2383C/T variants TT genotype carried a fourfold risk [P = 0.002; OR, 4.04]. Haplotype analysis exhibited predisposition to allergic asthmawith CC/TT [P = 0.01; OR 5.93 (95%CI)], AA/CC [P = 0.01; OR 3.29] and AA/TT haplotypes [P = 0; OR 11.86 (1.31-85.87)]. A negative correlation between IgE and Vitamin D was found [r = -0.30p-value 0.001] but a negative correlation betweenIgE and Vit D was established in the haplotype CC/TT [r = -0.45P = 0.002] and CC/CT [r = -0.52P = 0.04]. In allergic patients, the eosinophils count was high [p = 0.003] and the mean levels of pro-inflammatory cytokines IL-4 and IL-13 were elevated [P < 0.001] as well. CONCLUSIONS: The study suggests SNP -3279 -AA genotype and, -2383-TT genotype in association with certain haplotypes pose a risk for allergy development. There was no correlation between different genotypes and serum levels of various cytokines.


Assuntos
Asma/genética , Fatores de Transcrição Forkhead/genética , Polimorfismo de Nucleotídeo Único , Adulto , Asma/sangue , Eosinofilia/sangue , Eosinofilia/genética , Feminino , Humanos , Imunoglobulina E/sangue , Interleucina-13/sangue , Interleucina-4/sangue , Masculino , Vitamina D/sangue
4.
Nat Commun ; 11(1): 3865, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737319

RESUMO

Polygenic scores (PGS) have been widely used to predict disease risk using variants identified from genome-wide association studies (GWAS). To date, most GWAS have been conducted in populations of European ancestry, which limits the use of GWAS-derived PGS in non-European ancestry populations. Here, we derive a theoretical model of the relative accuracy (RA) of PGS across ancestries. We show through extensive simulations that the RA of PGS based on genome-wide significant SNPs can be predicted accurately from modelling linkage disequilibrium (LD), minor allele frequencies (MAF), cross-population correlations of causal SNP effects and heritability. We find that LD and MAF differences between ancestries can explain between 70 and 80% of the loss of RA of European-based PGS in African ancestry for traits like body mass index and type 2 diabetes. Our results suggest that causal variants underlying common genetic variation identified in European ancestry GWAS are mostly shared across continents.


Assuntos
Asma/genética , Diabetes Mellitus Tipo 2/genética , Hipertensão/genética , Modelos Genéticos , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto , África/epidemiologia , Idoso , Alelos , Ásia/epidemiologia , Asma/diagnóstico , Asma/epidemiologia , Asma/etnologia , Índice de Massa Corporal , Colesterol/sangue , Simulação por Computador , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etnologia , Europa (Continente)/epidemiologia , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipertensão/etnologia , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Prognóstico , Característica Quantitativa Herdável , Risco
5.
Adv Exp Med Biol ; 1207: 581-584, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671776

RESUMO

Asthma is one of the most common diseases of the respiratory system, with typical pathogenesis and pathological changes. The current research shows that autophagy is mainly involved in the pathogenesis of asthma by regulating the body's innate and adaptive immune responses. At the same time, a large number of epidemiological studies have shown that multiple autophagy genes affect the risk of asthma at the level of genetic polymorphism. This chapter will explore the relationship between autophagy and asthma.


Assuntos
Asma , Autofagia , Asma/genética , Asma/imunologia , Autofagia/genética , Autofagia/imunologia , Humanos , Polimorfismo Genético
6.
Medicine (Baltimore) ; 99(29): e20953, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702834

RESUMO

BACKGROUND: Previous investigations have illustrated that regulated upon activation, normal T-cell expressed and secreted (RANTES) polymorphisms are linked to susceptibility to childhood asthma; nevertheless, the findings continue to be controversial. Accordingly, we conducted the present meta-analysis to clarify the impact of RANTES genetic polymorphisms (-403G/A and -28C/G) on childhood asthma vulnerability. METHODS: A search for published literature was performed using the PubMed, EMBASE, Chinese National Infrastructure, Cochrane Library, Scopus, Web of Science, and WanFang databases and selected in the form of PICOS (participants, interventions, comparisons, outcomes, and study design) to identify all eligible research works. The link between RANTES genetic polymorphisms and childhood asthma susceptibility was evaluated by a pooled odds ratio with a 95% confidence interval. RESULTS: In total, 14 case-control studies were included in the analysis. No significant association existed between risk of childhood asthma and the -403G/A polymorphism subjected to any genetic framework in the overall population. In the stratified analysis, according to ethnicity, the -403G/A polymorphism was linked to augmented vulnerability to childhood asthma in Caucasians (allelic model: odds ratio [OR] = 1.63, 95% confidence interval [CI] = 1.04-2.57, P = .034; codominant model: OR = 2.20, 95% CI = 1.28-3.78, P = .004; dominant model: OR = 1.78, 95% CI = 1.01-3.13, P = .047; and recessive model: OR = 1.92, 95% CI = 1.11-3.30, P = .019). For the stratified analysis by atopic status, the -403G/A polymorphism was linked to augmented childhood asthma in the codominant (OR = 1.39, 95% CI = 1.02-1.91, P = .037) and dominant models (OR = 1.43, 95% CI = 1.02-2.01, P = .037) in atopic asthma. For the -28C/G polymorphism, there was a significant association between childhood asthma and the -28C/G variant (allelic model: OR = 1.33, 95% CI = 1.08-1.65, P = .009; codominant framework: OR = 2.14, 95% CI = 1.47-3.10, P < .001; dominant model: OR = 1.44, 95% CI = 1.07-1.93, P = .017; and recessive model: OR = 2.08, 95% CI = 1.44-3.02, P < .001). Stratified analysis based on ethnicity and the -28C/G polymorphism was linked to augmented vulnerability to childhood asthma in Asian and Caucasian populations. For the subgroup analysis by atopic status, no association was found in atopic and non-atopic asthma. CONCLUSION: The present meta-analysis indicated that the RANTES -403G/A and -28C/G polymorphisms contributed to the development of childhood asthma.


Assuntos
Asma/genética , Quimiocina CCL5/genética , Predisposição Genética para Doença , Polimorfismo Genético , Humanos
7.
PLoS Genet ; 16(6): e1008725, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32603359

RESUMO

Risk factors that contribute to inter-individual differences in the age-of-onset of allergic diseases are poorly understood. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic disease first develop, considering information from asthma, hay fever and eczema. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study (GWAS) of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. Forty-five variants had comparable effects on the onset of the three individual diseases and 38 were also associated with allergic disease case-control status in an independent study (n = 222,484). We observed a strong negative genetic correlation between age-of-onset and case-control status of allergic disease (rg = -0.63, P = 4.5x10-61), indicating that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. Subsequently, a multivariate GWAS of age-of-onset and case-control status identified a further 26 associations that were missed by the univariate analyses of age-of-onset or case-control status only. Collectively, of the 76 variants identified, 18 represent novel associations for allergic disease. We identified 81 likely target genes of the 76 associated variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, of which we highlight ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7 and UBE2L3. Our results support the notion that early and late onset allergic disease have partly distinct genetic architectures, potentially explaining known differences in pathophysiology between individuals.


Assuntos
Asma/genética , Eczema/genética , Polimorfismo de Nucleotídeo Único , Rinite Alérgica Sazonal/genética , Adolescente , Adulto , Idade de Início , Idoso , Asma/patologia , Criança , Eczema/patologia , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Rinite Alérgica Sazonal/patologia
8.
DNA Cell Biol ; 39(7): 1313-1321, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32543891

RESUMO

Toll-like receptors (TLRs) play crucial roles in the recognition of invading pathogens and the immune system. However, the effect of TLRs in asthma is still not fully known. This study was performed to better understand the role of TLR signatures in asthma. Blood samples from case-control studies (study 1: 348 asthmas and 39 normal controls and validation study 2: 411 asthmas and 87 normal controls) were enrolled. The single-sample gene set enrichment analysis method was performed to quantify the abundance of 21 TLR signatures. Gene ontology analysis and pathway function analysis were conducted for functional analysis, and a protein-protein interaction network was constructed. The area under the curve (AUC) value was used to assess the diagnostic capacity. In this study, TLR2/TLR3/TLR4 pathway, MyD88-dependent/independent TLR pathway, positive regulation of TLR4 pathway, and TLR binding signatures were significantly higher in asthma. Functional analysis showed that biological processes and pathways were still involved in TLR cascades and TLR signaling pathway. Eleven hub TLR-related genes were identified, and further validation demonstrated that the combination of TLR-related genes was a good diagnostic biomarker for asthma (AUC = 0.8). Our study provided more insight into the underlying immune mechanism of how TLR signatures affected asthma. The use of the easy-to-apply TLR-related genes might represent a promising blood-based biomarker for early detection of asthma.


Assuntos
Asma/diagnóstico , Asma/metabolismo , Receptores Toll-Like/metabolismo , Asma/genética , Asma/terapia , Biologia Computacional , Regulação da Expressão Gênica , Humanos , Imunoterapia , Prognóstico , Mapeamento de Interação de Proteínas
10.
J Allergy Clin Immunol ; 146(2): 315-324.e7, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32531372

RESUMO

BACKGROUND: More than 300 million people carry a diagnosis of asthma, with data to suggest that they are at a higher risk for infection or adverse outcomes from severe acute respiratory syndrome coronavirus 2. Asthma is remarkably heterogeneous, and it is currently unclear how patient-intrinsic factors may relate to coronavirus disease 2019. OBJECTIVE: We sought to identify and characterize subsets of patients with asthma at increased risk for severe acute respiratory syndrome coronavirus 2 infection. METHODS: Participants from 2 large asthma cohorts were stratified using clinically relevant parameters to identify factors related to angiotensin-converting enzyme-2 (ACE2) expression within bronchial epithelium. ACE-2-correlated gene signatures were used to interrogate publicly available databases to identify upstream signaling events and novel therapeutic targets. RESULTS: Stratifying by type 2 inflammatory biomarkers, we identified subjects who demonstrated low peripheral blood eosinophils accompanied by increased expression of the severe acute respiratory syndrome coronavirus 2 receptor ACE2 in bronchial epithelium. Genes highly correlated with ACE2 overlapped with type 1 and 2 IFN signatures, normally induced by viral infections. T-cell recruitment and activation within bronchoalveolar lavage cells of ACE2-high subjects was reciprocally increased. These patients demonstrated characteristics corresponding to risk factors for severe coronavirus disease 2019, including male sex, history of hypertension, low peripheral blood, and elevated bronchoalveolar lavage lymphocytes. CONCLUSIONS: ACE2 expression is linked to upregulation of viral response genes in a subset of type 2-low patients with asthma with characteristics resembling known risk factors for severe coronavirus disease 2019. Therapies targeting the IFN family and T-cell-activating factors may therefore be of benefit in a subset of patients.


Assuntos
Asma/epidemiologia , Asma/genética , Infecções por Coronavirus/epidemiologia , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/epidemiologia , Receptores Virais/genética , Adolescente , Adulto , Asma/classificação , Asma/imunologia , Betacoronavirus/genética , Betacoronavirus/imunologia , Biomarcadores/metabolismo , Brônquios/imunologia , Brônquios/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Estudos de Coortes , Infecções por Coronavirus/virologia , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interferon gama/genética , Interferon gama/imunologia , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/virologia , Mapeamento de Interação de Proteínas , Receptores Virais/imunologia , Fatores de Risco , Índice de Gravidade de Doença , Linfócitos T/classificação , Linfócitos T/imunologia , Linfócitos T/patologia , Transcriptoma , Estados Unidos/epidemiologia
11.
Life Sci ; 255: 117835, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32450169

RESUMO

AIMS: Emerging findings demonstrate the critical roles of noncoding RNA (ncRNA) in asthma development. Nevertheless, the biological roles of circular RNA (circRNA) in airway remodeling are still elusive. Here, the present research focuses on the regulation of circRNA circHIPK3 in airway smooth muscle cells (ASMCs) proliferation and migration. MATERIALS AND METHODS: The sequence of circRNA was detected using Sanger sequencing. Cellular phenotypes were detected using CCK-8 assay, transwell and flow cytometer assay. The potential binding of miRNA and downstream and upstream targets was detected using dual-luciferase reporter assay. KEY FINDINGS: Results showed that circHIPK3 was significantly upregulated in platelet-derived growth factor (PDGF) induced ASMCs. Functional analysis using CCK-8, transwell migration assays and flow cytometry analysis showed that circHIPK3 knockdown repressed proliferation, migration and up-regulated the apoptosis in ASMCs. Mechanistic assays showed that circHIPK3 sponged miR-326 in the cytoplasm, thereby targeting stromal interaction molecule 1 (STIM1) to regulate ASMCs' proliferation, migration and apoptosis. SIGNIFICANCE: Collectively, the data elucidates that circHIPK3 functions as a regulator in the airway remodeling during the asthma development through miR-326/STIM1 axis, providing a novel insight for the therapeutic target.


Assuntos
Asma/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs/genética , Miócitos de Músculo Liso/citologia , Proteínas de Neoplasias/genética , Proteínas Serina-Treonina Quinases/genética , Molécula 1 de Interação Estromal/genética , Remodelação das Vias Aéreas/genética , Apoptose/efeitos dos fármacos , Asma/genética , Proliferação de Células/genética , Técnicas de Silenciamento de Genes , Humanos , Fator de Crescimento Derivado de Plaquetas/metabolismo , RNA Circular/genética , Sistema Respiratório/citologia
12.
Adv Exp Med Biol ; 1253: 153-181, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32445095

RESUMO

Asthma and rhinitis are complex, heterogeneous diseases characterized by chronic inflammation of the upper and lower airways. While genome-wide association studies (GWAS) have identified a number of susceptible loci and candidate genes associated with the pathogenesis of asthma and allergic rhinitis (AR), the risk-associated alleles account for only a very small percent of the genetic risk. In allergic airway and other complex diseases, it is thought that epigenetic modifications, including DNA methylation, histone modifications, and non-coding microRNAs, caused by complex interactions between the underlying genome and the environment may account for some of this "missing heritability" and may explain the high degree of plasticity in immune responses. In this chapter, we will focus on the current knowledge of classical epigenetic modifications, DNA methylation and histone modifications, and their potential role in asthma and AR. In particular, we will review epigenetic variations associated with maternal airway disease, demographics, environment, and non-specific associations. The role of specific genetic haplotypes in environmentally induced epigenetic changes are also discussed. A major limitation of many of the current studies of asthma epigenetics is that they evaluate epigenetic modifications in both allergic and non-allergic asthma, making it difficult to distinguish those epigenetic modifications that mediate allergic asthma from those that mediate non-allergic asthma. Additionally, most DNA methylation studies in asthma use peripheral or cord blood due to poor accessibility of airway cells or tissue. Unlike DNA sequences, epigenetic alterations are quite cell- and tissue-specific, and epigenetic changes found in airway tissue or cells may be discordant from that of circulating blood. These two confounding factors should be considered when reviewing epigenetic studies in allergic airway disease.


Assuntos
Asma/genética , Epigênese Genética , Epigenômica , Interação Gene-Ambiente , Rinite Alérgica/genética , Estudo de Associação Genômica Ampla , Humanos
13.
Mol Immunol ; 123: 18-25, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32388106

RESUMO

INTRODUCTION: Asthma is a worldwide problem that is caused by complex underlying immune dysregulation. The identification of potential prognostic markers of asthma may provide information for treatment. The purpose of this study was to explore the key mechanisms involved in the development of asthma on the basis of microarray analysis. METHODS: The expression profile data of GSE43696, which contains 20 endobronchial epithelial brushing samples from healthy patients and 88 from asthma patients, were obtained from Gene Expression Omnibus. For the present study, we built co-expression modules by weighted gene co-expression network analysis (WGCNA). This new analysis strategy was applied to the data set to investigate the relationships underlying the modules and the pathogenesis of asthma. Functional enrichment analysis was performed on these co-expression genes from the modules, and a gene network was then constructed. In addition, mouse models of HDM-induced and OVA-induced asthma were established, and the expression of hub genes was measured. RESULTS: First, using WGCNA, 20 co-expression modules were constructed with 19,596 genes obtained from 108 human endobronchial epithelial brushing samples. The number of genes within the modules ranged from 41 to 845. According to the colours assigned by the system, the module positively correlated with asthma status was named 'red module', and the module positively correlated with asthma severity was named 'purple module'. The results of a functional enrichment analysis showed that the red module was mainly enriched in intracellular calcium-activated chloride channel activity, intracellular chloride channel activity and endopeptidase inhibitor activity. The purple module was mainly enriched in microtubule motor activity and microtubule-binding and motor activity. Moreover, the mRNA expression levels of the 15 hub genes were confirmed to be significantly upregulated in the HDM mouse model, and 12 hub genes were upregulated in the OVA model. CONCLUSIONS: The hub genes ANO7, PYCR1 and UBE2C might play potential roles in the pathogenesis of asthma. Our findings provided a framework of co-expression gene modules of asthma and led to the identification of some new markers that might be potential targets for the development of new drugs and diagnostic markers.


Assuntos
Asma/genética , Asma/patologia , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Adulto , Animais , Biomarcadores/análise , Brônquios/metabolismo , Brônquios/patologia , Células Cultivadas , Estudos de Coortes , Feminino , Regulação da Expressão Gênica , Estudos de Associação Genética/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries/métodos , Pessoa de Meia-Idade , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Índice de Gravidade de Doença , Transdução de Sinais/genética , Adulto Jovem
14.
Lancet Respir Med ; 8(5): 482-492, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32380068

RESUMO

BACKGROUND: African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12-21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12-21 locus. METHODS: We first did a genetic association study and meta-analysis using 17q12-21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12-21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12-21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA). FINDINGS: 17q12-21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p<0·0055 (for rs2305480_G, odds ratio [OR] 1·36 [95% CI 1·12-1·65], p=0·0014; and for rs8076131_A, OR 1·37 [1·13-1·67], p=0·0010). In upper airway epithelial cells from African American children, genotype at rs2305480 was the most significant eQTL for GSDMB (eQTL effect size [ß] 1·35 [95% CI 1·25-1·46], p<0·0001), and to a lesser extent showed an eQTL effect for post-GPI attachment to proteins phospholipase 3 (ß 1·15 [1·08-1·22], p<0·0001). No SNPs were eQTLs for ORMDL3. By contrast, in PBMCs, the five core SNPs were associated only with expression of GSDMB and ORMDL3. Genotype at rs12936231 (in zona pellucida binding protein 2) showed the strongest associations across both genes (for GSDMB, eQTLß 1·24 [1·15-1·32], p<0·0001; and for ORMDL3 (ß 1·19 [1·12-1·24], p<0·0001). The eQTL effects of rs2305480 on GSDMB expression were replicated in lower airway cells from African American adults (ß 1·29 [1·15-1·44], p<0·0001). INTERPRETATION: Our study suggests that SNPs regulating GSDMB expression in airway epithelial cells have a major role in childhood-onset asthma, whereas SNPs regulating the expression levels of 17q12-21 genes in resting blood cells are not central to asthma risk. Our genetic and gene expression data in African Americans and European Americans indicated GSDMB to be the leading candidate gene at this important asthma locus. FUNDING: National Institutes of Health, Office of the Director.


Assuntos
Afro-Americanos/genética , Asma/genética , Cromossomos Humanos Par 17 , Perfilação da Expressão Gênica , Estudos de Associação Genética , Criança , Células Epiteliais/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Leucócitos Mononucleares/metabolismo , Desequilíbrio de Ligação , Masculino , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Estados Unidos
16.
Thorax ; 75(7): 600-605, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32303624

RESUMO

Eosinophils are key effector cells in allergic diseases. Here we investigated Mcl-1 (an anti-apoptotic protein) in experimental allergic airway inflammation using transgenic overexpressing human Mcl-1 mice (hMcl-1) and reducing Mcl-1 by a cyclin-dependent kinase inhibitor. Overexpression of Mcl-1 exacerbated allergic airway inflammation, with increased bronchoalveolar lavage fluid cellularity, eosinophil numbers and total protein, and an increase in airway mucus production. Eosinophil apoptosis was suppressed by Mcl-1 overexpression, with this resistance to apoptosis attenuated by cyclin-dependent kinase inhibition which also rescued Mcl-1-exacerbated allergic airway inflammation. We propose that targeting Mcl-1 may be beneficial in treatment of allergic airway disease.


Assuntos
Asma/genética , Eosinófilos/patologia , Regulação da Expressão Gênica , Hipersensibilidade/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , RNA/genética , Animais , Apoptose , Asma/metabolismo , Asma/patologia , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Eosinófilos/metabolismo , Feminino , Hipersensibilidade/metabolismo , Hipersensibilidade/patologia , Contagem de Leucócitos , Camundongos , Camundongos Transgênicos , Proteína de Sequência 1 de Leucemia de Células Mieloides/biossíntese
17.
Am J Respir Crit Care Med ; 202(1): 51-64, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32255668

RESUMO

Rationale: MicroRNAs are potent regulators of biologic systems that are critical to tissue homeostasis. Individual microRNAs have been identified in airway samples. However, a systems analysis of the microRNA-mRNA networks present in the sputum that contribute to airway inflammation in asthma has not been published.Objectives: Identify microRNA and mRNA networks in the sputum of patients with asthma.Methods: We conducted a genome-wide analysis of microRNA and mRNA in the sputum from patients with asthma and correlated expression with clinical phenotypes. Weighted gene correlation network analysis was implemented to identify microRNA networks (modules) that significantly correlate with clinical features of asthma and mRNA expression networks. MicroRNA expression in peripheral blood neutrophils and lymphocytes and in situ hybridization of the sputum were used to identify the cellular sources of microRNAs. MicroRNA expression obtained before and after ozone exposure was also used to identify changes associated with neutrophil counts in the airway.Measurements and Main Results: Six microRNA modules were associated with clinical features of asthma. A single module (nely) was associated with a history of hospitalizations, lung function impairment, and numbers of neutrophils and lymphocytes in the sputum. Of the 12 microRNAs in the nely module, hsa-miR-223-3p was the highest expressed microRNA in neutrophils and was associated with increased neutrophil counts in the sputum in response to ozone exposure. Multiple microRNAs in the nely module correlated with two mRNA modules enriched for TLR (Toll-like receptor) and T-helper cell type 17 (Th17) signaling and endoplasmic reticulum stress. hsa-miR-223-3p was a key regulator of the TLR and Th17 pathways in the sputum of subjects with asthma.Conclusions: This study of sputum microRNA and mRNA expression from patients with asthma demonstrates the existence of microRNA networks and genes that are associated with features of asthma severity. Among these, hsa-miR-223-3p, a neutrophil-derived microRNA, regulates TLR/Th17 signaling and endoplasmic reticulum stress.


Assuntos
Asma/imunologia , Redes Reguladoras de Genes , MicroRNAs/metabolismo , Neutrófilos/metabolismo , Índice de Gravidade de Doença , Escarro/metabolismo , Adulto , Idoso , Asma/diagnóstico , Asma/genética , Biomarcadores/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Feminino , Estudo de Associação Genômica Ampla , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , RNA Mensageiro/metabolismo
18.
Am J Respir Crit Care Med ; 202(1): 65-72, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32272022

RESUMO

Rationale: Inhaled corticosteroids (ICS) are key treatments for controlling asthma and preventing asthma attacks. However, the responsiveness to ICS varies among individuals. MicroRNAs (miRNAs) have been lauded for their prognostic utility.Objectives: We hypothesized that circulating miRNAs obtained at baseline/prerandomization in the Childhood Asthma Management Program (CAMP) could serve as biomarkers and biologic mediators of ICS clinical response over the 4-year clinical trial period.Methods: We selected baseline serum samples from 462 CAMP subjects subsequently randomized to either ICS (budesonide) or placebo. Samples underwent small RNA sequencing, and read counts were normalized and filtered by depth and coverage. Linear regression was used to associate miRNAs with change in FEV1% (prebronchodilator FEV1 as a percent predicted) over the 4-year treatment period in both main effects and interaction models. We validated the function of the top associated miRNAs by luciferase reporter assays of glucocorticoid-mediated transrepression and predicted response to ICS through logistic regression models.Measurements and Main Results: We identified 7 miRNAs significantly associated with FEV1% change (P ≤ 0.05) and 15 miRNAs with significant interaction (P ≤ 0.05) to ICS versus placebo treatments. We selected three miRNAs for functional validation, of which hsa-miR-155-5p and hsa-miR-532-5p were significantly associated with changes in dexamethasone-induced transrepression of NF-κB. Combined, these two miRNAs were predictive of ICS response over the course of the clinical trial, with an area under the receiver operating characteristic curve of 0.86.Conclusions: We identified two functional circulating miRNAs predictive of asthma ICS treatment response over time.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/genética , Budesonida/uso terapêutico , MicroRNA Circulante/sangue , Administração por Inalação , Asma/sangue , Asma/diagnóstico , Biomarcadores/sangue , Criança , Feminino , Seguimentos , Volume Expiratório Forçado , Humanos , Modelos Lineares , Modelos Logísticos , Masculino , Resultado do Tratamento
19.
Am J Respir Cell Mol Biol ; 63(2): 172-184, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32275839

RESUMO

Air pollution particulate matter <2.5 µm (PM2.5) exposure is associated with poor respiratory outcomes. Mechanisms underlying PM2.5-induced lung pathobiology are poorly understood but likely involve cellular and molecular changes to the airway epithelium. We extracted and chemically characterized the organic and water-soluble components of air pollution PM2.5 samples, then determined the whole transcriptome response of human nasal mucociliary airway epithelial cultures to a dose series of PM2.5 extracts. We found that PM2.5 organic extract (OE), but not water-soluble extract, elicited a potent, dose-dependent transcriptomic response from the mucociliary epithelium. Exposure to a moderate OE dose modified the expression of 424 genes, including activation of aryl hydrocarbon receptor signaling and an IL-1 inflammatory program. We generated an OE-response gene network defined by eight functional enrichment groups, which exhibited high connectivity through CYP1A1, IL1A, and IL1B. This OE exposure also robustly activated a mucus secretory expression program (>100 genes), which included transcriptional drivers of mucus metaplasia (SPDEF and FOXA3). Exposure to a higher OE dose modified the expression of 1,240 genes and further exacerbated expression responses observed at the moderate dose, including the mucus secretory program. Moreover, the higher OE dose significantly increased the MUC5AC/MUC5B gel-forming mucin expression ratio and strongly downregulated ciliated cell expression programs, including key ciliating cell transcription factors (e.g., FOXJ1 and MCIDAS). Chronic OE stimulation induced mucus metaplasia-like remodeling characterized by increases in MUC5AC+ secretory cells and MUC5AC mucus secretions. This epithelial remodeling may underlie poor respiratory outcomes associated with high PM2.5 exposure.


Assuntos
Mucosa Nasal/diagnóstico por imagem , Material Particulado/efeitos adversos , Mucosa Respiratória/efeitos dos fármacos , Poluentes Atmosféricos/efeitos adversos , Poluição do Ar/efeitos adversos , Asma/induzido quimicamente , Asma/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Mucina-5AC/genética , Mucina-5B/genética , Fatores de Transcrição/genética
20.
Am J Respir Crit Care Med ; 202(2): 259-274, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32255672

RESUMO

Rationale: Obesity-related asthma disproportionately affects minority children and is associated with nonatopic T-helper type 1 (Th1) cell polarized inflammation that correlates with pulmonary function deficits. Its underlying mechanisms are poorly understood.Objectives: To use functional genomics to identify cellular mechanisms associated with nonatopic inflammation in obese minority children with asthma.Methods: CD4+ (cluster of differentiation 4-positive) Th cells from 59 obese Hispanic and African American children with asthma and 61 normal-weight Hispanic and African American children with asthma underwent quantification of the transcriptome and DNA methylome and genotyping. Expression and methylation quantitative trait loci revealed the contribution of genetic variation to transcription and DNA methylation. Adjusting for Th-cell subtype proportions discriminated loci where transcription or methylation differences were driven by differences in subtype proportions from loci that were independently associated with obesity-related asthma.Measurements and Main Results: Obese children with asthma had more memory and fewer naive Th cells than normal-weight children with asthma. Differentially expressed and methylated genes and methylation quantitative trait loci in obese children with asthma, independent of Th-cell subtype proportions, were enriched in Rho-GTPase pathways. Inhibition of CDC42 (cell division cycle 42), one of the Rho-GTPases associated with Th-cell differentiation, was associated with downregulation of the IFNγ, but not the IL-4, gene. Differential expression of the RPS27L (40S ribosomal protein S27-like) gene, part of the p53/mammalian target of rapamycin pathway, was due to nonrandom distribution of expression quantitative trait loci variants between groups. Differentially expressed and/or methylated genes, including RPS27L, were associated with pulmonary function deficits in obese children with asthma.Conclusions: We found enrichment of Rho-GTPase pathways in obese asthmatic Th cells, identifying them as a novel therapeutic target for obesity-related asthma, a disease that is suboptimally responsive to current therapies.


Assuntos
Afro-Americanos/genética , Asma/genética , Proteínas Ativadoras de GTPase/genética , Genômica , Hispano-Americanos/genética , Obesidade Pediátrica/genética , Fenótipo , Adolescente , Asma/fisiopatologia , Criança , Pré-Escolar , Feminino , Proteínas Ativadoras de GTPase/metabolismo , Voluntários Saudáveis , Humanos , Lactente , Masculino
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