RESUMEN
BACKGROUND: Toluene diisocyanate (TDI) causes occupational asthma by generating oxidative stress, leading to tissue injury and inflammation. Glutathione transferases (GSTs) are detoxifying enzymes that eliminate oxidative stress. We examined whether the genotypes of the GSTM1 and GSTT1 genes are associated with TDI-induced occupational asthma (TDI-OA). METHODS: The study population consisted of 26 asthmatics with a positive response to the TDI challenge (TDI-PA) and 27 asthmatics with negative responses (TDI-NA). GSTM1 and GSTT1 null and wild-type genotypes were determined using multiplex PCR. The plasma GSTM1 and GSTT1 protein concentrations were determined using ELISA. RESULTS: The GSTM1 null genotype was more frequent in the TDI-PA than in the TDI-NA (77.8 vs. 50.0%, OR = 3.5, p=0.03), while the frequency of the GSTT1 null genotype tended to be higher in the TDI-PA than in the TDI-NA (59.3 vs. 42.3%, OR = 1.98, p=0.21). When analyzed together, the GSTM1/GSTT1 null genotype was more frequent in the TDI-PA than in the TDI-NA (48.2 vs. 15.3%, OR = 6.5, p=0.04). The decline in the FEV in 1 s after TDI challenge was higher with the GSTM1/GSTT1 null than the GSTM1 wild-type/GSTT1 null genotypes (24.29% vs. 7.47%, p=0.02). The plasma GSTM1 level was lower with the GSTM1 null than with the GSTM1 wild-type genotypes both before (13.7 vs. 16.6 ng/mg, p=0.04) and after (12.9 vs. 17.1 ng/mg, p=0.007) the TDI challenge, while the GSTT1 level was not changed with either the GSTT1 null or wild-type genotype. CONCLUSIONS: The GSTM1 null genotype, but not GSTT1 alone, may confer susceptibility to TDI-OA. However, the genetic effect of the GSTM1 null genotype may be enhanced synergistically by the GSTT1 null genotype. The genetic effect of GSTM1 was validated in the plasma as the GSTM1 protein level. Therefore, the GSTM1 and GSTT1 genotypes may be useful diagnostic markers for TDI-OA.
Asunto(s)
Asma Ocupacional , 2,4-Diisocianato de Tolueno , Asma Ocupacional/inducido químicamente , Asma Ocupacional/genética , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Genotipo , Glutatión Transferasa/genética , Humanos , Polimorfismo Genético , Factores de RiesgoRESUMEN
BACKGROUND: Work exposures play a significant role in adult-onset asthma, but the mechanisms of work-related asthma are not fully elucidated. OBJECTIVE: We aimed to reveal the molecular mechanisms of work-related asthma associated with exposure to flour (flour asthma), isocyanate (isocyanate asthma), or welding fumes (welding asthma) and identify potential biomarkers that distinguish these groups from each other. METHODS: We used a combination of clinical tests, transcriptomic analysis, and associated pathway analyses to investigate the underlying disease mechanisms of the blood immune cells and the airway epithelium of 61 men. RESULTS: Compared with the healthy controls, the welding asthma patients had more differentially expressed genes than the flour asthma and isocyanate asthma patients, both in the airway epithelia and in the blood immune cells. In the airway epithelia, active inflammation was detected only in welding asthma patients. In contrast, many differentially expressed genes were detected in blood cells in all 3 asthma groups. Disease-related immune functions in blood cells, including leukocyte migration and inflammatory responses, and decreased expression of upstream cytokines such as TNF and IFN-γ were suppressed in all the asthma groups. In transcriptome-phenotype correlations, hyperresponsiveness (R ⼠|0.6|) had the highest clinical relevance and was associated with a set of exposure group-specific genes. Finally, biomarker subsets of only 5 genes specifically distinguished each of the asthma exposure groups. CONCLUSIONS: This study provides novel data on the molecular mechanisms underlying work-related asthma. We identified a set of 5 promising biomarkers in asthma related to flour, isocyanate, and welding fume exposure to be tested and clinically validated in future studies.
Asunto(s)
Contaminantes Ocupacionales del Aire/efectos adversos , Asma Ocupacional/genética , Harina/efectos adversos , Exposición por Inhalación/efectos adversos , Isocianatos/efectos adversos , Exposición Profesional/efectos adversos , Soldadura , Adulto , Asma Ocupacional/sangre , Asma Ocupacional/inmunología , Asma Ocupacional/fisiopatología , Biomarcadores , Biopsia , Movimiento Celular , Citocinas/sangre , Perfilación de la Expresión Génica , Humanos , Inmunoglobulina E/sangre , Leucocitos/inmunología , Masculino , Persona de Mediana Edad , Mucosa Nasal/patología , Óxido Nítrico/metabolismo , Pruebas de Función RespiratoriaRESUMEN
BACKGROUND: Isocyanates are major causes of occupational asthma, but susceptibility and mechanisms of diisocyanate-induced asthma (DA) remain uncertain. OBJECTIVE: The aim of this study was to identify DA-associated functional genetic variants through next-generation sequencing (NGS), bioinformatics, and functional assays. METHODS: NGS was performed in 91 workers with DA. Fourteen loci with known DA-associated single nucleotide polymorphisms (SNPs) were sequenced and compared with data from 238 unexposed subjects. Ranking of DA-associated SNPs based on their likelihood to affect gene regulatory mechanisms in the lung yielded 21 prioritized SNPs. Risk and nonrisk oligonucleotides were tested for binding of nuclear extracts from A549, BEAS-2B, and IMR-90 lung cell lines by using electrophoretic mobility shift assays. DNA constructs were cloned into a pGL3 promoter vector for luciferase gene reporter assays. RESULTS: NGS detected 130 risk variants associated with DA (3.1 × 10-6 to 6.21 × 10-4), 129 of which were located in noncoding regions. The 21 SNPs prioritized by using functional genomic data sets were in or proximal to 5 genes: cadherin 17 (CDH17; n = 10), activating transcription factor 3 (ATF3; n = 7), family with sequence similarity, member A (FAM71A; n = 2), tachykinin receptor 1 (TACR1; n = 1), and zinc finger and BTB domain-containing protein 16 (ZBTB16; n = 1). Electrophoretic mobility shift assays detected allele-dependent nuclear protein binding in A549 cells for 8 of 21 variants. In the luciferase assay 4 of the 21 SNPs exhibited allele-dependent changes in gene expression. DNA affinity precipitation and mass spectroscopy of rs147978008 revealed allele-dependent binding of H1 histones, which was confirmed by using Western blotting. CONCLUSIONS: We identified 5 DA-associated potential regulatory SNPs. Four variants exhibited effects on gene regulation (ATF rs11571537, CDH17 rs2446824 and rs2513789, and TACR1 rs2287231). A fifth variant (FAM71A rs147978008) showed nonrisk allele preferential binding to H1 histones. These results demonstrate that many DA-associated genetic variants likely act by modulating gene regulation.
Asunto(s)
Contaminantes Ocupacionales del Aire/toxicidad , Asma Ocupacional/inducido químicamente , Asma Ocupacional/genética , Isocianatos/toxicidad , Factor de Transcripción Activador 3/genética , Adulto , Cadherinas/genética , Proteínas Portadoras/genética , Línea Celular , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Receptores de Neuroquinina-1/genética , Adulto JovenAsunto(s)
Alérgenos/administración & dosificación , Asma Ocupacional/terapia , Medicina de Precisión/métodos , Alérgenos/inmunología , Asma Ocupacional/diagnóstico , Asma Ocupacional/economía , Asma Ocupacional/genética , Pruebas de Provocación Bronquial/métodos , Epigénesis Genética , Humanos , Pruebas Inmunológicas/métodos , Prioridad del Paciente , Selección de Paciente , Índice de Severidad de la Enfermedad , Factores Socioeconómicos , Resultado del Tratamiento , Indemnización para TrabajadoresRESUMEN
BACKGROUND: PAI-1 gain-of-function variants promote airway fibrosis and are associated with asthma and with worse lung function in subjects with asthma. OBJECTIVE: We sought to determine whether the association of a gain-of-function polymorphism in plasminogen activator inhibitor-1 (PAI-1) with airway obstruction is modified by asthma status, and whether any genotype effect persists after accounting for common exposures that increase PAI-1 level. METHODS: We studied 2070 Latino children (8-21y) with genotypic and pulmonary function data from the GALA II cohort. We estimated the relationship of the PAI-1 risk allele with FEV1/FVC by multivariate linear regression, stratified by asthma status. We examined the association of the polymorphism with asthma and airway obstruction within asthmatics via multivariate logistic regression. We replicated associations in the SAPPHIRE cohort of African Americans (n=1056). Secondary analysis included the effect of the at-risk polymorphism on postbronchodilator lung function. RESULTS: There was an interaction between asthma status and the PAI-1 polymorphism on FEV1 /FVC (P=.03). The gain-of-function variants, genotypes (AA/AG), were associated with lower FEV1 /FVC in subjects with asthma (ß=-1.25, CI: -2.14,-0.35, P=.006), but not in controls. Subjects with asthma and the AA/AG genotypes had a 5% decrease in FEV1 /FVC (P<.001). In asthmatics, the risk genotype (AA/AG) was associated with a 39% increase in risk of clinically relevant airway obstruction (OR=1.39, CI: 1.01, 1.92, P=.04). These associations persisted after exclusion of factors that increase PAI-1 including tobacco exposure and obesity. CONCLUSIONS AND CLINICAL RELEVANCE: The decrease in the FEV1 /FVC ratio associated with the risk genotype was modified by asthma status. The genotype increased the odds of airway obstruction by 75% within asthmatics only. As exposures known to increase PAI-1 levels did not mitigate this association, PAI-1 may contribute to airway obstruction in the context of chronic asthmatic airway inflammation.
Asunto(s)
Obstrucción de las Vías Aéreas/genética , Obstrucción de las Vías Aéreas/metabolismo , Mutación con Ganancia de Función , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , Adolescente , Adulto , Obstrucción de las Vías Aéreas/epidemiología , Obstrucción de las Vías Aéreas/fisiopatología , Alelos , Asma Ocupacional/epidemiología , Asma Ocupacional/genética , Asma Ocupacional/metabolismo , Asma Ocupacional/fisiopatología , Niño , Estudios de Cohortes , Etnicidad , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Pruebas de Función Respiratoria , Adulto JovenRESUMEN
Respiratory tract sensitization can have significant acute and chronic health implications. While induction of respiratory sensitization is widely recognized for some chemicals, validated standard methods or frameworks for identifying and characterizing the hazard are not available. A workshop on assessment of respiratory sensitization was held to discuss the current state of science for identification and characterization of respiratory sensitizer hazard, identify information facilitating development of validated standard methods and frameworks, and consider the regulatory and practical risk management needs. Participants agreed on a predominant Th2 immunological mechanism and several steps in respiratory sensitization. Some overlapping cellular events in respiratory and skin sensitization are well understood, but full mechanism(s) remain unavailable. Progress on non-animal approaches to skin sensitization testing, ranging from in vitro systems, -omics, in silico profiling, and structural profiling were acknowledged. Addressing both induction and elicitation phases remains challenging. Participants identified lack of a unifying dose metric as increasing the difficulty of interpreting dosimetry across exposures. A number of research needs were identified, including an agreed list of respiratory sensitizers and other asthmagens, distinguishing between adverse effects from immune-mediated versus non-immunological mechanisms. A number of themes emerged from the discussion regarding future testing strategies, particularly the need for a tiered framework respiratory sensitizer assessment. These workshop present a basis for moving towards a weight-of-evidence assessment.
Asunto(s)
Exposición por Inhalación/efectos adversos , Hipersensibilidad Respiratoria/inducido químicamente , Sistema Respiratorio/efectos de los fármacos , Pruebas de Toxicidad/métodos , Alternativas a las Pruebas en Animales , Animales , Asma Ocupacional/inducido químicamente , Asma Ocupacional/genética , Asma Ocupacional/inmunología , Asma Ocupacional/fisiopatología , Dermatitis Alérgica por Contacto/etiología , Humanos , Hipersensibilidad Respiratoria/genética , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/fisiopatología , Sistema Respiratorio/inmunología , Sistema Respiratorio/fisiopatología , Medición de Riesgo , Células Th2/efectos de los fármacos , Células Th2/inmunología , ToxicogenéticaRESUMEN
OBJECTIVE: The aim of this study is to evaluate inflammatory markers and pro-inflammatory CD14 and Toll-like Receptor 4 (TLR4) polymorphisms in workers exposed to flour dust. METHODS: Polymorphisms in TLR4 and CD14 were identified in our study population of 167 workers that included 63 healthy subjects (HS), 45 atopic subjects (A), and 59 subjects diagnosed clinically with occupational asthma/rhinitis (OAR). Endpoint measures in this study included fractional exhaled nitric oxide and serum concentrations of interleukin IL-6, IL-8, and tumor necrosis factor-alpha (TNF-α). RESULTS: We identified a polymorphism in CD14 (rs2569190) that may be differentially expressed (Pâ=â0.06). IL-6 concentrations in the serum were significantly higher in the A and OAR groups (Pâ<â0.01) than in subjects in the HS group, while IL-8 concentrations were significantly elevated only in the OAR group (Pâ<â0.01). Interestingly, TNF-α concentrations in the OAR group were significantly reduced when compared with subjects in the HS group (Pâ<â0.01). CONCLUSION: Cytokines are likely a defensive response in atopic and healthy workers. A protective genotype is hypothesized for occupational asthma.
Asunto(s)
Asma Ocupacional/genética , Polvo , Harina/efectos adversos , Receptores de Lipopolisacáridos/genética , Polimorfismo Genético , Receptor Toll-Like 4/genética , Adulto , Asma Ocupacional/sangre , Estudios de Casos y Controles , Femenino , Humanos , Hipersensibilidad/sangre , Interleucina-6/sangre , Interleucina-8/sangre , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/sangreRESUMEN
BACKGROUND: A high prevalence of contact dermatitis (CD) and respiratory symptoms has been observed in the construction industry, probably due to widespread exposure to irritants and allergens. It is unknown whether carriers of loss-of-function mutations in the gene encoding filaggrin (FLG), a known risk gene for eczema and asthma, are at increased risk. OBJECTIVES: To investigate associations of FLG mutations with CD and respiratory symptoms in Dutch construction workers. METHODS: A questionnaire including items on dermal and respiratory symptoms such as wheeze, shortness of breath and asthma was administered to construction workers. Total and specific serum IgE was analysed by enzyme immunoassays. Four FLG loss-of-function mutations were genotyped. CD was diagnosed by a team of a dermatologist and a clinical occupational medicine specialist using photographs of the subjects' hands and self-reported questionnaire data. RESULTS: Of the 506 participating workers, 6·3% carried at least one FLG mutation. Mild CD was diagnosed by the specialists in 34·0%, and severe CD in an additional 24·3%. CD was considered work related in 282 of 295 subjects (95·6%). Carriers of FLG variants had an increased risk of CD compared with subjects carrying wild-type alleles [mild CD: odds ratio (OR) 5·71, 95% confidence interval (CI) 1·63-20·06; severe CD: OR 8·26, 95% CI 2·32-29·39]. FLG variants and the presence of CD were not associated with respiratory symptoms and atopy. CONCLUSIONS: Contact dermatitis prevalence in construction workers is high. FLG loss-of-function mutations increase the risk of CD even further. FLG mutations were not associated with respiratory symptoms or atopy.
Asunto(s)
Industria de la Construcción , Dermatitis Profesional/genética , Proteínas de Filamentos Intermediarios/genética , Mutación/genética , Adulto , Alérgenos/efectos adversos , Asma Ocupacional/epidemiología , Asma Ocupacional/genética , Dermatitis Irritante/epidemiología , Dermatitis Irritante/genética , Dermatitis Profesional/epidemiología , Femenino , Proteínas Filagrina , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Hipersensibilidad/epidemiología , Hipersensibilidad/genética , Masculino , Países Bajos/epidemiología , Ruidos Respiratorios/genética , Factores de Riesgo , Autoinforme , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To investigate whether genetic variants of N-acetyltransferase (NAT) genes are associated with diisocyanate asthma (DA). METHODS: The study population consisted of 354 diisocyanate-exposed workers. Genotyping was performed using a 5'-nuclease polymerase chain reaction assay. RESULTS: The NAT2 rs2410556 and NAT2 rs4271002 variants were significantly associated with DA in the univariate analysis. In the first logistic regression model comparing DA+ and asymptomatic worker groups, the rs2410556 (Pâ=â0.004) and rs4271002 (Pâ<â0.001) single nucleotide polymorphisms and the genotype combination, NAT2 rs4271002*NAT1 rs11777998, showed associations with DA risk (Pâ=â0.014). In the second model comparing DA+ and DA- groups, NAT2 rs4271002 variant and the combined genotype, NAT1 rs8190845*NAT2 rs13277605, were significantly associated with DA risk (Pâ=â0.022, Pâ=â0.036, respectively). CONCLUSIONS: These findings suggest that variations in the NAT2 gene and their interactions contribute to DA susceptibility.
Asunto(s)
Arilamina N-Acetiltransferasa/genética , Asma Ocupacional/inducido químicamente , Contaminantes Ambientales/toxicidad , Predisposición Genética a la Enfermedad , Genotipo , Isocianatos/toxicidad , Polimorfismo de Nucleótido Simple , Adulto , Asma Ocupacional/genética , Canadá , Femenino , Marcadores Genéticos , Técnicas de Genotipaje , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , EspañaRESUMEN
Occupational asthma (OA) is a complex disease that is often hard to diagnose due to difficulties in detecting relevant exposure, along with inherent differences in disease susceptibility. Numerous studies have attempted to identify relevant biological and genetic markers for OA and to devise tools capable of detecting exposure to the causative agent. Immunological markers, including skin prick test reactivity and specific IgE and IgG antibodies can be used to detect high-molecular-weight allergens in cases of baker's asthma. For OA induced by low-molecular-weight agents, such as isocyanate, potential biomarkers include serum-specific IgE and IgG antibodies to isocyanate-HSA conjugate and IgG to cytokeratin 19 and transglutaminase-2. For protein-based markers, ferritin/transferrin and vitamin D-binding protein levels have been suggested for isocyanate-OA. Genetic markers of susceptibility to isocyanate-OA include human leukocyte antigen and CTNNA3. Further investigations will be needed to identify better biomarkers for OA, which may be used to inform clinical decision.
Asunto(s)
Asma Ocupacional/inmunología , Marcadores Genéticos , Alérgenos/inmunología , Animales , Asma Ocupacional/genética , Biomarcadores , Humanos , Inmunoglobulina E/inmunología , Polimorfismo GenéticoRESUMEN
BACKGROUND: S100A8 and S100A9 can be produced by lipopolysaccharide-stimulated granulocytes and provoke an innate immune-mediated airway inflammation. Involvement of S100A8 and S100A9 has been implicated in asthma. To further understand the role of S100A8 and S100A9 during innate immune responses in baker's asthma, we investigated the associations of serum S100A8 and S100A9 with exposure to bakery allergens and polymorphisms of the Toll-like receptor 4 (TLR4) gene. METHODS: Totally, 381 bakery workers and 100 unexposed healthy controls were recruited. Skin prick tests for bakery allergens were performed. Serum levels of S100A8, S100A9, myeloperoxidase (MPO), tumor necrosis factor (TNF)-α, and interleukin (IL)-8 were measured using ELISA. Predictive values of serum S100A8 and S100A9 in bakery workers were evaluated by receiver-operating characteristic (ROC) curves. Polymorphisms of TLR4 -2027Ax2192;G and -1608Tx2192;C were genotyped. RESULTS: Higher serum levels of S100A8 and S100A9 were noted in bakery workers compared to the normal controls (p < 0.001); however, no significant differences were noted according to work-related symptoms. The area under the ROC curve of serum S100A8 was 0.886 for occupational exposure (p < 0.001). The TLR4 -1608CC genotype was significantly associated with a higher serum S100A8 level (p = 0.025). Serum S100A8 and S100A9 levels were correlated with serum levels of MPO (r = 0.396 and 0.189, respectively), TNF-α (r = 0.536 and 0.280, respectively), and IL-8 (r = 0.540 and 0.205, respectively; p < 0.001 for all). CONCLUSION: S100A8 and S100A9 are involved in innate immune responses under the regulation of TLR4 polymorphisms in baker's asthma pathogenesis. Serum S100A8 could be a potential biomarker for predicting occupational exposure to wheat flour in bakery workers.
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Asma Ocupacional/sangre , Calgranulina A/sangre , Calgranulina B/sangre , Adulto , Alérgenos , Asma Ocupacional/genética , Asma Ocupacional/inmunología , Calgranulina A/inmunología , Calgranulina B/inmunología , Femenino , Harina , Humanos , Inmunidad Innata , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Interleucina-8/sangre , Masculino , Peroxidasa/sangre , Polimorfismo de Nucleótido Simple , República de Corea , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Triticum/inmunología , Factor de Necrosis Tumoral alfa/sangre , Adulto JovenRESUMEN
Asthma is a complex chronic inflammatory disease of the airways caused by the interaction of genetic susceptibility with environmental influences. Genome-wide association studies (GWAS) represent the most powerful approach for asthma, that have identified several genes (e.g., IL18R1, IL33, SMAD3, ORMDL3, HLA-DQ and IL2RB loci). HLA super-locus is a genomic region in the chromosomal position 6p21. Since no gene can be considered as an asthma gene, able to reflect the complex etiology and the heterogeneity of the disease the terms 'phenotype' and more recently 'endotype' have been used. This review, according to literature availability, focuses on the relationship between human leukocyte antigens (HLA) region specifically the HLA class II genes and different asthma phenotypes/endotypes, such as allergic asthma/Th2 associated, occupational and aspirin-sensitive asthma. The most common HLA haplotypes in the different asthma phenotypes are HLA-DRB1in allergic asthma, HLA-DQB1in occupational asthma and HLA-DPB1 in aspirin-sensitive asthma. However, it is difficult to study the role of class II genes in vivo because of the heterogeneity of human population, the complexity of MHC, and the strong linkage disequilibrium among different class II genes. Despite the variation and the inconsistency of the HLA haplotypes and alleles in different types of asthma, the association between HLA class II genes and asthma has been demonstrated in the majority of studies.
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Asma Inducida por Aspirina/genética , Asma Ocupacional/genética , Regulación de la Expresión Génica/inmunología , Antígenos de Histocompatibilidad Clase II/genética , Fenotipo , Asma Inducida por Aspirina/inmunología , Asma Inducida por Aspirina/fisiopatología , Asma Ocupacional/inmunología , Asma Ocupacional/fisiopatología , Cromosomas Humanos Par 6 , Heterogeneidad Genética , Sitios Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Haplotipos , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Desequilibrio de LigamientoRESUMEN
Allergic disease is an important occupational health concern, with work-related asthma and allergic contact dermatitis being the most frequently diagnosed occupational illnesses. Diisocyanates, particularly toluene 2,4-diisocyanate (TDI), have been the leading cause of occupational asthma for many years. Understanding the mechanisms behind allergic disease is critical for treatment and prevention. Recently, the study of post-transcriptional regulation by microRNAs (miRNA) has shed light on mechanisms of allergic disease. The present studies report the expression of miRNA during the sensitization phase of an allergic response to TDI in a murine model. Female BALB/c mice were dermally exposed to TDI (0.1-15% [v/v]) or vehicle. RNA was isolated from superficial parotid lymph nodes at timepoints between 1 h and 15 days post-exposure and then miRNA expression was analyzed using array and real-time quantitative PCR analysis. Consistent changes in miRNA expression were identified for miR-21, miR-22, miR-27b, miR-31, miR-126, miR-155, miR-210, and miR-301a. Following TDI exposure, peak expression was observed by Day 4 for the majority of miRNA evaluated with trends in expression correlated to exposure concentration. Confirmed and predicted targets were identified using Diana-microT, miRanda, miRwalk, and Targetscan algorithms. Evaluation of mRNA expression of cytokine and transcription factor targets suggests that miRNA may have a central role early in TDI sensitization. Understanding the role of these miRNA and their specific mechanism of action in sensitization to TDI may provide pertinent information for the identification of other chemical sensitizers while also contributing to the treatment and prevention of allergic disease.
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Asma Ocupacional/genética , Irritantes/administración & dosificación , Ganglios Linfáticos/efectos de los fármacos , MicroARNs/análisis , 2,4-Diisocianato de Tolueno/administración & dosificación , Administración Cutánea , Animales , Asma Ocupacional/inducido químicamente , Asma Ocupacional/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Ganglios Linfáticos/fisiología , Ratones , Ratones Endogámicos BALB C , Análisis por Micromatrices , Factores de Transcripción/metabolismoRESUMEN
Occupational asthma (OA) is a difficult diagnosis to make. The present review describes the work environments in which workers are at risk for developing OA, the characteristics of the individuals in whom OA should be suspected and the investigation that can be performed to diagnose the condition. Accurately diagnosing OA is crucial because of the major social and economic consequences of this diagnosis on the patient.
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Asma Ocupacional/diagnóstico , Asma Ocupacional/etiología , Asma Ocupacional/genética , Predisposición Genética a la Enfermedad , Humanos , Factores de Riesgo , Lugar de TrabajoRESUMEN
OBJECTIVES: To characterise occupational wheat allergic phenotypes (rhino-conjunctivitis, asthma and dermatitis) and immunoglobulin (IgE) sensitisation to particular wheat allergens in bakers. METHODS: We conducted clinical and immunological evaluations of 81 consecutive bakers reporting occupational symptoms using commercial tests (skin prick test (SPT), specific IgE, ISAC microarray) and six additional dot-blotted wheat allergens (Tri a 39, Tri a Trx, Tri a GST, Tri a 32, Tri a 12, Tri a DH). RESULTS: Wheat SPT resulted positive in 29 bakers and was associated with work-related asthma (p<0.01). Wheat IgE was detected in 51 workers and was associated with work-related asthma (p<0.01) and rhino-conjunctivitis (p<0.05). ISAC Tri a 30 was positive in three workers and was associated with work-related dermatitis (p<0.05). Wheat dot-blotted allergens were positive in 22 bakers. Tri a 32 and Tri a GST were positive in 13 and three bakers, respectively, and both were associated with work-related dermatitis (p<0.05). This association increased (p<0.01) when Tri a 32, Tri a GST and Tri a 30 were analysed together (p<0.01). Wheat IgE levels were associated with work-related dermatitis (p<0.01). CONCLUSIONS: Wheat IgE levels and wheat microarrayed allergens may be associated with some occupational allergic phenotypes. The extension of the panel of wheat allergens may be promising for discriminating the clinical manifestations of baker's allergy.
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Inmunización , Inmunoglobulina E/genética , Exposición Profesional/efectos adversos , Hipersensibilidad al Trigo/genética , Hipersensibilidad al Trigo/inmunología , Adulto , Alérgenos , Asma Ocupacional/genética , Asma Ocupacional/inmunología , Conjuntivitis/genética , Conjuntivitis/inmunología , Estudios Transversales , Dermatitis Alérgica por Contacto/genética , Dermatitis Alérgica por Contacto/inmunología , Femenino , Industria de Alimentos , Perfilación de la Expresión Génica , Humanos , Inmunoglobulina E/inmunología , Italia , Masculino , Persona de Mediana Edad , Fenotipo , Rinitis/genética , Rinitis/inmunología , Medición de Riesgo , Sensibilidad y Especificidad , Pruebas Cutáneas/métodos , Adulto JovenRESUMEN
BACKGROUND: The influence of genetic predictors of inflammation and atopy on occupational asthma in apprentices is not known. OBJECTIVES: To assess the influence of genetic polymorphisms of IL4RA, IL13, TNFA, IL1A, and IL5 on the decline of lung function and bronchial hyperresponsiveness in a prospective follow-up study of baker/pastry maker and hairdresser apprentices. METHODS: A total of 351 apprentices were included in the study. We performed skin testing, spirometry, fractional exhaled nitric oxide measurement, and methacholine hyperreactivity testing at the initial visit and during and at the end of the 18-month training period. Gene variants of IL4RA, IL13, TNFA, IL1A, and IL5 were determined in DNA from nasal lavage. RESULTS: IL13 R130Q/IL4RA S478P or IL13 R130Q//IL4RA Q551R were significant predictors of the decrease of forced expiratory volume and forced vital capacity (P ≤ .006). Genotype GG of TNFAG308A was associated with bronchial hyperresponsiveness in the whole population and in nonatopic individuals (90.63% vs 9.38%; odds ratio, 3.78; 95% confidence interval, 1.10-12.83). TNFA GA and IL5 CC and TNFA GA and IL1A CC were 2 epistatic predictors of exhaled nitrogen monoxide decrease during follow-up (P = .02 and P = .004, respectively). The association with TNFA GA and IL1A CC was the most significant in nonatopic bakers (P < .001). CONCLUSION: We evidenced a predicting influence of IL13/IL4RA and TNFA in the early exposure to allergens and irritants that precedes occupational asthma. The significance of the associations in the absence of atopy suggests an influence of the genetics predictors related to inflammatory pathways.
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Asma Ocupacional/genética , Inflamación/genética , Adolescente , Obstrucción de las Vías Aéreas/genética , Obstrucción de las Vías Aéreas/fisiopatología , Asma Ocupacional/diagnóstico , Asma Ocupacional/epidemiología , Hiperreactividad Bronquial/genética , Hiperreactividad Bronquial/fisiopatología , Espiración , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Incidencia , Interleucina-13/genética , Masculino , Óxido Nítrico/análisis , Exposición Profesional , Polimorfismo Genético , Estudios Prospectivos , Receptores de Interleucina-4/genética , Riesgo , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Evaluation of genes polymorphic system of xenobiotics biotransformation in patients with occupational allergodermatoses showed significantly higher percentage of incidence of polymorphic variants of genes CYP 1A1 *2C and EPHX1 AND-415G compared with population control. A combination of 3 or more adverse hetero--and homozygous gene alleles CYP 1A1, CYP3A4, EPHX1 and deletions of genes GSTM1 and GSTT1, is characterized by earlier (with the experience of work in harmful conditions up to 5 years) development, severe and unfavorable prognosis of occupational pathology of the skin.
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Biotransformación/genética , Dermatitis Profesional , Polimorfismo Genético , Xenobióticos , Adulto , Asma Ocupacional/inducido químicamente , Asma Ocupacional/genética , Comorbilidad , Dermatitis Alérgica por Contacto/genética , Dermatitis Profesional/etiología , Dermatitis Profesional/genética , Eccema/inducido químicamente , Eccema/genética , Femenino , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Pronóstico , Factores de Tiempo , Xenobióticos/efectos adversos , Xenobióticos/farmacocinéticaRESUMEN
Allergic sensitization results from a complex interaction between genetic and environmental factors. Earlier studies have shown that highly polymorphic HLA genes are associated with a variety of allergies. Several important respiratory allergens belong to the family of lipocalin proteins. These include occupational sensitizers, such as cow Bos d 2 or rat Rat n 1, and prevalent indoor sensitizers, such as dog Can f 1 or cockroach Bla g 4. HLA associations with sensitization to lipocalin allergens are incompletely known. In the present study we have investigated an association between HLA alleles and sensitization to the major cow allergen Bos d 2. The HLA-DR/DQ genotypes of 40 Bos d 2-sensitized subjects having occupational asthma were determined by polymerase chain reaction (PCR) and the results were compared with the genotypes of 151 unrelated Finnish subjects. The frequencies of HLA class II alleles DRB1*0101, DRB1*0404, DQB1*0302, and DQB1*0501 were significantly higher among Bos d 2-sensitized than among control subjects. In addition, the allergic subjects expressed significantly lower frequencies of HLA-DRB1*0301 and DQB1*0201 alleles than did the control subjects. These data suggest that the HLA class II alleles DRB1*0101, DRB1*0404, DQB1*0302, and DQB1*0501, and the haplotypes that include them, are associated with sensitization to the major cow allergen Bos d 2, whereas HLA-DRB1*0301 and DQB1*0201 are dissociated with it. Amino acid analysis provides a biologically plausible explanation for the HLA associations.
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Antígenos de Plantas/inmunología , Asma Ocupacional/inmunología , Frecuencia de los Genes/inmunología , Cadenas beta de HLA-DQ/inmunología , Cadenas beta de HLA-DR/inmunología , Hipersensibilidad/inmunología , Adulto , Alelos , Alérgenos , Animales , Antígenos de Plantas/genética , Antígenos de Plantas/metabolismo , Asma Ocupacional/genética , Asma Ocupacional/metabolismo , Sitios de Unión , Estudios de Casos y Controles , Bovinos , Femenino , Genotipo , Cadenas beta de HLA-DQ/genética , Cadenas beta de HLA-DQ/metabolismo , Cadenas beta de HLA-DR/genética , Cadenas beta de HLA-DR/metabolismo , Haplotipos , Humanos , Hipersensibilidad/genética , Hipersensibilidad/metabolismo , Lipocalinas/genética , Lipocalinas/inmunología , Lipocalinas/metabolismo , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Unión ProteicaRESUMEN
Occupational asthma (OA) is one of the most common forms of work-related lung disease in all industrialized nations. The clinical management of patients with OA depends on an understanding of the multifactorial pathogenetic mechanisms that can contribute to this disease. This article discusses the various immunologic and nonimmunologic mechanisms and genetic susceptibility factors that drive the inflammatory processes of OA.