RESUMO
Asthma can be controlled well in most patients by inhaled ß-adrenoreceptor (ß2 AR) agonists and steroids. Poor response to ß2 AR agonists is difficult to predict, especially in young children and by lung function testing, which may be affected by multiple influences. As an alternative approach, we analyzed ex vivo neutrophilic superoxide inhibition in response to ß2 AR stimulation. In 60 healthy volunteers, this assay was unaffected by sex, age, smoking, atopy or asthma status. Furthermore, we assessed effects of genetic variants in ß2 AR by sequencing the ADRB2 gene in our cohort and relating genotypes to ß2 AR-mediated neutrophilic superoxide inhibition. Gly16Arg genotypes correlated with minor decrease in overall adrenoresponse in this small study population. Taken together, ex vivo testing of the ß2 AR response in human neutrophils represents a robust tool with good signal-to-noise ratio at physiological ß2 AR agonist concentrations, and this assay may be useful to complement future pharmacogenetic studies in asthma.
Assuntos
Agonistas Adrenérgicos beta/uso terapêutico , Neutrófilos/metabolismo , Variantes Farmacogenômicos , Superóxidos/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Alelos , Asma/tratamento farmacológico , Asma/genética , Asma/imunologia , Biomarcadores , Feminino , Genótipo , Humanos , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Polimorfismo de Nucleotídeo Único , Espécies Reativas de Oxigênio/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: Genomewide association studies (GWASs) of asthma have identified single-nucleotide polymorphisms (SNPs) that modestly increase the risk for asthma. This could be due to phenotypic heterogeneity of asthma. Bronchial hyperresponsiveness (BHR) is a phenotypic hallmark of asthma. We aim to identify susceptibility genes for asthma combined with BHR and analyse the presence of cis-eQTLs among replicated SNPs. Secondly, we compare the genetic association of SNPs previously associated with (doctor's diagnosed) asthma to our GWAS of asthma with BHR. METHODS: A GWAS was performed in 920 asthmatics with BHR and 980 controls. Top SNPs of our GWAS were analysed in four replication cohorts, and lung cis-eQTL analysis was performed on replicated SNPs. We investigated association of SNPs previously associated with asthma in our data. RESULTS: A total of 368 SNPs were followed up for replication. Six SNPs in genes encoding ABI3BP, NAF1, MICA and the 17q21 locus replicated in one or more cohorts, with one locus (17q21) achieving genomewide significance after meta-analysis. Five of 6 replicated SNPs regulated 35 gene transcripts in whole lung. Eight of 20 asthma-associated SNPs from previous GWAS were significantly associated with asthma and BHR. Three SNPs, in IL-33 and GSDMB, showed larger effect sizes in our data compared to published literature. CONCLUSIONS: Combining GWAS with subsequent lung eQTL analysis revealed disease-associated SNPs regulating lung mRNA expression levels of potential new asthma genes. Adding BHR to the asthma definition does not lead to an overall larger genetic effect size than analysing (doctor's diagnosed) asthma.
Assuntos
Asma/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Pulmão/metabolismo , Locos de Características Quantitativas , Alelos , Asma/epidemiologia , Estudos de Casos e Controles , Mapeamento Cromossômico , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Pulmão/imunologia , Masculino , Metanálise como Assunto , Países Baixos/epidemiologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Vigilância da PopulaçãoRESUMO
BACKGROUND: Genomewide association studies identified ORMDL3 as a plausible asthma candidate gene. ORMDL proteins regulate sphingolipid metabolism and ceramide homeostasis and participate in lymphocyte activation and eosinophil recruitment. Strong sequence homology between the three ORMDL genes and ORMDL protein conservation among different species suggest that they may have shared functions. We hypothesized that if single nucleotide polymorphisms (SNPs) in ORMDL3 alter its gene expression and play a role in asthma, variants in ORMDL1 and ORMDL2 might also be associated with asthma. METHODS: Asthma associations of 44 genotyped SNPs were determined in at least 1303 subjects (651 asthmatics). ORMDL expression was evaluated in peripheral blood mononuclear cells (PBMC) from 55 subjects (eight asthmatics) before and after allergen stimulation, and in blood (n = 60, 5 asthmatics). Allele-specific cis-effects on ORMDL expression were assessed. Interactions between human ORMDL proteins were determined in living cells. RESULTS: Sixteen SNPs in all three ORMDLs were associated with asthma (14 in ORMDL3). Baseline expression of ORMDL1 (P = 1.7 × 10(-6) ) and ORMDL2 (P = 4.9 × 10(-5) ) was significantly higher in PBMC from asthmatics, while induction of ORMDLs upon stimulation was stronger in nonasthmatics. Disease-associated alleles (rs8079416, rs4795405, rs3902920) alter ORMDL3 expression. ORMDL proteins formed homo- and heterooligomers and displayed similar patterns of interaction with SERCA2 and SPT1. CONCLUSIONS: Polymorphisms in ORMDL genes are associated with asthma. Asthmatics exhibit increased ORMDL levels, suggesting that ORMDLs contribute to asthma. Formation of heterooligomers and similar interaction patterns with proteins involved in calcium homeostasis and sphingolipid metabolism could indicate shared biological roles of ORMDLs, influencing airway remodeling and hyperresponsiveness.
Assuntos
Asma/genética , Regulação da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas de Membrana/genética , Mutação , Fatores Etários , Alelos , Asma/imunologia , Asma/metabolismo , Estudos de Casos e Controles , Mapeamento Cromossômico , Epistasia Genética , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Proteínas de Membrana/metabolismo , Família Multigênica , Razão de Chances , Polimorfismo de Nucleotídeo Único , Ligação ProteicaRESUMO
Recent studies indicate that urbanization is having a pronounced effect on disease patterns in developing countries. To understand the immunological basis of this, we examined mRNA expression in whole blood of genes involved in immune activation and regulation in 151 children aged 5-13 years attending rural, urban low socioeconomic status (SES) and urban high-SES schools in Ghana. Samples were also collected to detect helminth and malaria infections. Marked differences in gene expression were observed between the rural and urban areas as well as within the urban area. The expression of both interleukin (IL)-10 and programmed cell death protein 1 increased significantly across the schools from urban high SES to urban low SES to rural (P-trend <0.001). Although IL-10 gene expression was significantly elevated in the rural compared with the urban schools (P<0.001), this was not associated with parasitic infection. Significant differences in the expression of toll-like receptors (TLRs) and their signaling genes were seen between the two urban schools. Genetic differences could not fully account for the gene expression profiles in the different groups as shown by analysis of IL-10, TLR-2 and TLR-4 gene polymorphisms. Immune gene expression patterns are strongly influenced by environmental determinants and may underlie the effects of urbanization seen on health outcomes.
Assuntos
Perfilação da Expressão Gênica , Interleucina-10/genética , Receptor de Morte Celular Programada 1/genética , RNA Mensageiro/genética , População Rural , Receptores Toll-Like/genética , População Urbana , Adolescente , Criança , Feminino , Gana , Helmintíase/epidemiologia , Helmintíase/genética , Humanos , Interleucina-10/metabolismo , Malária/epidemiologia , Malária/genética , Masculino , Polimorfismo Genético , Pobreza , Receptor de Morte Celular Programada 1/metabolismo , RNA Mensageiro/metabolismo , Receptores Toll-Like/metabolismoRESUMO
BACKGROUND: Genomewide association and epigenetic studies found a region within the RAD50 gene on chromosome 5q31 to be associated with total serum IgE levels and asthma. In mice, this region harbors a locus control region for nearby TH 2 cytokines, which is characterized by four Rad50 DNase I hypersensitive sites (RHS4-7). Among these, RHS7 seems to have the strongest impact on TH 2 differentiation. We investigated whether within the human homolog of RHS7, functional polymorphisms exist, which could affect DNA methylation or gene expression in the 5q31 locus and might have an influence on asthma status or IgE regulation. METHODS: The human RHS7 region was fine mapped using 1000 genomes database information. In silico analysis and electrophoretic mobility shift assays were used to assess SNP function. Allele-specific effects on DNA methylation were evaluated in cord blood (n = 73) and at age of 4.5 years (n = 61) by pyrosequencing. Allele-specific effects on RAD50, IL4, and IL13 expression were analyzed in 100 subjects. Associations with asthma and IgE levels were investigated in the MAGICS/ISAAC II population (n = 1145). RESULTS: Polymorphism rs2240032 in the RHS7 region is suggestive of allele-specific transcription factor binding, affects methylation of the IL13 promoter region and influences RAD50 and IL4 expression (lowest P = 0.0027). It is also associated with total serum IgE levels (P = 0.0227). CONCLUSION: A functional relevant polymorphism in the TH 2 locus control region, equivalent to RHS7 in mice, affects DNA methylation and gene expression within 5q31 and influences total serum IgE on the population level.
Assuntos
Asma/genética , Metilação de DNA , Regulação da Expressão Gênica/imunologia , Região de Controle de Locus Gênico/genética , Polimorfismo de Nucleotídeo Único , Células Th2/imunologia , Hidrolases Anidrido Ácido , Adulto , Asma/imunologia , Criança , Metilação de DNA/imunologia , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/imunologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Imunoglobulina E/sangue , Interleucina-13/genética , Interleucina-13/imunologia , Região de Controle de Locus Gênico/imunologia , Masculino , Reação em Cadeia da PolimeraseRESUMO
BACKGROUND: Both FCER2 and FCER1A encode subunits of IgE receptors. Variants in FCER1A were previously identified as major determinants of IgE levels in genome-wide association studies. METHODS: Here we investigated in detail whether FCER2 polymorphisms affect IgE levels alone and/or by interaction with FCER1A polymorphisms. To cover the genetic information of FCER2, 21 single-nucleotide polymorphisms (SNPs) were genotyped by Illumina HumanHap300 BeadChip (5 SNPs) and the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS; 14 SNPs) in at least 1303 Caucasian children (651 asthmatics) (ISAAC II/ MAGICS population); genotypes of two SNPs were imputed. RESULTS: SNP rs3760687 showed the most consistent effect on total serum IgE levels (b [SE] = -0.38 [0.16]; P = 0.016), while FCER2 polymorphisms in general were predominantly associated with mildly-to-moderately increased IgE levels (50th and 66th percentiles). Gene-by-gene interaction analysis suggests that FCER2 polymorphism rs3760687 influences IgE levels mainly in individuals not homozygous for the risk allele of FCER1A polymorphism rs2427837, which belongs to the major IgE-determining tagging bin in the population. CONCLUSION: FCER2 polymorphism rs3760687 affects moderately elevated total serum IgE levels, especially in the absence of homozygosity for the risk allele of FCER1A SNP rs2427837.
Assuntos
Asma/genética , Predisposição Genética para Doença/genética , Imunoglobulina E/genética , Lectinas Tipo C/genética , Polimorfismo de Nucleotídeo Único , Receptores de IgE/genética , Criança , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
BACKGROUND: Genome-wide association studies (GWAS) repeatedly identified 1q23 (FCER1A), 5q31 (RAD50-IL13 and IL4), and 12q13 (STAT6) as major susceptibility loci influencing the regulation of total serum IgE levels. As GWAS may be insufficient to capture causal variants, we performed fine-mapping and re-genotyping of the three loci using 1000 Genomes Project datasets. METHODS: Linkage disequilibrium tagging polymorphisms and polymorphisms of putative functional relevance were genotyped by chip technology (24 polymorphisms) or MALDI-TOF-MS (40 polymorphisms) in at least 1303 German children (651 asthmatics). The effect of polymorphisms on total serum IgE, IgE percentiles, and atopic diseases was assessed, and a risk score model was applied for gene-by-gene interaction analyses. Functional effects of putative causal variants from these three loci were studied in silico. RESULTS: Associations from GWAS were confirmed and extended. For 1q23 and 5q31, the majority of associations were found with mild to moderately elevated IgE levels, while in the 12q13 locus, single-nucleotide polymorphisms (SNPs) were associated with strongly elevated IgE levels. Gene-by-gene interaction analyses suggested that the presence of mutations in all three loci increases the risk for elevated IgE up to fourfold. CONCLUSION: This fine-mapping study confirmed previous associations and identified novel associations of SNPs in 1q23, 5q31, and 12q13 with different levels of serum IgE and their concomitant contribution to IgE regulation.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 5 , Estudos de Associação Genética , Imunoglobulina E/sangue , Locos de Características Quantitativas , Alelos , Asma/sangue , Asma/genética , Asma/imunologia , Epistasia Genética , Feminino , Estudo de Associação Genômica Ampla , Genômica , Genótipo , Humanos , Hipersensibilidade/genética , Hipersensibilidade/imunologia , Imunoglobulina E/imunologia , Desequilíbrio de Ligação , Masculino , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Interferon-regulatory factors (IRFs) play a crucial role in immunity, not only influencing interferon expression but also T cell differentiation. IRF-4 was only recently recognized as a further major player in T cell differentiation. OBJECTIVE: As IRF-1 polymorphisms were shown to be associated with atopy and allergy, we comprehensively investigated effects of IRF-4 variants on allergy, asthma and related phenotypes in German children. METHODS: Fifteen tagging single nucleotide polymorphisms (SNPs) in the IRF-4 gene were genotyped by MALDI-TOF MS in the cross-sectional ISAAC phase II study population from Munich and Dresden (age 9-11; N = 3099). Replication was performed in our previously established genome-wide association study (GWAS) data set (N = 1303) consisting of asthma cases from the Multicenter Asthma Genetic in Childhood (MAGIC) study and reference children from the ISAAC II study. RESULTS: SNPs were not significantly associated with asthma but with bronchial hyperresponsiveness, atopy and, most interestingly, with recurrent bronchitis in the first data set. The IRF-4 variant rs9378805 was associated with recurrent bronchitis in the ISAAC population and replicated in the GWAS data set where further SNPs showed associations with recurrent bronchitis and asthma. CONCLUSIONS: We found genetic associations in IRF-4 to be associated with recurrent bronchitis in our two study populations. Associated polymorphisms are localized in a putative regulatory element in the 3'UTR region of IRF-4. These findings suggest a putative role of IRF-4 in the development of bronchitis.
Assuntos
Asma/genética , Bronquite/genética , Fatores Reguladores de Interferon/genética , Polimorfismo Genético , Regiões 3' não Traduzidas , Alelos , Criança , Estudos Transversais , Éxons , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único , RecidivaRESUMO
BACKGROUND: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. OBJECTIVE: To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. METHODS: In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. RESULTS: We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms(SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1BSNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. CONCLUSIONS AND CLINICAL RELEVANCE: DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.
Assuntos
Índice de Massa Corporal , Estudo de Associação Genômica Ampla , Adolescente , Adulto , Idoso , Alelos , Asma/complicações , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
BACKGROUND: The transcription factor STAT6 is crucial for activation of the interleukin (IL)-4/IL-13 pathway and has been linked to regulatory T cells (Tregs). Associations of STAT6 polymorphisms with IgE levels were described; however, their impact on neonatal immune responses and early disease development is unknown. METHODS: STAT6 polymorphisms were genotyped in cord blood mononuclear cells by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Gene expression was assessed by real-time polymerase chain reaction (PCR) and cytokines by Multiplex. At age 3 years, atopic diseases were assessed by questionnaires. RESULTS: STAT6 rs324011 but not rs1059513 polymorphism was associated with significant or borderline significant decreased mRNA expression of Treg-associated genes (FOXP3, GITR, LAG3). Heterozygotes and minor allele homozygotes of rs324011 had low levels of tumor necrosis factor alpha (TNF-α) and increased interferon gamma (IFN-γ) (P ≤ 0.04), while heterozygotes and minor allele homozygotes of rs1059513 had increased TNF-α and Granulocyte-macrophage colony-stimulating factor (GM-CSF) (P ≤ 0.05). In minor allele homozygotes of rs324011, expression of Treg-associated genes was strongly inverse correlated with IFN-γ (unstimulated, r = -0.7, P = 0.111; LpA stimulation, r = -0.8, P = 0.011), but not in heterozygotes or major allele homozygotes. Heterozygotes and minor allele homozygotes of rs324011 presented a lower risk of atopic dermatitis and obstructive bronchitis until age 3 years. CONCLUSIONS: Two STAT6 polymorphisms were associated with altered immune responses already at birth. STAT6 rs324011 was associated with lower neonatal Treg and increased Th1 response. Those neonates had a lower risk of atopic dermatitis and obstructive bronchitis until 3 years. Our data suggest a role for STAT6 polymorphisms in early immune regulation and implications on early atopic disease development.
Assuntos
Citocinas/sangue , Hipersensibilidade Imediata/genética , Hipersensibilidade Imediata/imunologia , Polimorfismo de Nucleotídeo Único , Fator de Transcrição STAT6/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Alelos , Antígenos CD/genética , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Bronquite/genética , Bronquite/imunologia , Bronquite/metabolismo , Pré-Escolar , Estudos de Coortes , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Estudos de Associação Genética , Genótipo , Humanos , Hipersensibilidade Imediata/diagnóstico , Hipersensibilidade Imediata/metabolismo , Recém-Nascido , Masculino , Avaliação de Resultados da Assistência ao Paciente , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
BACKGROUND: Genetic susceptibility and environmental influences are important contributors to the development of asthma and atopic diseases. Epigenetic mechanisms may facilitate gene by environment interactions in these diseases. METHODS: We studied the rural birth cohort PASTURE (Protection against allergy: study in rural environments) to investigate (a) whether epigenetic patterns in asthma candidate genes are influenced by farm exposure in general, (b) change over the first years of life, and (c) whether these changes may contribute to the development of asthma. DNA was extracted from cord blood and whole blood collected at the age of 4.5 years in 46 samples per time point. DNA methylation in 23 regions in ten candidate genes (ORMDL1, ORMDL2, ORMDL3, CHI3L1, RAD50, IL13, IL4, STAT6, FOXP3, and RUNX3) was assessed by pyrosequencing, and differences between strata were analyzed by nonparametric Wilcoxon-Mann-Whitney tests. RESULTS: In cord blood, regions in ORMDL1 and STAT6 were hypomethylated in DNA from farmers' as compared to nonfarmers' children, while regions in RAD50 and IL13 were hypermethylated (lowest P-value (STAT6) = 0.001). Changes in methylation over time occurred in 15 gene regions (lowest P-value (IL13) = 1.57*10(-8)). Interestingly, these differences clustered in the genes highly associated with asthma (ORMDL family) and IgE regulation (RAD50, IL13, and IL4), but not in the T-regulatory genes (FOXP3, RUNX3). CONCLUSIONS: In this first pilot study, DNA methylation patterns change significantly in early childhood in specific asthma- and allergy-related genes in peripheral blood cells, and early exposure to farm environment seems to influence methylation patterns in distinct genes.
Assuntos
Agricultura , Asma/genética , Asma/imunologia , Metilação de DNA , Exposição Ambiental , Hipersensibilidade/genética , Hipersensibilidade/imunologia , Criança , Pré-Escolar , Epigênese Genética , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Projetos PilotoRESUMO
BACKGROUND: Genome-wide association studies (GWAS) have identified many risk loci for asthma, but effect sizes are small, and in most cases, the biological mechanisms are unclear. Targeted metabolite quantification that provides information about a whole range of pathways of intermediary metabolism can help to identify biomarkers and investigate disease mechanisms. Combining genetic and metabolic information can aid in characterizing genetic association signals with high resolution. This work aimed to investigate the interrelation of current asthma, candidate asthma risk alleles and a panel of metabolites. METHODS: We investigated 151 metabolites, quantified by targeted mass spectrometry, in fasting serum of asthmatic and nonasthmatic individuals from the population-based KORA F4 study (N = 2925). In addition, we analysed effects of single-nucleotide polymorphisms (SNPs) at 24 asthma risk loci on these metabolites. RESULTS: Increased levels of various phosphatidylcholines and decreased levels of various lyso-phosphatidylcholines were associated with asthma. Likewise, asthma risk alleles from the PDED3 and MED24 genes at the asthma susceptibility locus 17q21 were associated with increased concentrations of various phosphatidylcholines with consistent effect directions. CONCLUSIONS: Our study demonstrated the potential of metabolomics to infer asthma-related biomarkers by the identification of potentially deregulated phospholipids that associate with asthma and asthma risk alleles.
Assuntos
Asma/genética , Asma/metabolismo , Perfilação da Expressão Gênica , Metaboloma , Fosfatidilcolinas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos Transversais , Feminino , Loci Gênicos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo ÚnicoAssuntos
Corticosteroides/administração & dosagem , Asma/genética , Cromossomos Humanos Par 17/genética , Polimorfismo de Nucleotídeo Único , Administração por Inalação , Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Asma/patologia , Progressão da Doença , Feminino , Humanos , Masculino , Falha de TratamentoRESUMO
Immunoglobulin E (IgE) mediated immune responses seem to be directed against parasites and neoplasms, but are best known for their involvement in allergies. The IgE network is tightly controlled at different levels as outlined in this review. Genetic determinants were suspected to influence IgE regulation and IgE levels considerably for many years. Linkage and candidate gene studies suggested a number of loci and genes to correlate with total serum IgE levels, and recently genome-wide association studies (GWAS) provided the power to identify genetic determinants for total serum IgE levels: 1q23 (FCER1A), 5q31 (RAD50, IL13, IL4), 12q13 (STAT6), 6p21.3 (HLA-DRB1) and 16p12 (IL4R, IL21R). In this review, we analyse the potential role of these GWAS hits in the IgE network and suggest mechanisms of how genes and genetic variants in these loci may influence IgE regulation.
Assuntos
Imunoglobulina E/imunologia , Imunoglobulina E/metabolismo , Imunomodulação/genética , Imunomodulação/imunologia , Animais , Asma/sangue , Asma/genética , Asma/imunologia , Dermatite Atópica/sangue , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Regulação da Expressão Gênica , Ligação Genética , Estudo de Associação Genômica Ampla , Humanos , Imunoglobulina E/sangue , Locos de Características Quantitativas , Receptores de IgE/imunologia , Receptores de IgE/metabolismoRESUMO
BACKGROUND: Influenza infections acquired in hospital show increased mortality, especially in elderly patients with risk factors. Nevertheless, vaccination rates are low among both high-risk patients and healthcare workers (HCWs). AIM: To more effectively prevent influenza infections in the hospital during the influenza season, a strict mouth-nose protection (MNP) requirement was introduced for all staff throughout the shift on the affected wards as an intervention and its effect on nosocomial infection rates was studied. METHODS: The present data were obtained in a retrospective, monocentric analysis over a period of four consecutive influenza seasons from 2015 to 2019. MNP for all staff during the whole shift as an intervention was introduced in 2017 and for the following seasons if at least three influenza patients were in the ward at the same time. Data from hospitalized influenza patients before and after intervention were compared with regard to nosocomial incidences and mortality. FINDINGS: In the years with strict mandatory MNP (2017-2019), the nosocomial influenza incidence fell nearly 50% (odds ratio: 0.40; 95% confidence interval: 0.28-0.56; P < 0.001) accompanied by a significant reduction in nosocomial mortality by 85% (0.15; 0.02-0.70; P = 0.007). The infectious pressure indicated by influenza incidences and patient-days at risk were comparable before and after intervention, as was the low rate of vaccine uptake by nurses. CONCLUSION: Mandatory MNP for HCWs effectively protects patients from nosocomial influenza infections and mortality.
Assuntos
Infecção Hospitalar , Vacinas contra Influenza , Influenza Humana , Idoso , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/prevenção & controle , Pessoal de Saúde , Hospitais , Humanos , Influenza Humana/epidemiologia , Influenza Humana/prevenção & controle , Recursos Humanos em Hospital , Políticas , Estudos Retrospectivos , Estações do Ano , VacinaçãoRESUMO
BACKGROUND: Hospitals need to be protected from SARS-CoV-2 infections to protect vulnerable patients. Thus, a safe, efficient, and cost-effective SARS-CoV-2 testing system for hospitals, in addition to standard hygiene measures and vaccination of staff, is necessary. Here we report on the feasibility and performance of a pool real-time reverse-transcriptase polymerase-chain-reaction (rRT-PCR) test system at, medium and high incidence. METHODS: We implemented a testing concept based on gargling at home and pooling of samples in the hospital before PCR testing in the laboratory. We used two PCR systems (point of care and standard 96-well plate system) to adapt to challenges in the hospital setting and respond to a rising incidence in the Omicron wave. FINDINGS: During our 10-week study period, we performed 697 pool PCRs (8793 tests in total) and identified 65 asymptomatic staff members by pool PCR and 94 symptomatic staff members by positive individual PCR. Virus loads in those detected by pool testing were significantly lower (P<0.001). The test system remained workable even during the peak of the Omicron wave and no outbreaks occurred in any specific area of the hospital during the study period. Unvaccinated individuals were over-represented in the positively tested (37% vs 22% positive tests, P=0.04). The test procedure was well accepted by a majority of the hospital staff (84%). CONCLUSION: Repeated gargle pool rRT-PCR testing can be implemented quickly in hospitals and is an effective, easily adaptable and well-accepted test system for hospitals, even during phases with very high infection rates.
Assuntos
Teste para COVID-19 , Reação em Cadeia da Polimerase em Tempo Real , COVID-19/diagnóstico , COVID-19/epidemiologia , Hospitais , Humanos , Incidência , Reação em Cadeia da Polimerase em Tempo Real/métodos , SARS-CoV-2/genéticaAssuntos
Pneumopatias/etiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Fumar/efeitos adversos , Criança , Estudos de Coortes , Epigênese Genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Estudos Prospectivos , Fumar/genéticaRESUMO
Innate immunity is a pivotal defence system of higher organisms. Based on a limited number of receptors, it is capable of recognizing pathogens and to initiate immune responses. Major components of these innate immunity pathogen recognition receptors are the toll-like receptors (TLRs), a family of 11 in humans. They are all membrane bound and through dimerization and complex downstream signaling, TLRs elicit a variety of specific and profound effects. In recent years, the role of TLRs signaling was not only investigated in infection and inflammation but also in allergy. Fuelled by the hygiene hypothesis, which suggests that allergies develop because of a change in microbial exposure and associated immune signals early in life, it had been speculated that alterations in TLRs signaling could influence allergy development. Thus, TLR genes, genetic variations of these genes, and their association with asthma and other atopic diseases were investigated in recent years. This review provides an overview of TLR genetics in allergic diseases.