RESUMO
BACKGROUND: Previous studies showed controversial results for the influence of pregnancy-related and perinatal factors on subsequent respiratory and atopic diseases in children. The aim of this study was to assess the association between perinatal variables and the prevalence of asthma, bronchial hyperreactivity (BHR), flexural eczema (FE), allergic rhinitis, and sensitization in childhood and early adulthood. METHODS: The studied population was first examined in Munich and Dresden in 1995/1996 at age 9-11 years. Participants were followed until age 19-24 years using questionnaires and clinical examinations. Associations between perinatal data and subsequent atopic diseases were examined using logistic regression analyses adjusting for potential confounders. RESULTS: Cesarean section was statistically significantly associated with BHR in early adulthood (odds ratio 4.8 [95% confidence interval 1.5-15.2]), while assisted birth was associated with presence of asthma symptoms in childhood (2.2 [1.2-3.9]), FE symptoms (2.2 [1.2-4.3]) and doctor's diagnosis of atopic dermatitis (1.9 [1.0-3.4]) in childhood, and sensitization in early adulthood (2.2 [1.1-4.3]). Lower birth length (1.9 [1.1-3.2]), lower birthweight (0.5 [0.3-0.9]), and higher birthweight (0.6 [0.4-1.0]) were predictive of sensitization in early adulthood compared to average birth length and birthweight, respectively. None of the other perinatal factors showed statistically significant associations with the outcomes. CONCLUSIONS: Our results indicate that children who are born by cesarean section and especially by assisted birth, might be at greater risk for developing asthma, FE, and sensitization and should hence be monitored. Prenatal maternal stress might partly explain these associations, which should be further investigated.
Assuntos
Hipersensibilidade/epidemiologia , Cesárea/efeitos adversos , Criança , Extração Obstétrica/efeitos adversos , Feminino , Humanos , Hipersensibilidade/etiologia , Trabalho de Parto Induzido/efeitos adversos , Estudos Longitudinais , Masculino , Razão de Chances , Gravidez , Prevalência , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: The highly consistent association of growing up on a farm with a reduced asthma risk has so far been attributed to direct farm exposure. In contrast, geographic determinants of the larger environment have never been assessed. In this study, the effects of proximity to farms and environmental variables in relation to the residential address on asthma and atopy were assessed. METHODS: Addresses of 2265 children of the Bavarian arm of the GABRIELA study were converted into geocodes. Proximity to the nearest cow farm was calculated, and environmental characteristics were derived from satellite data or terrestrial monitoring. Bacterial diversity in mattress dust samples was assessed in 501 children by sequencing of the 16S rRNA amplicons. Logistic regression models were used to calculate associations between outcomes and exposure variables. RESULTS: Asthma and atopy were inversely associated with the presence of a farm within a radius of maximum 100 m. The environmental variables greenness, tree cover, soil sealing, altitude, air pollution differed not only between farm and non-farm children but also between farm children with and without another farm nearby. The latter distinction revealed strong associations with characteristics of traditional farms including a broader diversity of microbial exposure, which mainly contributed to the protective effect on asthma. In non-farm children, the protective effect of a farm nearby was completely explained by consumption of farm milk. CONCLUSIONS: Clustering of farms within a neighborhood of 100 m is strongly associated with the protective effect on asthma and may represent a more traditional style of farming with broader microbial exposure.
Assuntos
Poluição do Ar/efeitos adversos , Exposição Ambiental/efeitos adversos , Hipersensibilidade/etiologia , Animais , Bactérias/imunologia , Criança , Poeira/imunologia , Fazendas , Mapeamento Geográfico , Inquéritos Epidemiológicos , Habitação , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/microbiologia , Imunoglobulina E/sangue , Modelos Logísticos , Fatores de RiscoRESUMO
BACKGROUND: Previous observational studies have implied breastmilk fatty acid composition may play a role in the development of atopic eczema or atopic sensitization in breastfed infants and toddlers. However, studies investigating associations with wheeze and asthma in later childhood are scarce and did not account for inherent correlation of compositional data. Our aim was to explore the association of maternal milk fatty acid composition with childhood wheezing phenotypes and asthma up to age 13 years using a new statistical approach. METHODS: Breastmilk was collected 6 weeks and 6 months postdelivery in the Ulm Birth Cohort Study (n=720 and n=454, respectively). Concentrations of 28 fatty acids were measured by high-resolution capillary gas-liquid chromatography. To control for constant-sum constraint, concentration data were transformed using the centered log ratio method. Compositional biplots and correlation matrices were used to group centered log ratio transformed fatty acids. Adjusted risk ratios with parent-reported wheezing phenotypes and doctor-diagnosed asthma were computed using a modified Poisson regression. RESULTS: We observed no straightforward evidence of associations between overall breastmilk fatty acid composition and specific wheeze phenotypes or doctor-diagnosed asthma. CONCLUSION: Using appropriate statistical methodology, we report null associations. These findings may partly be attributable to several cohort-specific factors associated with breastfeeding and breastmilk collection. Further studies could improve on ours by analyzing samples of breastmilk and formula and by including all children for whom these are exclusively or together the major source of fatty acids in the first months of life.
Assuntos
Asma/etiologia , Ácidos Graxos/análise , Leite Humano/química , Sons Respiratórios/etiologia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Ácidos Graxos/efeitos adversos , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Lactente , Masculino , Razão de ChancesRESUMO
BACKGROUND: There is a substantial body of evidence on the epidemiology of allergic conditions, which has advanced the understanding of these conditions. We aimed to systematically identify systematic reviews and meta-analyses on the epidemiology of allergic diseases to assess what has been studied comprehensively and what areas might benefit from further research. METHODS: We searched PubMed and EMBASE up to 12/2014 for systematic reviews on epidemiological research on allergic diseases. We indexed diseases and topics covered and extracted data on the search characteristics of each systematic review. RESULTS: The search resulted in 3991 entries after removing duplicates, plus 20 other items found via references and conference abstracts; 421 systematic reviews were relevant and included in this overview. The majority contained some evidence on asthma (72.9%). Allergic rhinitis, atopic eczema and food hypersensitivity were covered in 15.7%, 24.5% and 9.0%, respectively. Commonly studied risk factors for atopic eczema included dietary and microbial factors, while for asthma, pollution and genetic factors were often investigated in systematic reviews. There was some indication of differing search characteristics across topics. CONCLUSION: We present a comprehensive overview with an indexed database of published systematic reviews in allergy epidemiology. We believe that this clarifies where most research interest has focussed and which areas could benefit from further research. We propose that this effort is updated every few years to include the most recently published evidence and to extend the search to an even broader list of hypersensitivity/allergic disorders.
Assuntos
Hipersensibilidade/epidemiologia , Asma/epidemiologia , Dermatite Atópica/epidemiologia , Hipersensibilidade Alimentar/epidemiologia , Humanos , Literatura de Revisão como Assunto , Rinite Alérgica/epidemiologiaRESUMO
BACKGROUND: High microbial diversity in the environment has been associated with lower asthma risk, particularly in children exposed to farming. It remains unclear whether this effect operates through an altered microbiome of the mucosal surfaces of the airways. METHODS: DNA from mattress dust and nasal samples of 86 school age children was analyzed by 454 pyrosequencing of the 16S rRNA gene fragments. Based on operational taxonomic units (OTUs), bacterial diversity and composition were related to farm exposure and asthma status. RESULTS: Farm exposure was positively associated with bacterial diversity in mattress dust samples as determined by richness (P = 8.1 × 10-6 ) and Shannon index (P = 1.3 × 10-5 ). Despite considerable agreement of richness between mattress and nasal samples, the association of richness with farming in nasal samples was restricted to a high gradient of farm exposure, that is, exposure to cows and straw vs no exposure at all. In mattress dust, the genera Clostridium, Facklamia, an unclassified genus within the family of Ruminococcaceae, and six OTUs were positively associated with farming. Asthma was inversely associated with richness [aOR = 0.48 (0.22-1.02)] and Shannon index [aOR = 0.41 (0.21-0.83)] in mattress dust and to a lower extent in nasal samples [richness aOR 0.63 = (0.38-1.06), Shannon index aOR = 0.66 (0.39-1.12)]. CONCLUSION: The stronger inverse association of asthma with bacterial diversity in mattress dust as compared to nasal samples suggests microbial involvement beyond mere colonization of the upper airways. Whether inhalation of metabolites of environmental bacteria contributes to this phenomenon should be the focus of future research.
Assuntos
Asma/epidemiologia , Asma/etiologia , Exposição Ambiental/efeitos adversos , Microbiologia Ambiental , Microbiota , Mucosa/microbiologia , Bactérias/classificação , Bactérias/genética , Biodiversidade , Criança , Estudos Transversais , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Farm exposure protects against development of allergies early in life. At 4.5 years, protection against asthma by farm-milk exposure was partially mediated by regulatory T cells (Tregs). The aim of this study was to investigate the critical time window of the 'asthma-protective' farm effect via Tregs during childhood immune maturation. METHODS: Tregs were assessed longitudinally at 4.5 and 6 years in 111 children (56 farm and 55 reference children) from the PASTURE/EFRAIM birth cohort (flow cytometry). Peripheral blood mononuclear cells were cultured unstimulated (U), with phorbol 12-myristate 13-acetate/ionomycin (PI) or lipopolysaccharide (LPS), and stained for Tregs (CD4+ CD25high FOXP3upper20% ). mRNA expression of Treg/Th1/Th2/Th17-associated cell markers was measured ex vivo. Suppressive capacity of Tregs on effector cells and cytokines was assessed. Detailed questionnaires assessing farm exposures and clinical phenotypes from birth until age 6 years were answered by the parents. RESULTS: Treg percentage before and after stimulation and FOXP3mRNA expression ex vivo decreased from age 4.5 to 6 years (P(U,LPS) < 0.001; P(PI) = 0.051; P(FOXP3) < 0.001). High vs low farm-milk and animal-stable exposure was associated with decreased LPS-stimulated Treg percentage at age 6 years (P(LPS) = 0.045). Elevated LPS-stimulated-Treg percentage at age 6 was associated with increased risk of asthma (aOR = 11.29, CI: 0.96-132.28, P = 0.053). Tregs from asthmatics vs nonasthmatics suppressed IFN-γ (P = 0.015) and IL-9 (P = 0.023) less efficiently. mRNA expression of Th1/Th2/Th17-associated cell markers decreased between 4.5 and 6 years (P < 0.001). CONCLUSIONS: Tregs at the age of 6 years were decreased with farm exposure and increased within asthmatics, opposite to age 4.5 years. This immunological switch defines a critical 'time window' for Treg-mediated asthma protection via environmental exposure before age 6 years.
Assuntos
Exposição Ambiental , Fazendas , Imunidade , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Fatores Etários , Alérgenos/imunologia , Animais , Asma/epidemiologia , Asma/etiologia , Biomarcadores , Criança , Pré-Escolar , Citocinas/metabolismo , Feminino , Seguimentos , Expressão Gênica , Humanos , Imunoglobulina E/imunologia , Lactente , Recém-Nascido , Contagem de Linfócitos , Masculino , Fenótipo , Vigilância da População , Gravidez , RNA Mensageiro/genética , Inquéritos e Questionários , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismoRESUMO
This study investigated the association between confirmed moisture damage in homes and systemic subclinical inflammation in children. Home inspections were performed in homes of 291 children at the age of 6 years. Subclinical inflammation at the age of 6 years was assessed by measuring the circulating levels of C-reactive protein (CRP) and leukocytes in peripheral blood and fractional exhaled nitric oxide (FeNO). Proinflammatory cytokines interleukin (IL)-1ß and IL-6 and tumor necrosis factor (TNF)-α were measured in unstimulated, and in phorbol 12-myristate 13-acetate and ionomycin (PI), lipopolysaccharide (LPS), or peptidoglycan (PPG)-stimulated whole blood. Major moisture damage in the child's main living areas (living room, kitchen, or child's bedroom) and moisture damage with mold in the bathroom were associated with increased levels of CRP and stimulated production of several proinflammatory cytokines. There were no significant associations between moisture damage/visible mold and leukocyte or FeNO values. The results suggest that moisture damage or mold in home may be associated with increased systemic subclinical inflammation and proinflammatory cytokine responsiveness.
Assuntos
Poluição do Ar em Ambientes Fechados/efeitos adversos , Fungos/crescimento & desenvolvimento , Habitação , Umidade/efeitos adversos , Inflamação/etiologia , Vapor/efeitos adversos , Poluição do Ar em Ambientes Fechados/análise , Proteína C-Reativa/análise , Criança , Citocinas/sangue , Expiração , Feminino , Humanos , Inflamação/sangue , Contagem de Leucócitos , Masculino , Óxido Nítrico/análise , Vapor/análiseRESUMO
BACKGROUND: Gut microbiota and intestinal inflammation regulate the development of immune-mediated diseases, such as allergies. Fecal calprotectin is a biomarker of intestinal inflammation. OBJECTIVE: We evaluated the association of early-age fecal calprotectin levels to the later development of allergic diseases in children from farming and non-farming environments and further studied the effect of gut microbiota on the fecal calprotectin levels. METHODS: Fecal calprotectin was measured from 758 infants participating in the PASTURE study at the age of 2 months using the ELISA method. Serum-specific IgE levels were measured at 6 years of age. Data of environmental factors, doctor-diagnosed atopic dermatitis (AD) and asthma were collected by questionnaire. Multivariate logistic regression models were used for analysis. The composition of fecal microbiota was analysed in a subgroup of 120 infants with 16S rRNA pyrosequencing. The effect of Escherichia coli lipopolysaccharide (LPS) on in vitro monocyte IL-10 secretion was studied by flow cytometry. RESULTS: The infants with high fecal calprotectin levels at 2 months, that is above the 90th percentile, had an increased risk of developing AD and asthma/asthmatic bronchitis by the age of 6 years (aOR 2.02 (1.06-3.85) and 2.41 (1.25-4.64), respectively). High fecal calprotectin levels correlated negatively with fecal Escherichia. LPS from E. coli stimulated production of IL-10 in monocytes. CONCLUSION AND CLINICAL RELEVANCE: High degree intestinal inflammation at 2 months of age, detected as high fecal calprotectin, predicted asthma and AD by the age of 6 years and was linked to low abundance of fecal Escherichia. Impaired IL-10 activation due to the lack of colonization with E. coli could explain the intestinal inflammation associated high fecal calprotectin and later risk of asthma and AD. Our results have implications for the design of probiotic treatments and suggest that early intestinal colonization has long-term health effects.
Assuntos
Asma/epidemiologia , Asma/metabolismo , Dermatite Atópica/epidemiologia , Dermatite Atópica/metabolismo , Enteropatias/epidemiologia , Enteropatias/metabolismo , Complexo Antígeno L1 Leucocitário/metabolismo , Fatores Etários , Asma/etiologia , Bactérias , Biomarcadores , Criança , Pré-Escolar , Estudos de Coortes , Dermatite Atópica/etiologia , Fezes/química , Feminino , Microbioma Gastrointestinal , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/etiologia , Hipersensibilidade/metabolismo , Lactente , Interleucina-10/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Razão de Chances , Gravidez , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
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
BACKGROUND: The role of breastfeeding for the development of atopic diseases in childhood is contradictory. This might be due to differences in the composition of breast milk and levels of antimicrobial and anti-inflammatory components. OBJECTIVE: The objective of this study was to examine whether levels of total immunoglobulin A (IgA) or transforming growth factor-ß1 (TGF-ß1) in breast milk were associated with the risk of developing atopic dermatitis (AD), atopic sensitization or asthma at early age taking breastfeeding duration into account. METHODS: The birth cohort study PASTURE conducted in Finland, France, Germany and Switzerland provided 610 breast milk samples collected 2 months after delivery in which soluble IgA (sIgA) and TGF-ß1 levels were measured by ELISA. Duration of breastfeeding was assessed using weekly food frequency diaries from month 3 to month 12. Data on environmental factors, AD and asthma were collected by questionnaires from pregnancy up to age 6. Atopic status was defined by specific IgE levels in blood collected at the ages of 4 and 6 years. Multivariate logistic regression models were used for statistical analysis. RESULTS: Soluble IgA and TGF-ß1 levels in breast milk differed between countries, and sIgA levels were associated with environmental factors related to microbial load, for example, contact to farm animals or cats during pregnancy, but not with raw milk consumption. sIgA levels were inversely associated with AD up to the of age 2 years (P-value for adjusted linear trend: 0.005), independent of breastfeeding duration. The dose of sIgA ingested in the first year of life was associated with reduced risk of AD up to the age of 2 (aOR, 95% CI: 0.74; 0.55-0.99) and 4 years (0.73; 0.55-0.96). No clear associations between sIgA and atopy or asthma up to age 6 were observed. TGF-ß1 showed no consistent association with any investigated health outcome. CONCLUSION AND CLINICAL RELEVANCE: IgA in breast milk might protect against the development of AD.
Assuntos
Dermatite Atópica/imunologia , Imunoglobulina A/imunologia , Leite Humano/imunologia , Adulto , Fatores Etários , Animais , Aleitamento Materno , Criança , Pré-Escolar , Estudos de Coortes , Dermatite Atópica/epidemiologia , Dermatite Atópica/metabolismo , Dieta , Meio Ambiente , Europa (Continente) , Feminino , Humanos , Imunoglobulina A/metabolismo , Lactente , Recém-Nascido , Leite , Leite Humano/química , Leite Humano/metabolismo , Gravidez , Inquéritos e Questionários , Fator de Crescimento Transformador beta1/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: Prospective studies investigating the role of serum vitamin E concentrations during early life in the development of childhood allergies and asthma are limited. OBJECTIVE: To study the associations between serum vitamin E concentrations at first year of life and longitudinal development of atopy, atopic dermatitis, wheeze, and asthma up to 6 years of age. METHODS: The setting was the PASTURE study, a multicenter prospective birth cohort study in five European rural settings. Children of 1133 mothers recruited during pregnancy were followed from birth with measurement of serum vitamin E levels at year 1 and repeated assessments of serum immunoglobulin E antibodies (year 1, 4.5, 6), atopic dermatitis, wheezing symptoms, and asthma (year 1, 1.5, 2, 3, 4, 5, 6). RESULTS: At 6 years of age, 66% and 82% of the original 1133 subjects underwent blood test for IgE and answered the questionnaire, respectively. We did not observe any statistically significant associations between serum vitamin E concentrations at year 1 and the endpoints, but borderline inverse associations between alpha tocopherol and wheezing without cold (OR 0.45, 95% CI 0.19-1.09) and any wheezing symptom (OR 0.52, 95% CI 0.27-1.02). CONCLUSIONS: Serum vitamin E concentrations at year 1 were not associated with allergies or asthma by 6 years of age. While further prospective studies with repeated assessments of vitamin E during early life may clarify its putative role in the development of the diseases, it is also possible that the antioxidant hypothesis in the development of allergies and asthma does not hold.
Assuntos
Asma/sangue , Asma/epidemiologia , Dermatite Atópica/sangue , Dermatite Atópica/epidemiologia , Hipersensibilidade Imediata/sangue , Hipersensibilidade Imediata/epidemiologia , Sons Respiratórios , Vitamina E/sangue , Criança , Pré-Escolar , Europa (Continente)/epidemiologia , Humanos , Incidência , Lactente , Razão de Chances , Prevalência , Estudos Prospectivos , Risco , Fatores de Risco , População RuralRESUMO
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: Early-life exposure to environmental microbial agents may be associated with the development of allergies. The aim of the study was to identify better ways to characterize microbial exposure as a predictor of respiratory symptoms and allergies. METHODS: A birth cohort of 410 children was followed up until 6 years of age. Bacterial endotoxin, 3-hydroxy fatty acids, N-acetyl-muramic acid, fungal extracellular polysaccharides (EPS) from Penicillium and Aspergillus spp., ß-D-glucan, ergosterol, and bacterial or fungal quantitative polymerase chain reactions (qPCRs) were analyzed from dust samples collected at 2 months of age. Asthma, wheezing, cough, and atopic dermatitis were assessed using repeated questionnaires. Specific IgEs were determined at the age of 1 and 6 years. RESULTS: Only few associations were found between single microbial markers and the studied outcomes. In contrast, a score for the total quantity of microbial exposure, that is, sum of indicators for fungi (ergosterol), Gram-positive (muramic acid) bacteria, and Gram-negative (endotoxin) bacteria, was significantly (inverted-U shape) associated with asthma incidence (P < 0.001): the highest risk was found at medium levels (adjusted odds ratio (aOR) 2.24, 95% confidence interval (95% CI) 0.87-5.75 for 3rd quintile) and the lowest risk at the highest level (aOR 0.34, 95% CI 0.09-1.36 for 5th quintile). The microbial diversity score, that is, sum of detected qPCRs, was inversely associated with risk of wheezing and was significantly (inverted-U shape) associated with sensitization to inhalant allergens. CONCLUSION: Score for quantity of microbial exposure predicted asthma better than single microbial markers independently of microbial diversity and amount of dust. Better indicators of total quantity and diversity of microbial exposure are needed in studies on the development of asthma.
Assuntos
Asma/epidemiologia , Asma/etiologia , Exposição Ambiental , Microbiologia Ambiental , Alérgenos/imunologia , Asma/diagnóstico , Criança , Pré-Escolar , Estudos de Coortes , Poeira , Finlândia/epidemiologia , Seguimentos , Humanos , Incidência , Lactente , Recém-Nascido , Razão de Chances , Vigilância da População , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Many studies report that damp housing conditions are associated with respiratory symptoms. Less is known about mechanisms and possible effect modifiers. Studies of dampness in relation to allergic sensitization and eczema are scarce. OBJECTIVE: We study the influence of damp housing conditions world-wide on symptoms and objective outcomes. METHODS: Cross-sectional studies of 8-12-year-old children in 20 countries used standardized methodology from Phase Two of the International Study of Asthma and Allergies in Childhood (ISAAC). Symptoms of asthma, rhinitis and eczema, plus residential exposure to dampness and moulds, were ascertained by parental questionnaires (n = 46 051). Skin examination, skin prick tests (n = 26 967) and hypertonic saline bronchial challenge (n = 5713) were performed. In subsamples stratified by wheeze (n = 1175), dust was sampled and analysed for house dust mite (HDM) allergens and endotoxin. RESULTS: Current exposure to dampness was more common for wheezy children (pooled odds ratio 1.58, 95% CI 1.40-1.79) and was associated with greater symptom severity among wheezers, irrespective of atopy. A significant (P < 0.01) adverse effect of dampness was also seen for cough and phlegm, rhinitis and reported eczema, but not for examined eczema, nor bronchial hyperresponsiveness. HDM sensitization was more common in damp homes (OR 1.16, 1.03-1.32). HDM-allergen levels were higher in damp homes and were positively associated with HDM-sensitization, but not wheeze. CONCLUSION: A consistent association of dampness with respiratory and other symptoms was found in both affluent and non-affluent countries, among both atopic and non-atopic children. HDM exposure and sensitization may contribute, but the link seems to be related principally to non-atopic mechanisms.
Assuntos
Asma/etiologia , Eczema/etiologia , Exposição Ambiental/efeitos adversos , Fungos , Umidade/efeitos adversos , Rinite Alérgica Perene/etiologia , Índice de Gravidade de Doença , Asma/imunologia , Asma/fisiopatologia , Testes de Provocação Brônquica , Criança , Estudos Transversais , Eczema/imunologia , Eczema/fisiopatologia , Feminino , Humanos , Masculino , Rinite Alérgica , Rinite Alérgica Perene/imunologia , Rinite Alérgica Perene/fisiopatologia , Testes CutâneosRESUMO
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: 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: Evidence exists that a farming environment in childhood may provide protection against atopic respiratory disease. In the GABRIEL project based in Poland and Alpine regions of Germany, Austria and Switzerland, we aimed to assess whether a farming environment in childhood is protective against allergic diseases in Poland and whether specific exposures explain any protective effect. METHODS: In rural Poland, 23 331 families of schoolchildren completed a questionnaire enquiring into farming practices and allergic diseases (Phase I). A subsample (n = 2586) participated in Phase II involving a more detailed questionnaire on specific farm exposures with objective measures of atopy. RESULTS: Farming differed between Poland and the Alpine centres; in the latter, cattle farming was prevalent, whereas in Poland 18% of village farms kept ≥1 cow and 34% kept ≥1 pig. Polish children in villages had lower prevalences of asthma and hay fever than children from towns, and in the Phase II population, farm children had a reduced risk of atopy measured by IgE (aOR = 0.72, 95% CI 0.57, 0.91) and skin prick test (aOR = 0.65, 95% CI 0.50, 0.86). Early-life contact with grain was inversely related to the risk of atopy measured by IgE (aOR = 0.66, 95% CI 0.47, 0.92) and appeared to explain part of the farming effect. CONCLUSION: While farming in Poland differed from that in the Alpine areas as did the exposure-response associations, we found in communities engaged in small-scale, mixed farming, there was a protective farming effect against objective measures of atopy potentially related to contact with grain or associated farm activities.