Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Clin Exp Allergy ; 48(3): 297-305, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29168291

RESUMO

BACKGROUND: Genetic studies of eczema have identified many genes, which explain only 14% of the heritability. Missing heritability may be partly due to ignored gene-gene (G-G) interactions. OBJECTIVE: Our aim was to detect new interacting genes involved in eczema. METHODS: The search for G-G interaction in eczema was conducted using a two-step approach, which included as a first step, a biological selection of genes, which are involved either in the skin or epidermis development or in the collagen metabolism, and as a second step, an interaction analysis of the selected genes. Analyses were carried out at both SNP and gene levels in three asthma-ascertained family samples: the discovery dataset of 388 EGEA (Epidemiological study on the Genetics and Environment of Asthma) families and the two replication datasets of 253 SLSJ (Saguenay-Lac-Saint-Jean) families and 207 MRCA (Medical Research Council) families. RESULTS: One pair of SNPs, rs2287807 in COL5A3 and rs17576 in MMP9, that were detected in EGEA at P ≤ 10-5 showed significant interaction by meta-analysis of EGEA, SLSJ and MRCA samples (P = 1.1 × 10-8 under the significant threshold of 10-7 ). Gene-based analysis confirmed strong interaction between COL5A3 and MMP9 (P = 4 × 10-8 under the significant threshold of 4 × 10-6 ) by meta-analysis of the three datasets. When stratifying the data on asthma, this interaction remained in both groups of asthmatic and non-asthmatic subjects. CONCLUSION: This study identified significant interaction between two new genes, COL5A3 and MMP9, which may be accounted for by a degradation of COL5A3 by MMP9 influencing eczema susceptibility. Further confirmation of this interaction as well as functional studies is needed to better understand the role of these genes in eczema.


Assuntos
Colágeno Tipo V/genética , Eczema/genética , Epistasia Genética/genética , Predisposição Genética para Doença/genética , Metaloproteinase 9 da Matriz/genética , Adulto , Idoso , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
2.
Genes Immun ; 15(4): 247-55, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24646526

RESUMO

To study the genetics of asthma, a familial collection was built in the Saguenay-Lac-Saint-Jean (SLSJ) region, which is localized in northeastern Quebec, Canada, and which is characterized by a young founder effect. Recruitment was performed through probands with a specific asthma phenotype. The collection includes 1394 individuals distributed in 271 families. A phenotypic profile including more than 75 phenotypic characteristics was defined for each participant using a standardized questionnaire, respiratory measures and allergic tests. A genome-wide association study on 1214 of these samples for asthma-related phenotypes (asthma, atopy and rhinitis) and for white blood cell types was performed. These analyses allowed associating 10 single nucleotide polymorphisms (SNPs) with P<1 × 10(-5) with asthma-related phenotypes and 11 SNPs with white blood cell counts. Among them, four SNPs are located in or near genes with functions related to asthma or allergy. Moreover, several loci were identified as 5q31.1 that includes 22 SNPs associated with atopy (P<1 × 10(-3)) and located near a cytokine cluster, and 17q21.2 with seven SNPs associated with asthma. This study highlights the value of a familial collection with a fine phenotypic description and characterized by a young founder effect in the search of the genetic determinants involved in complex traits such as asthma.


Assuntos
Asma/genética , Cromossomos Humanos Par 17/genética , Efeito Fundador , Estudo de Associação Genômica Ampla , Família Multigênica , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , França , Loci Gênicos , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade
3.
Nat Genet ; 28(1): 87-91, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11326283

RESUMO

The genetics of asthma and atopy have been difficult to determine because these diseases are genetically heterogeneous and modified by environment. The pedigrees in our study (n=86) originate in eastern central Finland (Kainuu province). According to census records, this region had only 200 households (2,000 inhabitants) in the mid sixteenth to mid seventeenth centuries. The current population of 100,000 represents the expansion of these founders within the past 400 years. Because this population is relatively homogeneous, we hypothesized that the molecular genetic mechanisms underlying asthma might also have reduced heterogeneity and therefore be easier to dissect than in mixed populations. A recent twin family study supported a strong genetic component for asthma in Finland. We carried out a genome-wide scan for susceptibility loci in asthma in the Kainuu subpopulation. We identified two regions of suggestive linkage and studied them further with higher-density mapping. We obtained evidence for linkage in a 20-cM region of chromosome 7p14-p15 for three phenotypes: asthma, a high level of immunoglobulin E (IgE; atopy) and the combination of the phenotypes. The strongest linkage was seen for high serum IgE (non-parametric linkage (NPL) score 3.9, P=0.0001), exceeding the threshold for genome-wide significance based on simulations. We also observed linkage between this locus and asthma or atopy in two independent data sets.


Assuntos
Asma/genética , Cromossomos Humanos Par 7/genética , Efeito Fundador , Hipersensibilidade Imediata/genética , Asma/epidemiologia , Mapeamento Cromossômico , Feminino , Finlândia/epidemiologia , Ligação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Genoma Humano , Humanos , Hipersensibilidade Imediata/epidemiologia , Imunoglobulina E , Masculino , Linhagem
4.
Clin Exp Allergy ; 42(5): 625-37, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22515387

RESUMO

Patients with severe asthma have asthma symptoms which are difficult to control, require high dosages of medication, and continue to experience persistent symptoms, asthma exacerbations or airflow obstruction. Epidemiological and clinical evidences point to the fact that severe asthma is not a single phenotype. Cluster analyses have identified subclasses of severe asthma using parameters such as patient characteristics, and cytokine profiles have also been useful in classifying moderate and severe asthma. The IL-4/IL-13 signalling pathway accounts for the symptoms experienced by a subset of severe asthmatics with allergen-associated symptoms and high serum immunoglobulin E (IgE) levels, and these patients are generally responsive to anti-IgE treatment. The IL-5/IL-33 signalling pathway is likely to play a key role in the disease pathogenesis of those who are resistant to high doses of inhaled corticosteroid but responsive to systemic corticosteroids and anti-IL5 therapy. The IL-17 signalling pathway is thought to contribute to 'neutrophilic asthma'. Although traditionally viewed as players in the defence mechanism against viral and intracellular bacterial infection, mounting evidence supports a role for Th1 cytokines such as IL-18 and IFN-γ in severe asthma pathogenesis. Furthermore, these cytokine signalling pathways interact to contribute to the spectrum of clinical pathological outcomes in severe asthma. To date, glucocorticoids are the most effective anti-asthma drugs available, yet severe asthma patients are typically resistant to the effects of glucocorticoids. Glucocorticoid receptor dysfunction and histone deacetylase activity reduction are likely to contribute to glucocorticoid resistance in severe asthma patients. This review discusses recent development in different cytokine signalling pathways, their interactions and steroid resistance, in the context of severe asthma pathogenesis.


Assuntos
Asma/etiologia , Acetilação , Animais , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Resistência a Medicamentos , Glucocorticoides/uso terapêutico , Histonas/metabolismo , Humanos , Índice de Gravidade de Doença , Transdução de Sinais
5.
Clin Genet ; 80(3): 273-80, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20880125

RESUMO

Mucolipidosis II (ML II alpha/beta), or I-cell disease, is a rare genetic disease in which activity of the uridine diphosphate (UDP)-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) is absent. GlcNAc-phosphotransferase is a multimeric enzyme encoded by two genes, GNPTAB and GNPTG. A spectrum of mutations in GNPTAB has been recently reported to cause ML II alpha/beta. Most of these mutations were found to be private or rare. However, the mutation c.3503_3504delTC has been detected among Israeli and Palestinian Arab-Muslim, Turkish, Canadian, Italian, Portuguese, Irish traveller and US patients. We analysed 44 patients who were either homozygous or compound heterozygous for this deletion (22 Italians, 8 Arab-Muslims, 1 Turk, 3 Argentineans, 3 Brazilians, 2 Irish travellers and 5 Portuguese) and 16 carriers (15 Canadians and 1 Italian) for three intragenic polymorphisms: c.-41_-39delGGC, c.18G>A and c.1932A>G as well as two microsatellite markers flanking the GNPTAB gene (D12S1607 and D12S1727). We identified a common haplotype in all chromosomes bearing the c.3503_3504delTC mutation. In summary, we showed that patients carrying the c.3503_3504delTC deletion presented with a common haplotype, which implies a common origin of this mutation. Additionally, the level of diversity observed at the most distant locus indicates that the mutation is relatively ancient (around 2063 years old), and the geographical distribution further suggests that it probably arose in a peri-Mediterranean region.


Assuntos
Árabes/genética , Mucolipidoses/genética , Transferases (Outros Grupos de Fosfato Substituídos) , Árabes/história , Canadá , Análise Mutacional de DNA , Demografia/história , Europa (Continente) , Feminino , Frequência do Gene , Haplótipos , Heterozigoto , História Antiga , Homozigoto , Humanos , América Latina , Masculino , Região do Mediterrâneo , Mucolipidoses/fisiopatologia , Filogenia , Polimorfismo Genético , Deleção de Sequência , Transferases (Outros Grupos de Fosfato Substituídos)/deficiência , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Turquia
6.
Allergy ; 64(5): 746-53, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19254290

RESUMO

BACKGROUND: Serum immunoglobulin E (IgE) level is recognized to be under strong genetic control, but the causal and susceptibility genes remain to be identified. We sought to investigate the association between single nucleotide polymorphisms (SNPs) in the Toll-like receptor (TLR) signaling pathway and total serum IgE level. METHODS: A population of 206 patients with severe chronic rhinosinusitis (CRS) was used. Precise phenotyping of patients was accomplished by means of a questionnaire and clinical examination. Blood was drawn for measurement of total serum IgE, as well as DNA extraction. A maximally informative set of SNPs in the TLR1, 2, 3, 4, 6, 9, 10, CD14, MD2, MyD88, IRAK4, and TRAF6 genes were selected and genotyped. Significant findings were replicated in a second independent population of 956 subjects from 227 families with asthma. RESULTS: A total of 97 out of 104 SNPs were successfully genotyped. Three SNPs in IRAK4--rs1461567, rs4251513, and rs4251559--were associated with total serum IgE levels (P < 0.004). In the replication sample, the same SNPs as well as the same orientation of the risk allele were associated with IgE levels (P < 0.031). CONCLUSIONS: These results demonstrate a clear association between polymorphisms in the IRAK4 gene and serum IgE levels in patients with CRS and asthma. IRAK4 may be important in the regulation of IgE levels in patients with inflammatory diseases of the airways.


Assuntos
Frequência do Gene/genética , Hipersensibilidade/genética , Imunoglobulina E/sangue , Quinases Associadas a Receptores de Interleucina-1/genética , Adulto , Doença Crônica , Estudos Transversais , Feminino , Frequência do Gene/imunologia , Genótipo , Humanos , Hipersensibilidade/imunologia , Quinases Associadas a Receptores de Interleucina-1/imunologia , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Inquéritos e Questionários
7.
Exp Lung Res ; 35(5): 399-410, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19842841

RESUMO

Allergic asthma is a complex trait. Several approaches have been used to identify biomarkers involved in this disease. This study aimed at demonstrating the relevance and validity of microarrays in the definition of allergic asthma expression pattern. The authors compared the transcript expressions of bronchial biopsy of 2 different microarray experiments done 2 years apart, both including nonallergic healthy and allergic asthmatic subjects (n = 4 in each experiment). U95Av2 and U133A GeneChips detected respectively 89 and 40 differentially expressed genes. Fifty-five percent of the U133A genes were previously identified with the U95Av2 arrays. The immune signaling molecules and the proteolytic enzymes were the most preserved categories between the 2 experiments, because 3/4 of the genes identified by the U133A were also significant in the U95Av2 study for both categories. These results demonstrate the relevance of microarray experiments using bronchial tissues in allergic asthma. The comparison of these GeneChip studies suggests that earlier microarray results are as relevant as actual ones to target new genes of interest, particularly in function categories linked to the studied disease. Moreover, it demonstrates that microarrays are a valuable technology to target novel allergic asthma pathways as well as biomarkers.


Assuntos
Asma/genética , Brônquios/química , Perfilação da Expressão Gênica/métodos , Hipersensibilidade/genética , Análise de Sequência com Séries de Oligonucleotídeos , Adulto , Asma/patologia , Asma/fisiopatologia , Biópsia , Brônquios/patologia , Brônquios/fisiopatologia , Testes de Provocação Brônquica , Broncoscopia , Estudos de Casos e Controles , Feminino , Volume Expiratório Forçado/genética , Predisposição Genética para Doença , Humanos , Hipersensibilidade/patologia , Hipersensibilidade/fisiopatologia , Masculino , Fenótipo , RNA/análise , Reprodutibilidade dos Testes , Capacidade Vital/genética , Adulto Jovem
8.
Clin Genet ; 73(3): 236-44, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18190596

RESUMO

Mucolipidosis (ML) II (I-cell disease) is a lysosomal storage disorder caused by a deficiency of UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase. MLII is an autosomal recessive disease with a carrier rate estimated at 1/39 in Saguenay-Lac-Saint-Jean (SLSJ) (Quebec, Canada), which is the highest frequency documented worldwide. To identify the causing mutation, we sequenced GNPTAB exons in 27 parents of 16 MLII-deceased children from the SLSJ region as obligatory and potential carriers. We also performed a genealogical reconstruction for each parent to evaluate consanguinity levels and genetic contribution of ancestors. Our goal was to identify which parameters could explain the high MLII frequency observed in the SLSJ population. A single mutation (c.3503_3504delTC) was found in all obligatory carriers. In addition, 11 apparent polymorphisms were identified. The mutation was not detected in genomic DNA of 50 unrelated controls. Genealogical data show six founders (three couples) with a higher probability of having introduced the mutation in the population. The frequency of the mutation was increased as a consequence of this founder effect and of the resulting population structure. We suggest that c.3503_3504delTC is the allele causing MLII in the SLSJ population, and its high carrier rate is most likely explained by a founder effect.


Assuntos
Efeito Fundador , Mucolipidoses/enzimologia , Mucolipidoses/genética , Mutação/genética , Transferases (Outros Grupos de Fosfato Substituídos)/genética , População Branca/genética , Canadá , Estudos de Casos e Controles , Consanguinidade , Análise Mutacional de DNA , Genealogia e Heráldica , Geografia , Humanos
9.
Community Genet ; 10(4): 218-26, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17895627

RESUMO

OBJECTIVES: The purpose of this project was to evaluate the potential of the downward hierarchical clustering analysis (DHCA) for studying genetic heterogeneity, i.e. differences in allele frequency in subpopulations, such as the 15 public health regions of the province of Québec (Canada). METHODS: The study relied on an anonymized sample of 1,680 individuals who had participated in the Québec Heart Health Survey in 1990-1991. The genotyping of 11 variants in 8 candidate genes known to be involved in chronic inflammatory diseases, namely asthma and cardiovascular diseases, was performed using the amplification refractory mutation system and restriction fragment length polymorphism techniques. Only variants showing an allelic frequency >2% in the Québec Heart Health Survey (n = 8) were selected. DHCA techniques were then applied to model the geographical distribution of these 8 genetic variants in 15 Québec public health regions and to study genetic heterogeneity. RESULTS: The DHCA allowed to group public health regions and gene variants on the basis of genetic variability. For both asthma and cardiovascular diseases, 3 significant clusters of public health regions and 1 cluster of gene variants were identified. DISCUSSION: This study suggests that DHCA might be useful in studying genetic heterogeneity at the population level and for public health activities.


Assuntos
Asma/genética , Doenças Cardiovasculares/genética , Polimorfismo Genético , Adolescente , Adulto , Idoso , Alelos , Asma/epidemiologia , Doenças Cardiovasculares/epidemiologia , Distribuição de Qui-Quadrado , Doença Crônica , Análise por Conglomerados , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genética Populacional , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Quebeque/epidemiologia
11.
Am J Med Genet ; 88(5): 567-87, 1999 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-10490718

RESUMO

We completed a genome-wide scan for susceptibility loci for bipolar affective disorders in families derived from a rather homogeneous population in the Province of Québec. The genetic homogeneity of this population stems from the migration of founding families into this relatively isolated area of Québec in the 1830s. A possible founder effect, combined with a prevalence of very large families, makes this population ideal for linkage studies. Genealogies for probands can be readily constructed from a population database of acts of baptism and marriage from the early 1830s up to the present time (the BALSAC register). We chose probands with a DSM III diagnosis of bipolar affective disorder and who may be grouped within large families having genealogical origins with the founding population of the Saguenay-Lac-St-Jean area. Living members (n approximately 120) of a very large pedigree were interviewed using the Structured Clinical Interview for DSM III (SCID I), SCID II, and with a family history questionnaire. A diagnostic panel evaluated multisource information (interview, medical records, family history) and pronounced best-estimate consensus diagnoses on all family members. Linkage, SimAPM, SimIBD, and sib-pair analyses have been performed with 332 microsatellite probes covering the entire genome at an average spacing of 11 cM. GENEHUNTER and haplotype analyses were performed on regions of interest. Analysis of a second large pedigree in the same regions of interest permitted confirmation of presumed linkages found in the region of chromosome 12q23-q24.


Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 12 , Ligação Genética , Cromossomos Humanos Par 5 , Feminino , Seguimentos , Heterogeneidade Genética , Marcadores Genéticos , Predisposição Genética para Doença , Testes Genéticos , Genótipo , Haplótipos , Humanos , Escore Lod , Masculino , Linhagem , Quebeque
12.
Can Respir J ; 5(1): 16-21, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9556503

RESUMO

Asthma treatment has moved from bronchodilator therapy to an emphasis on anti-inflammatory therapy. Airway inflammation is believed to induce airway hyper-responsiveness (AHR) through the release of mediators that increase the airway response to agonists. However, the exact contribution of airway inflammation in the physiology of airway hyper-responsiveness remains undefined. Structural modifications in airways resulting from inflammation may contribute to the development and persistence of AHR and the development of asthma. This paper reviews some of the main components of airway inflammation and structural changes in asthma, and discusses how these processes may interact to modify airway function and induce respiratory symptoms.


Assuntos
Asma/etiologia , Asma/patologia , Brônquios/patologia , Hiper-Reatividade Brônquica/fisiopatologia , Resistência das Vias Respiratórias , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Citocinas/fisiologia , Epitélio/patologia , Fibrose/etiologia , Humanos , Inflamação/patologia , Esteroides
13.
Genes Immun ; 7(8): 632-9, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17082760

RESUMO

CX3CR1, a fractalkine receptor, mediates cell-adhesive and migratory functions in inflammation. Based on CX3CR1 expression observed in bronchial tissues of asthmatic subjects, we hypothesized that genetic variation at this locus may affect susceptibility to asthma. We carried out an association study and a haplotypic analysis with selected polymorphisms of the CX3CR1 in a familial asthmatic sample from a founder population. Genetic analyses performed by FBAT software showed five CX3CR1 single nucleotide polymorphisms (rs938203, rs2669849, rs1050592, T280M and V249I) with significant associations between their common alleles and asthma (P<0.004) in a dominant model. A haplotype formed with common alleles of rs1050592, T280M and V249I is also overtransmitted in asthmatic subjects (P=0.005) under a dominant model. The associations of V249I and rs2669849 have been validated in an independent case-control sample. For V249I, odds ratios (OR) are 2.16 (common homozygous) and 2.11 (heterozygous) in dominant model (P=0.031). For rs2669849, OR are 2.75 (common homozygous) and 1.86 (heterozygous) in additive model (P=0.007) and dominant model (P=0.059). These results suggest an asthma protective effect of the minor alleles in healthy control carriers. Further functional studies of CX3CR1 are needed to document its role in the pathophysiology of asthma.


Assuntos
Asma/genética , Predisposição Genética para Doença , Variação Genética , Receptores de Quimiocinas/genética , Adolescente , Adulto , Receptor 1 de Quimiocina CX3C , Feminino , Componentes do Gene , Haplótipos/genética , Humanos , Desequilíbrio de Ligação , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Quebeque , Receptores de Quimiocinas/metabolismo
14.
Genes Immun ; 6(6): 519-27, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15988535

RESUMO

Reduced infection by mycobacteria, including Mycobacterium tuberculosis, may be partly responsible for increased prevalence of allergic and autoimmune diseases in developed countries. In a murine model of innate resistance to mycobacteria, the Nramp1 gene has been shown to affect asthma susceptibility. From this observation, it was proposed that human NRAMP1 may be a modulator of asthma risk in human populations. To experimentally test the candidacy of NRAMP1 in asthma susceptibility, we characterized five genetic variants of NRAMP1 (5'CAn, 274C>T, 469+14G>C, D543N, and 1729+del4) in an asthma family-based cohort from northeastern Quebec. We did not observe any significant association between NRAMP1 variants (either allele or haplotype specific) with asthma, atopy, or serum immunoglobulin E levels. These results demonstrate that, in spite of direct involvement of Nramp1 in a murine asthma model, in human populations NRAMP1 is not likely to be a major contributor to the genetic etiology of asthma and asthma-related phenotypes.


Assuntos
Asma/genética , Proteínas de Transporte de Cátions/genética , Predisposição Genética para Doença , Hipersensibilidade Imediata/genética , Polimorfismo de Nucleotídeo Único , Canadá , Genótipo , Haplótipos , Humanos , Imunoglobulina E/sangue , População Branca/genética
15.
Clin Invest Med ; 19(6): 461-9, 1996 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8959356

RESUMO

OBJECTIVE: To determine whether there is an increased prevalence and degree of airway hyperresponsiveness (AHR) and atopy in families of patients with asthma. DESIGN: Case-control study. SETTING: Asthma clinic and surrounding community. PATIENTS: A group of 28 families (n = 122) with one member who had attended the asthma clinic and a control group of 28 families (n = 122) from the same community. INTERVENTIONS: Each family member completed a questionnaire and underwent expiratory flow measurement, skin prick tests for allergies, methacholine tests and measurement of total serum IgE level and blood eosinophil count. OUTCOME MEASURES: Presence of atopy and AHR and relations between asymptomatic AHR or asthma and atopy, serum IgE levels or blood eosinophil counts. RESULTS: The group of families with a member with asthma had an increased prevalence of atopy and AHR, lower PC20 methacholine and higher serum IgE levels in comparison with controls, even when the first identified family members with asthma and their matched controls were not included. The subjects with atopy in the group with a patient with asthma had higher atopic indices and serum IgE levels than those in the control group, in whom asymptomatic AHR was less closely related to atopy. There was a significant correlation between PC20 methacholine level and atopic index, between blood eosinophil count and serum IgE level, and between atopic index and serum IgE level, for all groups. The proportion of women with asymptomatic AHR was almost twice as high as that of men. CONCLUSION: First-degree relatives of subjects with asthma have a higher prevalence of AHR, atopy and elevated serum IgE levels than controls from nonasthmatic families. Subjects with atopy in families of patients with asthma have higher atopic indices and degree of AHR than controls with atopy.


Assuntos
Asma/genética , Asma/fisiopatologia , Volume Expiratório Forçado , Hipersensibilidade Imediata , Cloreto de Metacolina , Adulto , Alérgenos/imunologia , Asma/imunologia , Eosinófilos , Feminino , Humanos , Imunoglobulina E/sangue , Contagem de Leucócitos , Masculino , Cloreto de Metacolina/administração & dosagem , Testes Cutâneos
16.
Am J Respir Crit Care Med ; 156(2 Pt 1): 403-9, 1997 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9279216

RESUMO

The physiopathology and significance of asymptomatic airway hyperresponsiveness (AHR) are still to be defined. Over a 3-yr period, we compared clinical, immunologic, and physiologic features of 30 subjects who had asymptomatic AHR with those of 30 symptomatic asthmatic subjects and 30 normoresponder subjects (age: 31.9 +/- 1.4 yr [mean +/- SEM]; n = 90). Each subject completed a respiratory questionnaire and underwent spirometry, measurement of bronchodilator response and peak expiratory flows, an allergy skin-prick test, blood eosinophil count, assay for total serum IgE level, and methacholine challenge. These tests were repeated annually, at the same period of the year, for 3 yr. Subjects with asymptomatic AHR had greater bronchodilator responses (p = 0.001), variability of peak expiratory flow rate (PEFR) (p = 0.02), and prevalence of atopy (p = 0.02) than did the normoreactive subjects. Compared with asthmatic subjects, subjects with asymptomatic AHR had a lower blood eosinophil count (p = 0.004), higher mean FEV1 (p = 0.006), and weaker bronchodilator response (p = 0.02), but an even greater perception of bronchoconstriction (p < 0.001). After 3 yr, the concentration of methacholine provoking a 20% decrease in FEV1 (PC20) had decreased significantly in the asymptomatic AHR subjects (p < 0.0001) as compared with the other two groups, and of the 28 subjects studied at this time, four (14.3%) had developed asthma symptoms. These last four subjects were atopic and exposed to animals when they developed asthma, had a familial history of asthma, and had an increased baseline AHR as compared with the subjects who did not develop symptoms. In conclusion, this study shows that over a 3-yr period, subjects with asymptomatic AHR had a greater increase in airway responsiveness and frequency of development of asthma symptoms than did normoresponsive subjects. Allergen exposure in sensitized subjects at the time of the study, and genetic predisposition, seemed the main risk factors for the development of symptomatic asthma in this population.


Assuntos
Asma/fisiopatologia , Hiper-Reatividade Brônquica/diagnóstico , Adolescente , Adulto , Idoso , Análise de Variância , Asma/diagnóstico , Asma/imunologia , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/fisiopatologia , Testes de Provocação Brônquica/estatística & dados numéricos , Broncoconstritores , Feminino , Seguimentos , Humanos , Hipersensibilidade Imediata/imunologia , Hipersensibilidade Imediata/fisiopatologia , Masculino , Cloreto de Metacolina , Pessoa de Meia-Idade , Caracteres Sexuais , Inquéritos e Questionários , Fatores de Tempo
17.
Respiration ; 63(5): 304-8, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8885004

RESUMO

Tachyphylaxis to methacholine has been reported in nonasthmatic subjects. In a recent study on the prevalence of airway hyperresponsiveness (AHR) and atopy, we performed duplicate methacholine inhalation tests at a 60-min interval, in subjects with symptomatic asthma (n = 33), asymptomatic AHR (AAHR) (n = 72) and in a group of normal subjects (n = 130); 135/235 subjects were atopic. All subjects had a respiratory questionnaire, allergy skin prick tests, blood eosinophil counts and determination of total serum IgE level. In asthmatic subjects, PC20 just failed to be significantly higher on a second methacholine challenge (p = 0.09); when they were stratified according to severity of AHR and use of inhaled corticosteroids, we observed a significant increase in PC20 on the second test in asthmatic subjects with mild AHR not using corticosteroids (p < 0.01). In normal controls, PC20 methacholine was slightly increased on rechallenge (p < 0.01) as it was in those with AAHR (p < 0.01). There was no relationship between the magnitude of the change in PC20 and age, sex, baseline airway responsiveness, percent fall in FEV1 on the first challenge, atopic score, blood eosinophil counts and serum IgE levels. In conclusion, tachyphylaxis to methacholine is observed in normal or mild asthmatic subjects not using inhaled corticosteroids and in subjects with AAHR; however, in most subjects this change is of a small magnitude.


Assuntos
Asma/imunologia , Broncoconstritores , Cloreto de Metacolina , Hipersensibilidade Respiratória/imunologia , Taquifilaxia/fisiologia , Eosinófilos , Feminino , Humanos , Imunoglobulina E/sangue , Contagem de Leucócitos , Masculino , Testes Cutâneos
18.
Eur Respir J ; 14(1): 63-73, 1999 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10489830

RESUMO

To study the physiopathology and significance of asymptomatic airway hyperresponsiveness (AHR), the clinical and bronchial immunohistological parameters were evaluated in subjects with asymptomatic and symptomatic AHR. Asymptomatic subjects with AHR (eight females/two males, no respiratory symptoms, provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (PC20) <8 mg x mL(-1) and no treatment) were compared with asthmatic subjects paired for age, sex and PC20, and with nonatopic, nonasthmatic controls paired for age and sex. All three groups were evaluated once at baseline, whilst the asymptomatic AHR subjects were re-evaluated after 1 and 2 yrs. Measurements included spirometry, methacholine challenge, serum immunoglobulin (Ig)E, blood eosinophils, and bronchoscopy (at baseline and after 2 yrs only). At first evaluation, the mean blood eosinophil count, total serum IgE level, atopic index, baseline forced expiratory volume in one second (FEV1) and the degree of bronchial epithelial desquamation of the asymptomatic AHR subjects were similar to those of asthmatic subjects. However, they presented focal rather than the continuous bronchial subepithelial fibrosis observed in asthmatics. Their mucosal CD3, CD4, CD25, EG1 and EG2-positive cell counts were intermediate between those of the control subjects and asthmatics. At the end of the 2-yr follow-up, four of them had developed asthma symptoms. At this time, bronchial biopsies revealed an increase in the extent of subepithelial fibrosis and in the number of CD25 and CD4-positive cells, and a decrease in the number of CD8+ cells, particularly in subjects who developed asthma symptoms. These data suggest that asymptomatic airway hyperresponsiveness is associated with airway inflammation and remodelling, and that the appearance of asthma symptoms is associated with an increase in these features, particularly the CD4/CD8 ratio and airway fibrosis. Consequently, this study proposes an association between asymptomatic airway hyperresponsiveness and airway inflammation, structural changes and asthma although these relationships remain to be further evaluated.


Assuntos
Hiper-Reatividade Brônquica/fisiopatologia , Bronquite/fisiopatologia , Adolescente , Adulto , Asma/imunologia , Asma/patologia , Asma/fisiopatologia , Biópsia , Brônquios/imunologia , Brônquios/ultraestrutura , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/patologia , Bronquite/imunologia , Bronquite/patologia , Broncoscopia , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Seguimentos , Humanos , Imunoglobulina E/imunologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Linfócitos T/imunologia , Linfócitos T/patologia
19.
Immunogenetics ; 51(8-9): 695-702, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10941841

RESUMO

Following detection of linkage between atopy and chromosome 11q13 markers, association between this disorder and variants of the beta subunit of the high-affinity receptor for immunoglobulin E (FcepsilonRI-beta, a candidate gene for asthma-related conditions co-localizing within the same region) was reported in Australian, British and Japanese populations. Investigations in several other ethnic groups failed to replicate these observations. Due to the complexity of defining intermediate phenotypes related to asthma, detection of such associations may have been hampered by clinical misclassifications. To assess whether the FcepsilonRI-beta gene was involved in atopy and/or airway hyperresponsiveness (AHR) in the French-Canadian population, we conducted a case-control study in 200 subjects using strict criteria for asthma and related conditions. The Ile181Leu and Glu237Gly FcepsilonRI-beta sequence variants were tested exploiting two amplification refractory mutation systems. No association was detected between atopy or AHR and the Ile181Leu FcepsilonRI-beta variant. However, a strong association was observed between atopy and the Glu237Gly FcepsilonRI-beta variant (odds ratio=12.25). Four large Eastern Québec families (n=106 subjects) were also recruited to perform a genetic linkage study. We observed suggestive evidence of linkage between atopy and the Glu237Gly FcepsilonRI-beta variant (Zmax=2.30). This study is the first to detect the presence of an association between atopy and the Glu237Gly FcepsilonRI-beta variant in French-Canadians. Our data suggest that a susceptibility locus for atopy is located on chromosome 11q13 in this population.


Assuntos
Asma/genética , Ligação Genética , Variação Genética , Hipersensibilidade Imediata/genética , Receptores de IgE/genética , Adulto , Canadá , Estudos de Casos e Controles , Feminino , França/etnologia , Ácido Glutâmico/genética , Glicina/genética , Humanos , Masculino , Linhagem
20.
Clin Exp Allergy ; 27(1): 52-9, 1997 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9117881

RESUMO

BACKGROUND AND OBJECTIVES: The determinants of variability in the clinical expression of atopy are still to be documented. The goals of this study were to determine, in subjects with a clinical diagnosis of symptomatic asthma or rhinitis, what is the possible contribution of different types of indoor and outdoor allergens to the development of their disease, by looking at the prevalence and degree of sensitization to these allergens according to age and gender. SUBJECTS AND METHODS: We analysed allergy skin prick tests to common airborne indoor and outdoor allergens in 3371 consecutive patients, grouped according to diagnosis of allergic asthma, rhinitis, or both. For each of these three groups, we calculated the prevalence of sensitization to indoor/outdoor allergens, the atopic index (AI), the number of positive responses to allergy skin prick test and the mean wheal diameter (MWD) of these responses. RESULTS: The prevalence of atopy and the values of AI and MWD peaked in subjects aged 16 to 25 years, declining afterwards; in subjects > or = 18 years old, atopic indices were slightly higher in men than in women. In atopic subjects, the prevalence of sensitization was, in decreasing order, housedust (84.2%), cat hair-epithelium (76.5%), dog hair-dander (63.0%), house dust mite (54.2%), grasses (51.9%), trees (47.2%) and ragweed pollens (44.9%) and finally, moulds (25.4%). Among subjects sensitized only to outdoor allergens (n = 195). 73.8% had a rhinitis, 11.8% had asthma and 14.4% had both diagnoses; for those sensitized only to indoor allergens (n = 710), these values were respectively 48.6, 24.5 and 26.9%, and for those sensitized to both indoor and outdoor allergens (n = 1793), the comparable values were 55.5, 14.6 and 29.9%. CONCLUSION: These data show that in our population of subjects with respiratory allergic symptoms, indoor allergen sensitization is strongly associated with asthma, while exclusive sensitization to pollens is associated primarily with rhinitis. Sensitization was more prevalent for indoor allergens than for outdoor allergens in all groups determined according to diagnosis or age. Indices of atopy were higher in men in the group > or = 18 years old. Prevalence and degree of sensitization were shown to peak in young adults, regardless of the allergen, and to diminish with age. This study stresses the role of indoor allergens in the development of asthma and shows the variability of allergic manifestations according to the type of sensitization.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Alérgenos/efeitos adversos , Asma/epidemiologia , Imunização , Rinite/epidemiologia , Adolescente , Adulto , Idoso , Poluentes Atmosféricos/imunologia , Alérgenos/imunologia , Alternaria/imunologia , Animais , Antígenos de Fungos/efeitos adversos , Asma/etiologia , Asma/imunologia , Criança , Pré-Escolar , Feminino , Cabelo/imunologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Ácaros/imunologia , Pólen/imunologia , Prevalência , Quebeque/epidemiologia , Rinite/etiologia , Rinite/imunologia , Testes Cutâneos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA