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 ÚnicoRESUMO
Leukocyte immunoglobulin-like receptors (LILR) are expressed mostly on myelomonocytic cells where they are mediators of immunological tolerance. Two LILR genes, LILRA3 and LILRA6, exhibit marked copy number variation. We assessed the contribution of these genes to atopic dermatitis (AD) by analysing transmission in 378 AD families. The data indicated that copies of LILRA6 were over-transmitted to affected patients. They are consistent with a contribution of LILR genes to AD. They could affect the equilibrium between activating and inhibitory signals in the immune response.
Assuntos
Variações do Número de Cópias de DNA/genética , DNA/genética , Dermatite Atópica/genética , Dermatite Atópica/patologia , Suscetibilidade a Doenças , Receptores Imunológicos/genética , Criança , DNA/análise , Feminino , Humanos , Masculino , Reação em Cadeia da PolimeraseRESUMO
The immunoglobulin E (IgE)-associated locus on human chromosome 13q14 influencing asthma-related traits contains the genes PHF11 and SETDB2. SETDB2 is located in the same linkage disequilibrium region as PHF11 and polymorphisms within SETDB2 have been shown to associate with total serum IgE levels. In this report, we sequenced the 15 exons of SETDB2 and identified a single previously ungenotyped mutation (AT/G, rs386770867) in the 5'-untranslated region of the gene. The polymorphism was found to be significantly associated with serum IgE levels in our asthma cohort (P=0.0012). Electrophoretic mobility shift assays revealed that the transcription factor Ying Yang 1 binds to the AT allele, whereas SRY (Sex determining Region Y) binds to the G allele. Allele-specific transcription analysis (allelotyping) was performed in 35 individuals heterozygous for rs386770867 from a panel of 200 British families ascertained through probands with severe stage 3 asthma. The AT allele was found to be significantly overexpressed in these individuals (P=1.26×10(-21)). A dual-luciferase assay with the pGL3 luciferase reporter gene showed that the AT allele significantly affects transcriptional activities. Our results indicate that the IgE-associated AT/G polymorphism (rs386770867) regulates transcription of SETDB2.
Assuntos
Regiões 5' não Traduzidas , Cromossomos Humanos Par 13 , Histona-Lisina N-Metiltransferase/genética , Imunoglobulina E/genética , Proteínas Metiltransferases/genética , Adolescente , Adulto , Asma/enzimologia , Asma/genética , Criança , Ensaio de Desvio de Mobilidade Eletroforética , Éxons , Feminino , Humanos , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , População BrancaRESUMO
The beta-subunit of the high-affinity IgE receptor (Fc epsilon RI-beta) on chromosome 11 is maternally linked to atopy, the state of enhanced IgE responsiveness underlying allergic asthma and rhinitis. We have identified a common variant of Fc epsilon RI-beta, lle181Leu within the 4th transmembrane domain. Leu181 shows significant association with positive IgE responses in a random patient sample. Amongst 60 unrelated nuclear families with allergic asthmatic probands, Leu181 is identified in 10 (17%), is maternally inherited in each, and shows a strong association with atopy. Our data indicate that Fc epsilon RI-beta, subject to maternal modification, may be the atopy-causing locus on chromosome 11q.
Assuntos
Hipersensibilidade Imediata/genética , Hipersensibilidade Imediata/imunologia , Receptores de IgE/genética , Sequência de Aminoácidos , Sequência de Bases , Cromossomos Humanos Par 11 , DNA/genética , Feminino , Variação Genética , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Receptores de IgE/químicaRESUMO
We have carried out a genome screen for atopic dermatitis (AD) and have identified linkage to AD on chromosomes 1q21, 17q25 and 20p. These regions correspond closely with known psoriasis loci, as does a previously identified AD locus on chromosome 3q21. The results indicate that AD is influenced by genes with general effects on dermal inflammation and immunity.
Assuntos
Dermatite Atópica/genética , Ligação Genética , Predisposição Genética para Doença , Psoríase/genética , Criança , HumanosRESUMO
Atopic dermatitis (AD) and asthma are characterized by IgE-mediated atopic (allergic) responses to common proteins (allergens), many of which are proteinases. Loci influencing atopy have been localized to a number of chromosomal regions, including the chromosome 5q31 cytokine cluster. Netherton disease is a rare recessive skin disorder in which atopy is a universal accompaniment. The gene underlying Netherton disease (SPINK5) encodes a 15-domain serine proteinase inhibitor (LEKTI) which is expressed in epithelial and mucosal surfaces and in the thymus. We have identified six coding polymorphisms in SPINK5 (Table 1) and found that a Glu420-->Lys variant shows significant association with atopy and AD in two independent panels of families. Our results implicate a previously unrecognized pathway for the development of common allergic illnesses.
Assuntos
Asma/genética , Proteínas de Transporte , Dermatite Atópica/genética , Polimorfismo de Nucleotídeo Único , Inibidores de Serina Proteinase/genética , Sequência de Aminoácidos , Sequência de Bases , Primers do DNA , Humanos , Dados de Sequência Molecular , Proteínas Secretadas Inibidoras de Proteinases , Homologia de Sequência de Aminoácidos , Inibidor de Serinopeptidase do Tipo Kazal 5RESUMO
BACKGROUND: The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. OBJECTIVE: To identify common genetic variants affecting susceptibility to severe asthma. METHODS: A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480â889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. RESULTS: An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10((-8)) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10((-8)) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. CONCLUSIONS: The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.
Assuntos
Asma/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , População Branca/genética , Austrália , Estudos de Casos e Controles , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Metanálise como Assunto , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin condition that is characterized by a defective skin barrier. Despite the well-recognized role of proteases in skin barrier maintenance, relatively little is known of the contribution made by matrix metalloproteinases (MMPs) to the inflammatory process in AD. OBJECTIVES: To test a simple, novel ex vivo bioassay technique in an analysis of the MMPs present in wash samples taken from the skin surface of patients with AD. METHODS: Saline wash samples were collected from eczematous and unaffected areas of the skin of patients with AD and from the skin of normal controls. Wash samples were analysed for their MMP content using a functional peptide cleavage assay, gelatin zymography and an antibody array. RESULTS: Using a functional substrate cleavage assay, skin wash samples from AD lesions were shown to contain 10- to 24-fold more MMP activity than those from normal control skin (P < 0.02) and fivefold more than those from unaffected AD skin (P < 0.05); this activity was inhibited by a broad-spectrum MMP inhibitor Ro 31-9790. Gelatin zymography and antibody array analysis revealed substantial levels of MMP-8 (neutrophil collagenase) and MMP-9 (92-kDa gelatinase) in AD skin wash samples as well as lower levels of MMP-10 (stromelysin 2) and tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2; low levels of MMP-1 (fibroblast collagenase), MMP-3 (stromelysin 1) and TIMP-4 were also detected. CONCLUSIONS: A simple skin wash technique suitable for the quantitative and functional analysis of biomolecules in AD is described. Using this method we show that MMPs, and in particular MMP-8 and MMP-9, represent an important potential component of the pathology of AD. The method is expected to prove useful in advancing our understanding of AD and in identifying biomarkers for the evaluation of new therapies.
Assuntos
Dermatite Atópica/metabolismo , Metaloproteinases da Matriz/metabolismo , Pele/metabolismo , Adolescente , Biomarcadores/análise , Biomarcadores/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Humanos , Metaloproteinases da Matriz/análise , Índice de Gravidade de Doença , Pele/patologia , Testes Cutâneos/métodos , Inibidores Teciduais de Metaloproteinases/análise , Inibidores Teciduais de Metaloproteinases/metabolismoRESUMO
BACKGROUND: Common polymorphisms have been identified in genes suspected to play a role in asthma. We investigated their associations with wheeze and allergy in a case-control sample from Phase 2 of the International Study of Asthma and Allergies in Childhood. METHODS: We compared 1105 wheezing and 3137 non-wheezing children aged 8-12 years from 17 study centres in 13 countries. Genotyping of 55 candidate single nucleotide polymorphisms (SNPs) in 14 genes was performed using the Sequenom System. Logistic regression models were fitted separately for each centre and each SNP. A combined per allele odds ratio and measures of heterogeneity between centres were derived by random effects meta-analysis. RESULTS: Significant associations with wheeze in the past year were detected in only four genes (IL4R, TLR4, MS4A2, TLR9, P<0.05), with per allele odds ratios generally <1.3. Variants in IL4R and TLR4 were also related to allergen-specific IgE, while polymorphisms in FCER1B (MS4A2) and TLR9 were not. There were also highly significant associations (P<0.001) between SPINK5 variants and visible eczema (but not IgE levels) and between IL13 variants and total IgE. Heterogeneity of effects across centres was rare, despite differences in allele frequencies. CONCLUSIONS: Despite the biological plausibility of IgE-related mechanisms in asthma, very few of the tested candidates showed evidence of association with both wheeze and increased IgE levels. We were unable to confirm associations of the positional candidates DPP10 and PHF11 with wheeze, although our study had ample power to detect the expected associations of IL13 variants with IgE and SPINK5 variants with eczema.
Assuntos
Estudos de Associação Genética , Hipersensibilidade/genética , Sons Respiratórios/genética , Alérgenos/imunologia , Ásia , Asma/genética , Criança , Proteínas de Ligação a DNA/genética , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Equador , Eczema/genética , Europa (Continente) , Frequência do Gene/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Hipersensibilidade/sangue , Hipersensibilidade/imunologia , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Interleucina-13/genética , Subunidade alfa de Receptor de Interleucina-4/genética , Desequilíbrio de Ligação/genética , Receptores de Lipopolissacarídeos/genética , Nova Zelândia , Polimorfismo de Nucleotídeo Único/genética , Proteínas Secretadas Inibidoras de Proteinases/genética , Receptores de IgE/genética , Sons Respiratórios/imunologia , Rinite Alérgica Perene/genética , Rinite Alérgica Sazonal/genética , Inibidor de Serinopeptidase do Tipo Kazal 5 , Testes Cutâneos , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética , Receptor Toll-Like 9/genética , Fatores de Transcrição/genética , Fator de Crescimento Transformador beta1/genética , Fator de Necrose Tumoral alfa/genéticaRESUMO
The relative importance of atopy in the aetiology of rhinitis is largely unknown. The present study investigated the geographical variations in rhinitis in relation to atopy. The cross-sectional study involved 54,178 children (aged 8-12 yrs) from 30 study centres in 22 countries worldwide. Symptoms of rhinoconjunctivitis and rhinitis without conjunctivitis in the last 12 months were reported in parental questionnaires and children were skin-prick tested. The prevalence of rhinoconjunctivitis and rhinitis without conjunctivitis varied widely (1.5-24.5% and 1.4-45.2%, respectively). For rhinoconjunctivitis, the population attributable fraction (PAF) varied 0-71% for a positive skin-prick test to one or more seasonal allergens and 0-41% for perennial allergens. The PAF for sensitisation to seasonal and perennial allergens was higher in affluent countries (36 and 25%, respectively) than nonaffluent countries (1.3 and 12.6%, respectively). For rhinitis without conjunctivitis, the PAF for perennial allergens was 8 and 4% for affluent and nonaffluent countries, respectively. No significant PAF was found for seasonal allergens. Overall, atopy explained only a limited proportion of rhinitis symptoms, suggesting that the importance of other environmental factors has been under emphasised, particularly in less affluent countries. Atopy seems to be only marginally relevant for rhinitis without conjunctivitis, which seems mainly to reflect nonatopic rhinitis.
Assuntos
Hipersensibilidade/metabolismo , Rinite Alérgica Perene/epidemiologia , Rinite Alérgica Sazonal/epidemiologia , Rinite/imunologia , Alérgenos , Criança , Conjuntivite/metabolismo , Estudos Transversais , Feminino , Humanos , Masculino , Modelos Estatísticos , Prevalência , Rinite/metabolismo , Rinite Alérgica Perene/diagnóstico , Rinite Alérgica Sazonal/diagnóstico , Estações do Ano , Testes CutâneosRESUMO
Genome-wide screens are consistently finding linkage between asthma-associated traits and specific chromosomal loci. Several loci coincide with linkages to other inflammatory diseases, suggesting the presence of common pathways in their pathogenesis. Candidate-gene studies have found an association between a CD14 polymorphism and IgE levels, suggesting a mechanism for the increased prevalence of allergic disease. A polymorphism in Fc epsilon RI-beta shows parent-of-origin effects when associated with severe infantile eczema, further illustrating the complexity of gene-environment effects on the developing immune system.
Assuntos
Asma/genética , Inflamação/genética , Previsões , HumanosRESUMO
BACKGROUND: Genome-wide association studies have identified novel genetic associations for asthma, but without taking into account the role of active tobacco smoking. This study aimed to identify novel genes that interact with ever active tobacco smoking in adult onset asthma. METHODS: We performed a genome-wide interaction analysis in six studies participating in the GABRIEL consortium following two meta-analyses approaches based on 1) the overall interaction effect and 2) the genetic effect in subjects with and without smoking exposure. We performed a discovery meta-analysis including 4,057 subjects of European descent and replicated our findings in an independent cohort (LifeLines Cohort Study), including 12,475 subjects. RESULTS: First approach: 50 SNPs were selected based on an overall interaction effect at p<10-4. The most pronounced interaction effect was observed for rs9969775 on chromosome 9 (discovery meta-analysis: ORint = 0.50, p = 7.63*10-5, replication: ORint = 0.65, p = 0.02). Second approach: 35 SNPs were selected based on the overall genetic effect in exposed subjects (p <10-4). The most pronounced genetic effect was observed for rs5011804 on chromosome 12 (discovery meta-analysis ORint = 1.50, p = 1.21*10-4; replication: ORint = 1.40, p = 0.03). CONCLUSIONS: Using two genome-wide interaction approaches, we identified novel polymorphisms in non-annotated intergenic regions on chromosomes 9 and 12, that showed suggestive evidence for interaction with active tobacco smoking in the onset of adult asthma.
Assuntos
Asma/induzido quimicamente , Asma/genética , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Fumar/efeitos adversos , Adulto , Estudos de Coortes , Predisposição Genética para Doença/genética , Humanos , Polimorfismo de Nucleotídeo ÚnicoAssuntos
Asma/prevenção & controle , Dessensibilização Imunológica , Vacinação , Adulto , Alérgenos/efeitos adversos , Alérgenos/genética , Alérgenos/imunologia , Alérgenos/uso terapêutico , Animais , Asma/etiologia , Asma/imunologia , Criança , Dessensibilização Imunológica/efeitos adversos , Humanos , Hipersensibilidade Imediata/complicações , Tolerância Imunológica , Camundongos , Pessoa de Meia-IdadeAssuntos
Alérgenos/uso terapêutico , Arachis/imunologia , Terapia Genética/métodos , Hipersensibilidade Imediata/terapia , Administração Oral , Anafilaxia/terapia , Animais , Hipersensibilidade/terapia , Hipersensibilidade Imediata/economia , Tolerância Imunológica , Imunoglobulina E/imunologia , CamundongosRESUMO
NIDDM has a strong genetic component, as evidenced by the high level of concordance between identical twins. The nature of the genetic predisposition has remained largely unknown. Recently, the glucokinase gene locus on chromosome 7p has been shown to be linked to a subtype of NIDDM known as MODY in French and British pedigrees, and glucokinase mutations have been identified. To study the relationship between the glucokinase gene and NIDDM, we performed a linkage analysis in 12 Caucasian pedigrees ascertained through a proband with classical NIDDM. The LINKAGE program was used under four models, including autosomal dominant and recessive, with individuals with glucose intolerance counted as either affected or of unknown status. Linkage was significantly rejected with the dominant models (LOD scores -4.65, -4.25), and was unlikely with the recessive model when glucose intolerance was considered as affected (LOD score -1.38). These findings suggest that mutations in or near the glucokinase gene are unlikely to be the major cause of the inherited predisposition to NIDDM in Caucasian pedigrees, but do not exclude a role for this locus with a polygenic model, or a major role in some pedigrees.
Assuntos
Diabetes Mellitus Tipo 2/genética , Ligação Genética , Glucoquinase/genética , População Branca/genética , Adulto , Idoso , Sequência de Bases , DNA/sangue , DNA/genética , DNA/isolamento & purificação , Diabetes Mellitus Tipo 2/enzimologia , Família , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos , Linhagem , Reação em Cadeia da PolimeraseRESUMO
High-resolution mapping is essential for the positional cloning of complex disease genes. In outbred populations, linkage disequilibrium is expected to extend for short distances and could provide a powerful fine-mapping tool. Current family-based association tests use nuclear family members to define allelic transmission and controls, but ignore other types of relatives. Here we construct a general approach for scoring allelic transmission that accommodates families of any size and uses all available genotypic information. Family data allows for the construction of an expected genotype for every non-founder, and orthogonal deviates from this expectation are a measure of allelic transmission. These allelic transmission scores can be used to extend previously described tests of linkage disequilibrium for dichotomous or quantitative traits. Some of these tests are illustrated, together with a permutation framework for estimating exact significance levels. Simulation studies are used to investigate power and error rates of the approach. As a practical application, the method is used to investigate the relationship between circulating angiotensin-1 converting enzyme (ACE) levels and polymorphisms in the ACE gene using previously published data.
Assuntos
Mapeamento Cromossômico/métodos , Desequilíbrio de Ligação/genética , Peptidil Dipeptidase A/genética , Alelos , Simulação por Computador , Análise Mutacional de DNA , Doenças Genéticas Inatas/enzimologia , Doenças Genéticas Inatas/genética , Genótipo , Humanos , Modelos Genéticos , Linhagem , Penetrância , Peptidil Dipeptidase A/metabolismo , Polimorfismo Genético , PrevalênciaRESUMO
Asthma is a common, genetically complex human disease. Elevated serum immunoglobulin E (IgE) levels, elevated blood eosinophil counts, variably reduced spirometric measures and increased airway responsiveness (AR) are physiological traits which are characteristic of asthma. We investigated the genetic and environmental components of variance of serum total and specific IgE levels, blood eosinophil counts, the forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), and AR in an Australian population-based sample of 232 Caucasian nuclear families. With the exception of FVC levels, all traits were closely associated with clinical asthma in this population. Loge total serum IgE levels had a narrow-sense heritability (h2N) of 47.3% (SE = 10. 0%). Specific serum IgE levels against house dust mite and Timothy grass, measured as a RAST Index, had a h2N of 33.8% (SE = 7.3%). FEV1 levels had a h2N of 6.1% (SE = 11.6%), whilst FVC levels had a h2N of 30.6% (SE = 26.8%). AR, quantified by the loge dose-response slope to methacholine (DRS), had a h2N of 30.3% (SE = 12.3%). These data are consistent with the existence of important genetic determinants of the pathophysiological traits associated with asthma. Our study suggests that total and specific serum IgE levels, blood eosinophil counts and airways responsiveness to inhaled agonist are appropriate phenotypes for molecular investigations of the genetic susceptibility to asthma.
Assuntos
Asma/genética , Característica Quantitativa Herdável , Adolescente , Adulto , Fatores Etários , Asma/sangue , Asma/fisiopatologia , Austrália , Estatura , Estudos de Coortes , Interpretação Estatística de Dados , Eosinófilos/citologia , Saúde da Família , Feminino , Volume Expiratório Forçado , Humanos , Imunoglobulina E/sangue , Contagem de Leucócitos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Núcleo Familiar , Fatores Sexuais , FumarRESUMO
The region of human chromosome 6 containing the MHC has been identified as influencing asthma and atopy (allergy) by several genome-wide searches. The MHC contains many genes with potential effects on innate and specific immunity. As a first step in dissecting MHC influences on asthma and its underlying quantitative phenotypes, we have examined the HLA-DRB1 locus in a population sample consisting of 1004 individuals from 230 families from the rural Australian town of Busselton. The locus was strongly associated with the (log(e)) total serum IgE concentration, accounting for 4.0% of the sigma(2) (variance) in that trait (multi-allelic test, P=0.00001). The locus also influenced specific IgE titres to common allergens (multi-allelic tests, 2.8% sigma(2) for the house dust mite allergen Der p I, P=0.0013; 3.0% of sigma(2) for Der p II, P=0.0007; and 2.1% of sigma(2) for the cat allergen Fel d I, P=0.014). No associations were found to the categorical phenotype of asthma, or to the quantitative traits of peripheral blood eosinophil counts and bronchial hyper-responsiveness. Transmission disequilibrium tests excluded genetic admixture as a cause of false-positive findings. The results indicate that HLA-DRB1 alleles modulate the total serum IgE concentration and IgE responses to allergens, but do not account for the previous observations of linkage of asthma to the MHC.
Assuntos
Asma/genética , Antígenos HLA-DR/genética , Característica Quantitativa Herdável , Adulto , Asma/imunologia , Criança , Cromossomos Humanos Par 6 , Frequência do Gene , Variação Genética , Antígenos HLA-DR/imunologia , Cadeias HLA-DRB1 , Humanos , Masculino , Pessoa de Meia-Idade , FenótipoRESUMO
Atopy is a common and genetically heterogeneous syndrome predisposing to allergic asthma and rhinitis. A locus linked to the atopy phenotype has been shown to be present on chromosome 11q12-13. Linkage has only been seen in maternally derived alleles. We have constructed a genetic linkage map of the region, using 15 markers to span approximately 27 cM, and integrate previously published maps. Under a model of maternal inheritance, the atopy locus is placed within a 7-cM interval between D11S480 and D11S451. The interval contains the important candidate gene FCERIB.