Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 31
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nat Genet ; 51(10): 1486-1493, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31548716

RESUMO

Immune-disease-associated variants are enriched in active chromatin regions of T cells and macrophages. However, whether these variants function in specific cell states is unknown. Here we stimulated T cells and macrophages in the presence of 13 cytokines and profiled active and open chromatin regions. T cell activation induced major chromatin remodeling, while the presence of cytokines fine-tuned the magnitude of changes. We developed a statistical method that accounts for subtle changes in the chromatin landscape to identify SNP enrichment across cell states. Our results point towards the role of immune-disease-associated variants in early rather than late activation of memory CD4+ T cells, with modest differences across cytokines. Furthermore, variants associated with inflammatory bowel disease are enriched in type 1 T helper (TH1) cells, whereas variants associated with Alzheimer's disease are enriched in different macrophage cell states. Our results represent an in-depth analysis of immune-disease-associated variants across a comprehensive panel of activation states of T cells and macrophages.

2.
Nat Genet ; 51(2): 230-236, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30664745

RESUMO

Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we performed a genome-wide association study for osteoarthritis (77,052 cases and 378,169 controls), analyzing four phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discovered 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine-mapped to a single variant. We identified putative effector genes by integrating expression quantitative trait loci (eQTL) colocalization, fine-mapping, and human rare-disease, animal-model, and osteoarthritis tissue expression data. We found enrichment for genes underlying monogenic forms of bone development diseases, and for the collagen formation and extracellular matrix organization biological pathways. Ten of the likely effector genes, including TGFB1 (transforming growth factor beta 1), FGF18 (fibroblast growth factor 18), CTSK (cathepsin K), and IL11 (interleukin 11), have therapeutics approved or in clinical trials, with mechanisms of action supportive of evaluation for efficacy in osteoarthritis.


Assuntos
Predisposição Genética para Doença/genética , Osteoartrite do Quadril/genética , Adulto , Idoso , Bancos de Espécimes Biológicos , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Reino Unido
4.
Nat Genet ; 49(12): 1752-1757, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29083406

RESUMO

Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10-8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.


Assuntos
Asma/genética , Eczema/genética , Predisposição Genética para Doença/genética , Hipersensibilidade/genética , Rinite Alérgica Sazonal/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco
5.
J Allergy Clin Immunol ; 138(3): 748-753, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27038909

RESUMO

BACKGROUND: Asthma and allergic rhinitis (AR) are common allergic comorbidities with a strong genetic component in which epigenetic mechanisms might be involved. OBJECTIVE: We aimed to identify novel risk loci for asthma and AR while accounting for parent-of-origin effect. METHODS: We performed a series of genetic analyses, taking into account the parent-of-origin effect in families ascertained through asthma: (1) genome-wide linkage scan of asthma and AR in 615 European families, (2) association analysis with 1233 single nucleotide polymorphisms (SNPs) covering the significant linkage region in 162 French Epidemiological Study on the Genetics and Environment of Asthma families with replication in 154 Canadian Saguenay-Lac-Saint-Jean asthma study families, and (3) association analysis of disease and significant SNPs with DNA methylation (DNAm) at CpG sites in 40 Saguenay-Lac-Saint-Jean asthma study families. RESULTS: We detected a significant paternal linkage of the 4q35 region to asthma and allergic rhinitis comorbidity (AAR; P = 7.2 × 10(-5)). Association analysis in this region showed strong evidence for the effect of the paternally inherited G allele of rs10009104 on AAR (P = 1.1 × 10(-5), reaching the multiple-testing corrected threshold). This paternally inherited allele was also significantly associated with DNAm levels at the cg02303933 site (P = 1.7 × 10(-4)). Differential DNAm at this site was found to mediate the identified SNP-AAR association. CONCLUSION: By integrating genetic and epigenetic data, we identified that a differentially methylated CpG site within the melatonin receptor 1A (MTNR1A) gene mediates the effect of a paternally transmitted genetic variant on the comorbidity of asthma and AR. This study provides a novel insight into the role of epigenetic mechanisms in patients with allergic respiratory diseases.


Assuntos
Asma/genética , Ilhas de CpG , Herança Paterna , Receptor MT1 de Melatonina/genética , Rinite Alérgica/genética , Alelos , Asma/epidemiologia , Comorbidade , Metilação de DNA , Variação Genética , Genótipo , Humanos , Rinite Alérgica/epidemiologia
6.
Nat Commun ; 6: 8804, 2015 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-26542096

RESUMO

Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.


Assuntos
Asma/genética , Dermatite Atópica/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Adolescente , Adulto , Sistemas de Transporte de Aminoácidos Neutros/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas de Transporte/genética , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Progressão da Doença , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fator de Transcrição Ikaros/genética , Interleucina-4/genética , Cinesina/genética , Modelos Logísticos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Adulto Jovem
7.
Nat Genet ; 47(12): 1449-1456, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26482879

RESUMO

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.


Assuntos
Dermatite Atópica/etnologia , Dermatite Atópica/genética , Grupos Étnicos/genética , Loci Gênicos , Marcadores Genéticos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Dermatite Atópica/patologia , Humanos , Imunidade Inata/genética , Fatores de Risco , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
8.
Curr Opin Allergy Clin Immunol ; 15(5): 426-34, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26226353

RESUMO

PURPOSE OF REVIEW: We summarize current knowledge on the genetic determinants of skin barrier deficiency in relation to eczema and disease progression to other allergic manifestations. RECENT FINDINGS: There is increasing evidence that impairment of epidermal barrier function is not only a risk factor for the development of eczema but also for disease progression to allergic airway disease and food allergy. Support comes from recent association studies linking genetic variants in epidermal genes with eczema and food allergy, from monogenic diseases with severe skin barrier defects which display multiple allergic manifestations, and from mouse models providing a mechanism from skin inflammation to allergic reactions in the lung and intestine. SUMMARY: The key role of the skin barrier defect in the development of eczema and eczema-associated allergic diseases may have important implications for prevention and treatment strategies. Initial clinical trials with moisturizing creams revealed promising results for the prevention of eczema in early infancy. Their long-term effects will be critical to demonstrate the potential benefit of barrier repair therapy in allergic disease prevention.


Assuntos
Eczema/imunologia , Epiderme/imunologia , Hipersensibilidade Alimentar/imunologia , Intestinos/imunologia , Hipersensibilidade Respiratória/imunologia , Animais , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Progressão da Doença , Eczema/genética , Eczema/terapia , Epiderme/efeitos dos fármacos , Hipersensibilidade Alimentar/genética , Hipersensibilidade Alimentar/prevenção & controle , Humanos , Lactente , Intestinos/efeitos dos fármacos , Camundongos , Hipersensibilidade Respiratória/genética , Creme para a Pele/uso terapêutico
10.
PLoS Genet ; 11(3): e1005076, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25757221

RESUMO

Epidemiological studies suggest that allergy risk is preferentially transmitted through mothers. This can be due to genomic imprinting, where the phenotype effect of an allele depends on its parental origin, or due to maternal effects reflecting the maternal genome's influence on the child during prenatal development. Loss-of-function mutations in the filaggrin gene (FLG) cause skin barrier deficiency and strongly predispose to atopic dermatitis (AD). We investigated the 4 most prevalent European FLG mutations (c.2282del4, p.R501X, p.R2447X, and p.S3247X) in two samples including 759 and 450 AD families. We used the multinomial and maximum-likelihood approach implemented in the PREMIM/EMIM tool to model parent-of-origin effects. Beyond the known role of FLG inheritance in AD (R1meta-analysis = 2.4, P = 1.0 x 10-36), we observed a strong maternal FLG genotype effect that was consistent in both independent family sets and for all 4 mutations analysed. Overall, children of FLG-carrier mothers had a 1.5-fold increased AD risk (S1 = 1.50, Pmeta-analysis = 8.4 x 10-8). Our data point to two independent and additive effects of FLG mutations: i) carrying a mutation and ii) having a mutation carrier mother. The maternal genotype effect was independent of mutation inheritance and can be seen as a non-genetic transmission of a genetic effect. The FLG maternal effect was observed only when mothers had allergic sensitization (elevated allergen-specific IgE antibody plasma levels), suggesting that FLG mutation-induced systemic immune responses in the mother may influence AD risk in the child. Notably, the maternal effect reported here was stronger than most common genetic risk factors for AD recently identified through genome-wide association studies (GWAS). Our study highlights the power of family-based studies in the identification of new etiological mechanisms and reveals, for the first time, a direct influence of the maternal genotype on the offspring's susceptibility to a common human disease.


Assuntos
Dermatite Atópica/genética , Proteínas de Filamentos Intermediários/genética , Feminino , Estudo de Associação Genômica Ampla , Impressão Genômica , Humanos , Masculino , Metanálise como Assunto , Mutação
11.
Am J Hum Genet ; 96(1): 104-20, 2015 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-25574825

RESUMO

Atopic dermatitis and psoriasis are the two most common immune-mediated inflammatory disorders affecting the skin. Genome-wide studies demonstrate a high degree of genetic overlap, but these diseases have mutually exclusive clinical phenotypes and opposing immune mechanisms. Despite their prevalence, atopic dermatitis and psoriasis very rarely co-occur within one individual. By utilizing genome-wide association study and ImmunoChip data from >19,000 individuals and methodologies developed from meta-analysis, we have identified opposing risk alleles at shared loci as well as independent disease-specific loci within the epidermal differentiation complex (chromosome 1q21.3), the Th2 locus control region (chromosome 5q31.1), and the major histocompatibility complex (chromosome 6p21-22). We further identified previously unreported pleiotropic alleles with opposing effects on atopic dermatitis and psoriasis risk in PRKRA and ANXA6/TNIP1. In contrast, there was no evidence for shared loci with effects operating in the same direction on both diseases. Our results show that atopic dermatitis and psoriasis have distinct genetic mechanisms with opposing effects in shared pathways influencing epidermal differentiation and immune response. The statistical analysis methods developed in the conduct of this study have produced additional insight from previously published data sets. The approach is likely to be applicable to the investigation of the genetic basis of other complex traits with overlapping and distinct clinical features.


Assuntos
Hibridização Genômica Comparativa , Dermatite Atópica/genética , Estudo de Associação Genômica Ampla , Psoríase/genética , Alelos , Estudos de Casos e Controles , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 6/genética , Estudos de Coortes , Loci Gênicos , Humanos , Modelos Logísticos , Complexo Principal de Histocompatibilidade/genética , Polimorfismo de Nucleotídeo Único , Controle de Qualidade , Reprodutibilidade dos Testes
12.
Curr Opin Allergy Clin Immunol ; 13(5): 478-86, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23945175

RESUMO

PURPOSE OF REVIEW: Eczema and other allergic disorders are complex diseases caused by multiple genetic and environmental factors. Here, we review recent success in the identification of novel susceptibility loci for eczema. RECENT FINDINGS: Genome-wide association studies led to marked progress in unraveling the genetic determinants of allergic disorders. In the past 4 years, a total of 14 new eczema susceptibility loci have been identified and nearly all of them were successfully replicated. Seven additional eczema loci were recently identified by alternative strategies utilizing the remarkable overlap in the genetic cause of diverse immune-related traits. Apart from underlining the importance of the skin barrier in eczema, these studies point to specific immunological functions altered in eczema pathogenesis. SUMMARY: The new findings demonstrate that common pathways are involved in the development of eczema and other immune-related traits. Moreover, the genetic determinants shared between eczema, asthma, and allergic rhinitis should aid in resolving the molecular mechanisms triggering disease progression along the atopic march. The identification of the underlying genes and causal variants will be the major challenge for upcoming studies.


Assuntos
Eczema/genética , Hipersensibilidade/genética , Doenças do Sistema Imunitário/genética , Animais , Eczema/imunologia , Predisposição Genética para Doença , Humanos , Hipersensibilidade/imunologia , Doenças do Sistema Imunitário/imunologia , Polimorfismo Genético , Locos de Características Quantitativas/imunologia
13.
Nat Genet ; 45(7): 808-12, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23727859

RESUMO

Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds, and recent data indicate a role for autoreactivity in at least a subgroup of patients. FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency. To better define risk variants and identify additional susceptibility loci, we densely genotyped 2,425 German individuals with atopic dermatitis (cases) and 5,449 controls using the Immunochip array followed by replication in 7,196 cases and 15,480 controls from Germany, Ireland, Japan and China. We identified four new susceptibility loci for atopic dermatitis and replicated previous associations. This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis.


Assuntos
Dermatite Atópica/genética , Loci Gênicos , Predisposição Genética para Doença , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Dermatite Atópica/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Loci Gênicos/genética , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Alemanha , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Proteínas de Filamentos Intermediários/genética , Japão , Masculino , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único
14.
J Allergy Clin Immunol ; 132(2): 371-7, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23582566

RESUMO

BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease. Previous studies have revealed shared genetic determinants among different inflammatory disorders, suggesting that markers associated with immune-related traits might also play a role in AD. OBJECTIVE: We sought to identify novel genetic risk factors for AD. METHODS: We examined the results of all genome-wide association studies from a public repository and selected 318 genetic markers that were significantly associated with any inflammatory trait. These markers were considered candidates and tested for association with AD in a 3-step approach including 7 study populations with 7130 patients with AD and 9253 control subjects. RESULTS: A functional amino acid change in the IL-6 receptor (IL-6R Asp358Ala; rs2228145) was significantly associated with AD (odds ratio [OR], 1.15; P = 5 × 10(-9)). Interestingly, investigation of 2 independent population-based birth cohorts showed that IL-6R 358Ala specifically predisposes to the persistent form of AD (ORpersistent AD = 1.22, P = .0008; ORtransient AD = 1.04, P = .54). This variant determines the balance between the classical membrane-bound versus soluble IL-6R signaling pathways. Carriers of 358Ala had increased serum levels of soluble IL-6R (P = 4 × 10(-14)), with homozygote carriers showing a 2-fold increase. Moreover, we demonstrate that soluble IL-6R levels were higher in patients with AD than in control subjects (46.0 vs 37.8 ng/mL, P = .001). Additional AD risk variants were identified in RAD50, RUNX3, and ERBB3. CONCLUSION: Our study supports the importance of genetic variants influencing inflammation in the etiology of AD. Moreover, we identified a functional genetic variant in IL6R influencing disease prognosis and specifically predisposing to persistent AD.


Assuntos
Dermatite Atópica/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-6/genética , Adolescente , Alelos , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lactente , Recém-Nascido , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Receptores de Interleucina-6/sangue , Fatores de Risco
15.
J Allergy Clin Immunol ; 129(6): 1547-53.e3, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22657408

RESUMO

BACKGROUND: A previous genome-wide linkage scan in 295 families of the French Epidemiological Study on the Genetics and Environment of Asthma (EGEA) reported strong evidence of linkage of 11p14 to eczema. OBJECTIVE: Our purpose was to conduct fine-scale mapping of the 11p14 region to identify the genetic variants associated with eczema. METHODS: Association analyses were first conducted in the family sample from the French EGEA by using 2 methods: the family-based association method and logistic regression. Replication of the EGEA findings was sought in French Canadian and United Kingdom family samples, which, similarly to EGEA samples, were ascertained through asthma. We also tested for association in 2 German samples ascertained through eczema. RESULTS: We found significant association of eczema with 11p14 genetic variants in the vicinity of the linkage peak in EGEA (P = 10(-4) for rs1050153 by using the family-based association method, which reached the multiple testing-corrected threshold of 10(-4); P = .003 with logistic regression). Pooled analysis of the 3 asthma-ascertained samples showed strong improvement in the evidence for association (P = 6 × 10(-6) for rs293974, P = 3 × 10(-5) for rs1050153, and P = 8 × 10(-5) for rs15783). No association was observed in the eczema-ascertained samples. CONCLUSION: The significant single nucleotide polymorphisms are located within the overlapping anoctamin 3 (ANO3) and mucin 15 (MUC15) genes. Several lines of evidence suggest that MUC15 is a strong candidate for eczema. Further investigation is needed to confirm our findings and to better understand the role of the ANO3/MUC15 locus in eczema and its relationship with respect to asthma.


Assuntos
Asma/genética , Canais de Cloreto/genética , Eczema/genética , Loci Gênicos , Predisposição Genética para Doença , Mucinas/genética , Adolescente , Adulto , Alelos , Anoctaminas , Criança , Grupo com Ancestrais do Continente Europeu/genética , Família , Feminino , Genótipo , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
16.
BMC Med Genet ; 13: 8, 2012 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-22284537

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) provide an increasing number of single nucleotide polymorphisms (SNPs) associated with diseases. Our aim is to exploit those closely spaced SNPs in candidate regions for a deeper analysis of association beyond single SNP analysis, combining the classical stepwise regression approach with haplotype analysis to identify risk haplotypes for complex diseases. METHODS: Our proposed multi-locus stepwise regression starts with an evaluation of all pair-wise SNP combinations and then extends each SNP combination stepwise by one SNP from the region, carrying out haplotype regression in each step. The best associated haplotype patterns are kept for the next step and must be corrected for multiple testing at the end. These haplotypes should also be replicated in an independent data set. We applied the method to a region of 259 SNPs from the epidermal differentiation complex (EDC) on chromosome 1q21 of a German GWAS using a case control set (1,914 individuals) and to 268 families with at least two affected children as replication. RESULTS: A 4-SNP haplotype pattern with high statistical significance in the case control set (p = 4.13 × 10(-7) after Bonferroni correction) could be identified which remained significant in the family set after Bonferroni correction (p = 0.0398). Further analysis revealed that this pattern reflects mainly the effect of the well-known FLG gene; however, a FLG-independent haplotype in case control set (OR = 1.71, 95% CI: 1.32-2.23, p = 5.6 × 10(-5)) and family set (OR = 1.68, 95% CI: 1.18-2.38, p = 2.19 × 10(-3)) could be found in addition. CONCLUSION: Our approach is a useful tool for finding allele combinations associated with diseases beyond single SNP analysis in chromosomal candidate regions.


Assuntos
Algoritmos , Dermatite Atópica/genética , Estudo de Associação Genômica Ampla , Estudos de Casos e Controles , Cromossomos Humanos Par 1/genética , Genótipo , Haplótipos , Humanos , Proteínas de Filamentos Intermediários/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único , Análise de Regressão
17.
J Invest Dermatol ; 131(8): 1644-9, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21490620

RESUMO

The genetically determined impairment of the skin barrier is a primary cause of eczema. As numerous genes essential for an intact epidermis reside within the epidermal differentiation complex (EDC), we screened the National Center for Biotechnology Information (NCBI) database for putatively functional polymorphisms in the EDC genes and tested them for association with eczema. We identified 20 polymorphisms with predicted major impact on protein function. Of these, 4 were validated in 94 eczema patients: a nonsense mutation in FLG2 (rs12568784), a stop codon mutation in LCE1D (rs41268500), a 24-bp deletion in SPRR3 (rs28989168), and a frameshift mutation in S100A3 (rs11390146). The minor allele frequencies were 15.1, 6.1, 47.2, and 0.4%, respectively. Association testing of the validated polymorphisms in 555 eczema patients and 375 controls identified a significant effect of rs28989168 (SPRR3) on eczema. The association was replicated in another 1,314 cases and 1,322 controls, yielding an overall odds ratio of 1.30 (95% confidence interval 1.12-1.51; P=0.00067) for a dominant mode of inheritance. Small proline-rich proteins (SPRRs) are crossbridging proteins in the cornified cell envelope (CE), which provides the main barrier function of stratified squamous epithelia. The SPRR3 variant associated with eczema carried an extra 24-bp repeat in the central domain, which may alter the physical properties of the CE.


Assuntos
Proteínas Ricas em Prolina do Estrato Córneo/genética , Expansão das Repetições de DNA/genética , Eczema/epidemiologia , Eczema/genética , Epiderme/fisiologia , Idade de Início , Sequência de Aminoácidos , Sequência de Bases , Pré-Escolar , Códon sem Sentido , Códon de Terminação/genética , Bases de Dados Genéticas , Eczema/patologia , Epiderme/patologia , Mutação da Fase de Leitura , Testes Genéticos , Variação Genética , Humanos , Lactente , Desequilíbrio de Ligação , Dados de Sequência Molecular , Polimorfismo Genético , Fatores de Risco
18.
Hum Mol Genet ; 20(12): 2443-9, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21429916

RESUMO

In a genome-wide association study, a common variant on chromosome 11q13.5 (rs7927894[T]) has been identified as a susceptibility locus for eczema. We aimed to analyze the effect of this risk variant on asthma and hay fever and to determine its impact on the general population level in over 9300 individuals of the prospectively evaluated Avon Longitudinal Study of Parents and Children birth cohort. We demonstrate an association of rs7927894[T] with atopic asthma and with hay fever. The largest effect sizes were found in patients with the combined phenotype atopic asthma plus eczema [odds ratio (OR) = 1.50; 95% confidence interval (CI) 1.20-1.88; P = 3.7 × 10(-4)] and hay fever plus eczema (OR = 1.37; 95% CI 1.15-1.62; P = 3.8 × 10(-4)). We replicated the effects of rs7927894[T] on eczema-associated asthma and hay fever independently in the German GENUFAD (GEnetic studies in NUclear Families with Atopic Dermatitis) study and show that they are significantly larger than the effect observed in eczema. The estimated population attributable risk fractions for eczema, eczema-associated atopic asthma or hay fever were 9.3, 24.9 and 23.5%, respectively. Finally in eczema, we found a synergistic interaction of rs7927894[T] with filaggrin gene (FLG) mutations, which are a major cause of epidermal barrier dysfunction, and replicated the interaction in the German Multicenter Allergy Study birth cohort. The synergistic effect of rs7927894[T] and FLG mutations on eczema risk as well as the association of both variants with eczema-associated atopic asthma and hay fever point to an involvement of rs7927894[T] in a functional pathway that is linked to the barrier defect.


Assuntos
Cromossomos Humanos Par 11/genética , Eczema/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudos de Coortes , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Proteínas de Filamentos Intermediários/genética , Funções Verossimilhança , Modelos Logísticos , Estudos Longitudinais , Modelos Estatísticos , Mutação/genética , Razão de Chances , Fatores de Risco , Reino Unido
19.
Curr Opin Allergy Clin Immunol ; 10(5): 418-26, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20706116

RESUMO

PURPOSE OF REVIEW: The present review summarizes the new discoveries in the genetics of eczema, focusing on the results from the recently published first genome-wide association study. RECENT FINDINGS: The first genome-wide association study for eczema included 10 000 individuals and provided strong evidence for a new susceptibility locus for eczema in chromosome 11q13.5 (P = 7.6 x 10). Importantly, this finding has been confirmed by an independent research group. Homozygous carriers of the risk allele rs7927894[A] represent 11% of the population and their risk of developing eczema is 1.47 times higher than in no-carriers. This polymorphism also confers risk to Crohn's disease, suggesting the locus may be related to epithelial immunity or differentiation. This study also detected association with the epidermal differentiation complex in 1q21 and suggests that additional risk factors exist in this region apart from the well established mutations in the filaggrin gene. SUMMARY: The first genome-wide association study for eczema has convincingly identified a new susceptibility locus for eczema. However, the exit from this study was limited, as only one new locus was identified. Complementary strategies aiming to distinguish the 'true-association' signals from the false positive results, together with larger sample sizes are required in order to achieve the full potential of this promising approach.


Assuntos
Doença de Crohn/genética , Eczema/genética , Loci Gênicos/imunologia , Alelos , Diferenciação Celular/imunologia , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 11 , Doença de Crohn/imunologia , Eczema/imunologia , Loci Gênicos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Imunidade nas Mucosas/genética , Proteínas de Filamentos Intermediários/genética , Polimorfismo Genético , Fatores de Risco
20.
J Allergy Clin Immunol ; 123(4): 911-6, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19348926

RESUMO

BACKGROUND: Asthma prediction in early infancy is essential for the development of new preventive strategies. Loss-of-function mutations in the filaggrin gene (FLG) were identified as risk factors for eczema and associated asthma. OBJECTIVE: We evaluated the utility of the FLG mutations for the prediction of asthma. METHODS: Eight hundred seventy-one individuals of the prospective German Multicenter Allergy Study cohort were genotyped for 3 FLG mutations. Information on asthma, eczema, and food sensitization was available from birth to 13 years of age. Pulmonary function was measured from 7 to 13 years of age. The predictive value of the FLG mutations and of atopic phenotypes in infancy was assessed for asthma. RESULTS: In infants with eczema and sensitization to food allergens, the FLG mutations predicted childhood asthma with a positive predictive value of 100% (95% CI, 65.5% to 100%). This subgroup was characterized by a significant decrease in pulmonary function until puberty and represented 8.1% of all asthmatic children and 19.1% of patients with asthma after infantile eczema. We found a strong synergistic interaction between the FLG-null alleles and early food sensitization in the disease transition from eczema to asthma (relative excess risk due to interaction, 2.64; 95% CI, 1.70-3.98; P = .00040). CONCLUSION: FLG mutations and food sensitization represent 2 distinct mechanisms interacting in the pathogenesis of asthma. In infants with eczema and food sensitization, genotyping of the FLG mutations allows the prediction of asthma before the onset of symptoms. Our findings might facilitate the development of early subgroup-specific interventions to prevent the progression from eczema to asthma.


Assuntos
Asma/etiologia , Hipersensibilidade Alimentar/complicações , Proteínas de Filamentos Intermediários/genética , Mutação , Adolescente , Asma/fisiopatologia , Criança , Pré-Escolar , Eczema/complicações , Feminino , Humanos , Imunoglobulina E/sangue , Lactente , Pulmão/fisiopatologia , Masculino , Fatores de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA