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.
Assuntos
Cromatina/metabolismo , Citocinas/farmacologia , Estudo de Associação Genômica Ampla , Doenças do Sistema Imunitário/imunologia , Macrófagos/imunologia , Células Th1/imunologia , Cromatina/genética , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/genética , Ativação Linfocitária , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/metabolismoAssuntos
Carcinoma de Células Escamosas/genética , DNA Helicases/genética , Predisposição Genética para Doença , Ceratose/genética , Esclerodermia Localizada/genética , Neoplasias Cutâneas/genética , Adulto , Carcinoma de Células Escamosas/patologia , Células Cultivadas , Feminino , Fibroblastos , Haploinsuficiência , Humanos , Isoenzimas/genética , Queratinócitos , Ceratose/patologia , Masculino , Pessoa de Meia-Idade , Linhagem , Polimorfismo de Nucleotídeo Único , Cultura Primária de Células , Esclerodermia Localizada/patologia , Pele/citologia , Pele/patologia , Neoplasias Cutâneas/patologia , Sequenciamento Completo do Genoma , Adulto JovemRESUMO
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 , Proteínas Filagrinas , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fator de Transcrição Ikaros/genética , Interleucina-4/genética , Cinesinas/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 JovemRESUMO
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 RiscoRESUMO
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 , Proteínas Filagrinas , 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 RiscoRESUMO
Factor H is an essential regulatory protein that plays a critical role in the homeostasis of the complement system in plasma and in the protection of bystander host cells and tissues from damage by complement activation. Genetic and structural data generated during recent years have been instrumental to delineate the functional domains responsible for these regulatory activities in factor H, which is helping to understand the molecular basis underlying the different pathologies associated to factor H. This review summarises our current knowledge of the role of factor H in health and disease.
Assuntos
Fator H do Complemento/fisiologia , Bactérias/imunologia , Cromossomos Humanos Par 1/genética , Ativação do Complemento , Fator H do Complemento/química , Fator H do Complemento/genética , Genes , Variação Genética , Glomerulonefrite/genética , Glomerulonefrite/imunologia , Síndrome Hemolítico-Urêmica/genética , Síndrome Hemolítico-Urêmica/imunologia , Homeostase , Humanos , Mutação , Neoplasias/imunologia , Polimorfismo Genético , Estrutura Terciária de Proteína , Relação Estrutura-AtividadeRESUMO
The C4b-binding protein (C4BP) is a plasma glycoprotein implicated in the homeostasis of the complement and coagulation systems. It is composed of two polypeptides (alpha and beta), which form three plasma oligomers with different subunit compositions (alpha(7)beta(1), alpha(7)beta(0), and alpha(6)beta(1)). The beta chain-containing C4BP isoforms (C4BPbeta(+)isoforms) bind and inactivate protein S (PS), downregulating the activated protein C (APC)-dependent anticoagulatory pathway. Because PS deficiency is associated with recurrent thrombosis, it has been suggested that increased levels of C4BPbeta(+)isoforms might diminish the free PS plasma level, affecting the risk of developing thromboembolism. Previous work has tested this hypothesis, but no definitive conclusions were reached, mostly because nothing is known about the factors influencing the high variability in C4BP plasma levels in humans. As a part of the GAIT project, using variance component analysis, this work provides the first estimation of the relative contributions of genetic and environmental influences on the plasma levels of total C4BP and C4BPbeta(+)isoforms. Plasma levels of total C4BP and C4BPbeta(+)isoforms showed strong evidence of genetic regulation (heritability 37.7% and 42.5%, respectively). They were also affected by age, smoking, and exogenous sex hormones. Our results constitute the first step in localizing and evaluating potential quantitative trait loci that affect the plasma levels of C4BP and C4BPbeta(+). Furthermore, analysis of phenotypic and genetic correlations between C4BPbeta(+)plasma levels and the components of the APC anticoagulatory pathway (total PS, free PS, functional PS, and functional PC) suggests a genetic co-regulation of the proteins. These observations might have important implications in the individual susceptibility to thrombotic disease.