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1.
Am J Hum Genet ; 90(4): 636-47, 2012 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-22482804

RESUMO

Psoriasis (PS) and Crohn disease (CD) have been shown to be epidemiologically, pathologically, and therapeutically connected, but little is known about their shared genetic causes. We performed meta-analyses of five published genome-wide association studies on PS (2,529 cases and 4,955 controls) and CD (2,142 cases and 5,505 controls), followed up 20 loci that showed strongest evidence for shared disease association and, furthermore, tested cross-disease associations for previously reported PS and CD risk alleles in additional 6,115 PS cases, 4,073 CD cases, and 10,100 controls. We identified seven susceptibility loci outside the human leukocyte antigen region (9p24 near JAK2, 10q22 at ZMIZ1, 11q13 near PRDX5, 16p13 near SOCS1, 17q21 at STAT3, 19p13 near FUT2, and 22q11 at YDJC) shared between PS and CD with genome-wide significance (p < 5 × 10(-8)) and confirmed four already established PS and CD risk loci (IL23R, IL12B, REL, and TYK2). Three of the shared loci are also genome-wide significantly associated with PS alone (10q22 at ZMIZ1, p(rs1250544) = 3.53 × 10(-8), 11q13 near PRDX5, p(rs694739) = 3.71 × 10(-09), 22q11 at YDJC, p(rs181359) = 8.02 × 10(-10)). In addition, we identified one susceptibility locus for CD (16p13 near SOCS1, p(rs4780355) = 4.99 × 10(-8)). Refinement of association signals identified shared genome-wide significant associations for exonic SNPs at 10q22 (ZMIZ1) and in silico expression quantitative trait locus analyses revealed that the associations at ZMIZ1 and near SOCS1 have a potential functional effect on gene expression. Our results show the usefulness of joint analyses of clinically distinct immune-mediated diseases and enlarge the map of shared genetic risk loci.


Assuntos
Doença de Crohn/genética , Loci Gênicos , Predisposição Genética para Doença/genética , Psoríase/genética , Éxons/genética , Feminino , Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
2.
Mol Cell Biol ; 25(19): 8669-82, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16166646

RESUMO

alpha1-Adrenergic receptors mediate several biological effects of catecholamines, including the regulation of myocyte growth and contractility and transcriptional regulation of the atrial natriuretic factor (ANF) gene whose promoter contains an alpha1-adrenergic response element. The nuclear pathways and effectors that link receptor activation to genetic changes remain poorly understood. Here, we describe the isolation by the yeast one-hybrid system of a cardiac cDNA encoding a novel nuclear zinc finger protein, Zfp260, belonging to the Krüppel family of transcriptional regulators. Zfp260 is highly expressed in the embryonic heart but is downregulated during postnatal development. Functional studies indicate that Zfp260 is a transcriptional activator of ANF and a cofactor for GATA-4, a key cardiac regulator. Knockdown of Zfp260 in cardiac cells decreases endogenous ANF gene expression and abrogates its response to alpha1-adrenergic stimulation. Interestingly, Zfp260 transcripts are induced by alpha1-adrenergic agonists and are elevated in genetic models of hypertension and cardiac hypertrophy. The data identify Zfp260 as a novel transcriptional regulator in normal and pathological heart development and a nuclear effector of alpha1-adrenergic signaling.


Assuntos
Núcleo Celular/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Transdução de Sinais , Transativadores/química , Adenoviridae/genética , Sequência de Aminoácidos , Animais , Fator Natriurético Atrial/metabolismo , Sequência de Bases , Western Blotting , Proliferação de Células , Clonagem Molecular , DNA Complementar/metabolismo , Regulação para Baixo , Técnica Indireta de Fluorescência para Anticorpo , Regulação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Biblioteca Gênica , Genes Reporter , Células HeLa , Coração/embriologia , Humanos , Hipertensão/genética , Hipertrofia/genética , Imuno-Histoquímica , Óperon Lac , Dados de Sequência Molecular , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Oligonucleotídeos Antissenso/química , Plasmídeos/metabolismo , Regiões Promotoras Genéticas , Estrutura Terciária de Proteína , RNA/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos WKY , Ratos Sprague-Dawley , Proteínas Recombinantes/química , Homologia de Sequência de Aminoácidos , Fatores de Tempo , Transativadores/biossíntese , Transcrição Gênica , Ativação Transcricional , Dedos de Zinco
3.
J Invest Dermatol ; 132(4): 1133-40, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22170493

RESUMO

Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease affecting up to 30% of psoriasis vulgaris (PsV) cases and approximately 0.25 to 1% of the general population. To identify common susceptibility loci, we performed a meta-analysis of three imputed genome-wide association studies (GWAS) on psoriasis, stratified for PsA. A total of 1,160,703 single-nucleotide polymorphisms (SNPs) were analyzed in the discovery set consisting of 535 PsA cases and 3,432 controls from Germany, the United States, and Canada. We followed up two SNPs in 1,931 PsA cases and 6,785 controls comprising six independent replication panels from Germany, Estonia, the United States, and Canada. In the combined analysis, a genome-wide significant association was detected at 2p16 near the REL locus encoding c-Rel (rs13017599, P=1.18 × 10(-8), odds ratio (OR)=1.27, 95% confidence interval (CI)=1.18-1.35). The rs13017599 polymorphism is known to associate with rheumatoid arthritis (RA), and another SNP near REL (rs702873) was recently implicated in PsV susceptibility. However, conditional analysis indicated that rs13017599, rather than rs702873, accounts for the PsA association at REL. We hypothesize that c-Rel, as a member of the Rel/NF-κB family, is associated with PsA in the context of disease pathways that involve other identified PsA and PsV susceptibility genes including TNIP1, TNFAIP3, and NFκBIA.


Assuntos
Artrite Psoriásica/genética , Genes rel/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Adolescente , Adulto , Canadá , Estudos de Casos e Controles , Estônia , Genótipo , Alemanha , Humanos , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos , Adulto Jovem
4.
Nat Genet ; 42(11): 991-5, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20953188

RESUMO

Psoriasis is a multifactorial skin disease characterized by epidermal hyperproliferation and chronic inflammation, the most common form of which is psoriasis vulgaris (PsV). We present a genome-wide association analysis of 2,339,118 SNPs in 472 PsV cases and 1,146 controls from Germany, with follow-up of the 147 most significant SNPs in 2,746 PsV cases and 4,140 controls from three independent replication panels. We identified an association at TRAF3IP2 on 6q21 and genotyped two SNPs at this locus in two additional replication panels (the combined discovery and replication panels consisted of 6,487 cases and 8,037 controls; combined P = 2.36 × 10⁻¹° for rs13210247 and combined P = 1.24 × 10⁻¹6 for rs33980500). About 15% of psoriasis cases develop psoriatic arthritis (PsA). A stratified analysis of our datasets including only PsA cases (1,922 cases compared to 8,037 controls, P = 4.57 × 10⁻¹² for rs33980500) suggested that TRAF3IP2 represents a shared susceptibility for PsV and PsA. TRAF3IP2 encodes a protein involved in IL-17 signaling and which interacts with members of the Rel/NF-κB transcription factor family.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Psoríase/genética , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Proteínas Adaptadoras de Transdução de Sinal , Artrite Psoriásica/etiologia , Artrite Psoriásica/genética , Cromossomos Humanos Par 6 , Doenças em Gêmeos/genética , Predisposição Genética para Doença , Genótipo , Alemanha/epidemiologia , Antígenos HLA-C/genética , Humanos , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , Psoríase/complicações , Psoríase/epidemiologia , Irmãos , População Branca/genética
5.
Proc Natl Acad Sci U S A ; 104(37): 14747-52, 2007 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-17804789

RESUMO

Genome-wide association (GWA) studies offer a powerful unbiased method for the identification of multiple susceptibility genes for complex diseases. Here we report the results of a GWA study for Crohn's disease (CD) using family trios from the Quebec Founder Population (QFP). Haplotype-based association analyses identified multiple regions associated with the disease that met the criteria for genome-wide significance, with many containing a gene whose function appears relevant to CD. A proportion of these were replicated in two independent German Caucasian samples, including the established CD loci NOD2 and IBD5. The recently described IL23R locus was also identified and replicated. For this region, multiple individuals with all major haplotypes in the QFP were sequenced and extensive fine mapping performed to identify risk and protective alleles. Several additional loci, including a region on 3p21 containing several plausible candidate genes, a region near JAKMIP1 on 4p16.1, and two larger regions on chromosome 17 were replicated. Together with previously published loci, the spectrum of CD genes identified to date involves biochemical networks that affect epithelial defense mechanisms, innate and adaptive immune response, and the repair or remodeling of tissue.


Assuntos
Doença de Crohn/genética , Efeito Fundador , Predisposição Genética para Doença , Genoma Humano , Alelos , Cromossomos Humanos Par 17 , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 4 , Doença de Crohn/patologia , França/etnologia , Marcadores Genéticos , Genética Populacional , Haplótipos , Humanos , Proteína Adaptadora de Sinalização NOD2/genética , Mapeamento Físico do Cromossomo , Quebeque , Receptores de Interleucina/genética , Reprodutibilidade dos Testes , Fatores de Risco
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