Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 34
Filtrar
Mais filtros










Intervalo de ano de publicação
2.
PLoS One ; 7(8): e43661, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22937072

RESUMO

BACKGROUND: The number of copies of the HLA-DRB1 shared epitope, and the minor alleles of the STAT4 rs7574865 and the PTPN22 rs2476601 polymorphisms have all been linked with an increased risk of developing rheumatoid arthritis. In the present study, we investigated the effects of these genetic variants on disease activity and disability in patients with early arthritis. METHODOLOGY AND RESULTS: We studied 640 patients with early arthritis (76% women; median age, 52 years), recording disease-related variables every 6 months during a 2-year follow-up. HLA-DRB1 alleles were determined by PCR-SSO, while rs7574865 and rs2476601 were genotyped with the Taqman 5' allelic discrimination assay. Multivariate analysis was performed using generalized estimating equations for repeated measures. After adjusting for confounding variables such as gender, age and ACPA, the TT genotype of rs7574865 in STAT4 was associated with increased disease activity (DAS28) as compared with the GG genotype (ß coefficient [95% confidence interval] = 0.42 [0.01-0.83], p = 0.044). Conversely, the presence of the T allele of rs2476601 in PTPN22 was associated with diminished disease activity during follow-up in a dose-dependent manner (CT genotype = -0.27 [-0.56- -0.01], p = 0.042; TT genotype = -0.68 [-1.64- -0.27], p = 0.162). After adjustment for gender, age and disease activity, homozygosity for the T allele of rs7574865 in STAT4 was associated with greater disability as compared with the GG genotype. CONCLUSIONS: Our data suggest that patients with early arthritis who are homozygous for the T allele of rs7574865 in STAT4 may develop a more severe form of the disease with increased disease activity and disability.


Assuntos
Artrite/genética , Genótipo , Polimorfismo de Nucleotídeo Único , Fator de Transcrição STAT4/genética , Adulto , Idoso , Alelos , Artrite/imunologia , Avaliação da Deficiência , Feminino , Predisposição Genética para Doença , Cadeias HLA-DRB1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Índice de Gravidade de Doença
3.
Rheumatology (Oxford) ; 51(1): 52-9, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22087014

RESUMO

OBJECTIVE: To determine the role of Class II HLAs in SSc patients from Italy and Spain and in SSc patients of Caucasian ancestry. METHODS: Nine hundred and forty-four SSc patients (Italy 392 patients; Spain 452 patients) and 1320 ethnically matched healthy controls (Italy 398 patients; Spain 922 patients) were genotyped up to the fourth digit by PCR with sequence-specific oligonucleotides for HLA-DRB1, DQA1 and DQB1 loci. Patients included 390 ACA-positive and 254 anti-topo I-positive subjects. Associations between SSc or SSc-specific antibodies and HLA alleles or HLA haplotypes were sought via the chi-square test after 10 000-fold permutation testing. A meta-analysis including this study cohort and other Caucasoids samples was also conducted. RESULTS: In both the cohorts, the strongest association was observed between the HLA-DRB1*1104 allele and SSc or anti-topo I antibodies. The HLA-DRB1*1104 -DQA1*0501 -DQB1*0301 haplotype was overrepresented in Italian [odds ratio (OR) = 2.069, 95% asymptotic CIs (CI(95)) 1.486, 2.881; P < 0.001] and in Spanish patients (OR = 6.707, CI(95) 3.974, 11.319; P < 0.001) as well as in anti-topo-positive patients: Italy (OR = 2.642, CI(95) 1.78, 3.924; P < 0.001) and Spain (OR = 20.625, CI(95) 11.536, 36.876; P < 0.001). In both the populations we also identified an additional risk allele (HLA-DQB1*03) and a protective allele (HLA-DQB1*0501) in anti-topo-positive patients. The meta-analysis showed different statistically significant associations, the most interesting being the differential association between HLA-DRB1*01 alleles and ACAs (OR = 1.724, CI(95) 1.482, 2.005; P < 0.001) or topo I antibodies (OR = 0.5, CI(95) 0.384, 0.651; P < 0.001). CONCLUSIONS: We describe multiple robust associations between SSc and HLA Class II antigens in Caucasoids that may help to understand the genetic architecture of SSc.


Assuntos
Antígenos HLA-D/genética , Escleroderma Sistêmico/genética , Autoanticorpos/análise , Estudos de Casos e Controles , Predisposição Genética para Doença , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Teste de Histocompatibilidade/métodos , Humanos , Itália/epidemiologia , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/imunologia , Espanha/epidemiologia
4.
Rheumatology (Oxford) ; 50(11): 1976-81, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21875883

RESUMO

OBJECTIVES: The aim of this study was to confirm the implication of macrophage migration inhibitory factor (MIF) gene in SSc susceptibility or clinical phenotypes in a large European population. METHODS: A total of 3800 SSc patients and 4282 healthy controls of white Caucasian ancestry from eight different European countries were included in the study. The MIF -173 single nucleotide polymorphism (SNP) was selected as genetic marker and genotyped using Taqman 5' allelic discrimination assay. RESULTS: The MIF -173 SNP showed association with SSc [P = 0.04, odds ratio (OR) = 1.10, 95% CI 1.00, 1.19]. Analysis of the MIF -173 polymorphism according to SSc clinical phenotype revealed that the frequency of the -173*C allele was significantly higher in the dcSSc group compared with controls (P = 5.30E-03, OR = 1.21, 95% CI 1.07, 1.38). Conversely, the frequency of the MIF -173*C allele was significantly underrepresented in the lcSSc group compared with dcSSc patients, supporting previous findings [(P = 0.04, OR = 0.86, 95% CI 0.75, 0.99); meta-analysis including previous results (P = 0.005, OR = 0.83, 95% CI 0.73, 0.94)]. CONCLUSION: Our results confirm the role of MIF -173 promoter polymorphism in SSc, and provide evidence of a strong association with the dcSSc subgroup of patients. Hence, the MIF -173 variant is confirmed as a promising clinical phenotype genetic marker.


Assuntos
Predisposição Genética para Doença , Fatores Inibidores da Migração de Macrófagos/genética , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , Estudos de Casos e Controles , Marcadores Genéticos , Genótipo , Humanos , Razão de Chances , Escleroderma Sistêmico/sangue
5.
PLoS Genet ; 7(7): e1002178, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21779181

RESUMO

The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32×10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 × 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39×10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79×10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57×10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84×10(-21), OR = 0.55) and ATA (P = 1.14×10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Escleroderma Sistêmico/genética , Alelos , Autoanticorpos/imunologia , Feminino , Loci Gênicos/genética , Marcadores Genéticos , Antígenos HLA/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Escleroderma Sistêmico/classificação , Escleroderma Sistêmico/imunologia
6.
J Rheumatol ; 38(3): 446-9, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21159834

RESUMO

OBJECTIVE: To investigate the role of the Fc(α)RI 844 A>G functional polymorphism in the genetic predisposition to rheumatoid arthritis (RA) and systemic sclerosis (SSc) susceptibility. METHODS: The study population was composed of 1401 patients with SSc, 642 patients with RA, and 1317 healthy controls. The Fc(α)RI (CD89) single-nucleotide polymorphism rs16986050 was genotyped by pyrosequencing. RESULTS: We observed no significant deviation of the genotype and allele frequencies in RA and SSc compared to controls. A metaanalysis and a recessive and dominant model yielded similar negative results. CONCLUSION: Our data show that the Fc(α)RI 844 A>G polymorphism is not associated with SSc or RA susceptibility.


Assuntos
Antígenos CD/genética , Artrite Reumatoide/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Receptores Fc/genética , Escleroderma Sistêmico/genética , Idoso , Europa (Continente) , Feminino , Frequência do Gene , Genótipo , Humanos , Metanálise como Assunto , Pessoa de Meia-Idade
7.
Reumatol. clín. (Barc.) ; 6(supl.2): 12-15, sept. 2010. graf
Artigo em Espanhol | IBECS | ID: ibc-148871

RESUMO

La esclerosis sistémica o esclerodermia (SSc) es una patología autoinmune de expresión clínica variable englobada dentro del grupo de enfermedades genéticamente complejas, en la que se conjugan tanto factores ambientales como genéticos. Los genes de la región HLA fueron los primeros asociados con la susceptibilidad a padecer SSc, principalmente los alelosHLA-DRB1¿11/¿06/¿16. Sin embargo, mediante estudios de asociación, diferentes genes candidatos pertenecientes a la tríada autoinmunidad, disfunción endotelial y fibrosis han sido propuestos como genes implicados en la predisposición a esta enfermedad. A pesar de estos avances iniciales, hasta hace muy poco tiempo la mayoría de los estudios han estado dotados de un bajo poder estadístico, debido al pequeño número de pacientes incluidos y la falta de replicación en poblaciones independientes. Recientemente, el desarrollo de las plataformas de genotipado y de análisis de datos ha permitido aplicar al estudio de la genética de enfermedades complejas un nuevo tipo de estrategia conocida como estudios de asociación del genoma completo (GWAS, «genome wide association studies»), que se perfilan como una potente herramienta en el estudio de estas enfermedades multifactoriales. En este trabajo se pretende realizar una revisión de los recientes avances en el estudio de la genética de la esclerodermia, presentando los resultados obtenidos en el análisis de los principales genes candidatos fuera de la región HLA y la contribución de los GWAS a la comprensión de los mecanismos moleculares de esta enfermedad (AU)


Systemic sclerosis or scleroderma (SSc) is an autoimmune pathology with a variable clinical expression grouped within genetically complex diseases, in which environmental and genetical factors combine. Genes of the HLA regions were those first associated with susceptibility to present SSc, mainly the HLA-DRB1¿11/¿06/¿16 allelles. However, through association studies, different candidate genes that belong to the triad of autoimmunity, endothelial disfunction and fibrosis have been proposed as genes implicated in the predisposition to disease. In spite of these initial advances, up until recently most studies have had little statistical power, due to the small number of patients included and the lack of reproduction in independent populations. Recently, the development of genotyping platforms and data analysis has allowed for the application of a new type of strategy known as «genome wide association studies» the analysis of the genetics to complex diseases, which are potent tools in the study of these multifactorial diseases. This paper pretends to perform a review of the recent advances in the study of the genetics of scleroderma, presenting results obtained in the analysis of the main candidate genes outside the HLA regions and the contribution of GWAS to the understanding of the molecular mechanisms of this disease (AU)


Assuntos
Humanos , Escleroderma Sistêmico/genética , Estudo de Associação Genômica Ampla/métodos , Marcadores Genéticos , Predisposição Genética para Doença/genética , Complexo Principal de Histocompatibilidade/genética , Fator de Transcrição STAT4/genética , Fatores Reguladores de Interferon/genética , Proteínas Tirosina Fosfatases/genética
8.
J Rheumatol ; 37(8): 1673-9, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20551103

RESUMO

OBJECTIVE: To investigate the possible role of FCGR2A 519A>G and FCGR3A 559A>C functional polymorphisms in the genetic predisposition to susceptibility to systemic sclerosis (SSc) or clinical phenotype. METHODS: A total of 1566 patients with SSc and 2271 geographically matched controls were included in our study. We analyzed the genotype and allele frequencies of the FCGR2A 519A>G and FCGR3A 559A>C functional variants in 6 independent European cohorts of white patients with SSc, and white controls. The cohorts comprised 165 Dutch patients with SSc and 1326 controls, 236 Spanish patients with SSc and 257 controls, 267 German patients with SSc and 270 controls, 202 Swedish patients with SSc and 261 controls, 416 Italian patients with SSc and 157 controls, and additionally 280 English patients with SSc. Genotyping was performed using Taqman 5' allelic discrimination assay. The study reached a 99% power to detect the effect of a polymorphism at an OR of 1.3. RESULTS: Neither FCGR2A 519A>G nor FCGR3A 559A>C was significantly associated with susceptibility to SSc. We did not find an association with specific disease phenotypes, limited or diffuse cutaneous involvement, autoantibody profiles, or pulmonary involvement. CONCLUSION: Our study strongly suggests the lack of a role for the FCGR2A 519A>G and FCGR3A 559A>C polymorphisms in SSc susceptibility or clinical phenotype in 6 independent European cohorts.


Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Receptores de IgG/genética , Esclerodermia Difusa/genética , Esclerodermia Limitada/genética , Autoanticorpos/sangue , Europa (Continente) , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de IgG/sangue , Esclerodermia Difusa/sangue , Esclerodermia Difusa/diagnóstico , Esclerodermia Limitada/sangue , Esclerodermia Limitada/diagnóstico
9.
J Genet Genomics ; 37(4): 257-64, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20439102

RESUMO

In order to investigate the influence of functional polymorphisms of macrophage migration inhibitory factor (MIF), Fcg receptors CD16A (FCGR3A) and CD32A (FCGR2A) genes on susceptibility to pulmonary tuberculosis (PTB) in the Moroccan population, we analyzed 123 patients with PTB and 154 healthy controls. The genotyping for MIF-173 (G/C) (rs755622), FCGR2A-131H/R (rs1801274) and FCGR3A-158V/F (rs396991) was carried out using TaqMan SNP Genotyping Assay method. We found a statistically significant increase of the MIF -173CC homozygote genotype and MIF -173*C allele frequencies in PTB patients compared with healthy controls (17.07%versus 5.84%, P = 0.003; and 35.37%versus 26.30%, P = 0.02; respectively). In contrast, no association was observed between FCGR2A-131H/R and FCGR3A-158V/F polymorphisms and tuberculosis disease. Our finding suggests that MIF -173*C variant may play an important role in the development of active tuberculosis.


Assuntos
Predisposição Genética para Doença , Fatores Inibidores da Migração de Macrófagos/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de IgG/genética , Tuberculose Pulmonar/genética , Suscetibilidade a Doenças , Frequência do Gene , Testes Genéticos , Variação Genética , Humanos , Marrocos , Grupos Populacionais , Regiões Promotoras Genéticas/genética
10.
Nat Genet ; 42(5): 426-9, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20383147

RESUMO

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23, rs2056626, P = 2.09 x 10(-7) in the discovery samples, P = 3.39 x 10(-9) in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 x 10(-18)), IRF5 (P = 1.86 x 10(-13)) and STAT4 (P = 3.37 x 10(-9)) gene regions as SSc genetic risk factors.


Assuntos
Complexo CD3/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Escleroderma Sistêmico/genética , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco
11.
Reumatol Clin ; 6 Suppl 2: 12-5, 2010 Sep.
Artigo em Espanhol | MEDLINE | ID: mdl-21794758

RESUMO

Systemic sclerosis or scleroderma (SSc) is an autoimmune pathology with a variable clinical expression grouped within genetically complex diseases, in which environmental and genetical factors combine. Genes of the HLA regions were those first associated with susceptibility to present SSc, mainly the HLA-DRB1⁎11/⁎06/⁎16 allelles. However, through association studies, different candidate genes that belong to the triad of autoimmunity, endothelial disfunction and fibrosis have been proposed as genes implicated in the predisposition to disease. In spite of these initial advances, up until recently most studies have had little statistical power, due to the small number of patients included and the lack of reproduction in independent populations. Recently, the development of genotyping platforms and data analysis has allowed for the application of a new type of strategy known as «genome wide association studies¼ the analysis of the genetics to complex diseases, which are potent tools in the study of these multifactorial diseases. This paper pretends to perform a review of the recent advances in the study of the genetics of scleroderma, presenting results obtained in the analysis of the main candidate genes outside the HLA regions and the contribution of GWAS to the understanding of the molecular mechanisms of this disease.

12.
Ann Rheum Dis ; 69(4): 696-9, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19433411

RESUMO

OBJECTIVES: The TRAF1-C5 locus has recently been identified as a genetic risk factor for rheumatoid arthritis (RA). Since genetic risk factors tend to overlap with several autoimmune diseases, a study was undertaken to investigate whether this region is associated with type 1 diabetes (TID), celiac disease (CD), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). METHODS: The most consistently associated SNP, rs10818488, was genotyped in a total of 735 patients with T1D, 1049 with CD, 367 with SSc, 746 with SLE and 3494 ethnically- and geographically-matched healthy individuals. The replication sample set consisted of 99 patients with T1D, 272 with SLE and 482 healthy individuals from Crete. RESULTS: A significant association was detected between the rs10818488 A allele and T1D (OR 1.14, p=0.027) and SLE (OR 1.16, p=0.016), which was replicated in 99 patients with T1D, 272 with SLE and 482 controls from Crete (OR 1.64, p=0.002; OR 1.43, p=0.002, respectively). Joint analysis of all patients with T1D (N=961) and all patients with SLE (N=1018) compared with 3976 healthy individuals yielded an allelic common OR of 1.19 (p=0.002) and 1.22 (p=2.6 x 10(-4)), respectively. However, combining our dataset with the T1D sample set from the WTCCC resulted in a non-significant association (OR 1.06, p=0.087). In contrast, previously unpublished results from the SLEGEN study showed a significant association of the same allele (OR 1.19, p=0.0038) with an overall effect of 1.22 (p=1.02 x 10(-6)) in a total of 1577 patients with SLE and 4215 healthy individuals. CONCLUSION: A significant association was found for the TRAF1-C5 locus in SLE, implying that this region lies in a pathway relevant to multiple autoimmune diseases.


Assuntos
Doenças Autoimunes/genética , Cromossomos Humanos Par 9/genética , Fator 1 Associado a Receptor de TNF/genética , Doença Celíaca/genética , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética
13.
J Autoimmun ; 34(2): 155-62, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19796918

RESUMO

OBJECTIVE: Genetic studies in the systemic sclerosis (SSc), an autoimmune disease that clinically manifests with dermal and internal organ fibrosis and small vessel vasculopathy, have identified multiple susceptibility genes including HLA-class II, PTPN22, IRF5, and STAT4 which have also been associated with other autoimmune diseases, such as systemic lupus erythematosus (SLE). These data suggest that there are common autoimmune disease susceptibility genes. The current report sought to determine if polymorphisms in the C8orf13-BLK region (chromosome 8p23.1-B lymphoid tyrosine kinase), which is associated with SLE, are associated also with SSc. METHODS: Two variants in the C8orf13-BLK region (rs13277113 & rs2736340) were tested for association with 1050 SSc cases and 694 controls of North Americans of European descent and replicated in a second series 589 SSc cases and 722 controls from Spain. RESULTS: The "T" allele at rs2736340 variant was associated with SSc in both the U.S. and Spanish case-control series (P = 6.8 x 10(-5), OR 1.27, 95% CI 1.1-1.4). The "A" allele at rs13277113 variant was associated with SSc in the U.S. series only (P = 3.6 x 10(-4), OR 1.32, 95% CI 1.1-1.6) and was significant in the combined analyses of the two series (P = 2.0 x 10(-3); OR 1.20, 95% CI 1.1-1.3). Both variants demonstrated an association with the anti-centromere antibody (P = 2.2 x 10(-6) and P = 5.5 x 10(-4), respectively) and limited SSc (P = 3.3 x 10(-5) and P = 2.9 x 10(-3), respectively) in the combined analysis. Peripheral blood gene expression profiles suggest that B-cell receptor and NFkappaB signaling are dysregulated based on the risk haplotype of these variants. CONCLUSION: We identify and replicate the association of the C8orf13-BLK region as a novel susceptibility factor for SSc, placing it in the category of common autoimmune disease susceptibility genes.


Assuntos
Centrômero/imunologia , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , Quinases da Família src/genética , Autoanticorpos/sangue , Autoanticorpos/imunologia , Estudos de Casos e Controles , Cromossomos Humanos Par 8 , Grupo com Ancestrais do Continente Europeu , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/fisiopatologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Espanha , Estados Unidos , Quinases da Família src/imunologia
14.
Hum Mol Genet ; 18(3): 569-79, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-18981062

RESUMO

A gain-of-function R620W polymorphism in the PTPN22 gene, encoding the lymphoid tyrosine phosphatase LYP, has recently emerged as an important risk factor for human autoimmunity. Here we report that another missense substitution (R263Q) within the catalytic domain of LYP leads to reduced phosphatase activity. High-resolution structural analysis revealed the molecular basis for this loss of function. Furthermore, the Q263 variant conferred protection against human systemic lupus erythematosus, reinforcing the proposal that inhibition of LYP activity could be beneficial in human autoimmunity.


Assuntos
Lúpus Eritematoso Sistêmico/genética , Mutação de Sentido Incorreto , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/metabolismo , Sequência de Aminoácidos , Linhagem Celular , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Humanos , Lúpus Eritematoso Sistêmico/enzimologia , Modelos Moleculares , Dados de Sequência Molecular , Polimorfismo Genético , Estrutura Terciária de Proteína , Proteína Tirosina Fosfatase não Receptora Tipo 22/química , Fatores de Risco , Alinhamento de Sequência
15.
J Rheumatol ; 35(5): 850-4, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18381780

RESUMO

OBJECTIVE: To investigate the possible implication of CD24 gene in the genetic predisposition to giant cell arteritis (GCA). METHODS: A total of 120 patients diagnosed with biopsy-proven GCA and 195 ethnically matched controls from the same region were studied. Two putative functional polymorphisms, a C to T coding polymorphism (rs8734) and a TG deletion in the 3' untranslated region (rs3838646) were used as CD24 genetic markers and genotyped using a Taqman 5' allelic discrimination assay. RESULTS: The 2 genetic variants showed statistically significant differences between patients with GCA and controls. The strongest association was observed for the rs3838646 TG/del polymorphism, conferring on the "del" allele an increased risk of GCA genetic susceptibility (odds ratio 1.94, 95% confidence interval 1.15-3.27, p = 0.01). In addition, genotypes carrying the rs3838646 "del" allele showed an increased frequency among GCA patients compared to controls (OR 2.31, 95% CI 1.30-4.1, p = 0.003). For the rs8743, an increased frequency of Val/Val homozygous individuals in patients with GCA compared to controls (OR 6.08, 95% CI 1.50-24.63, p = 0.001) was observed. A high degree of linkage disequilibrium was estimated between the 2 polymorphisms (D' = 0.7) and the C/del haplotype was associated with an increased risk of GCA susceptibility (OR 2.10, 95% CI 1.23-3.60, p = 0.005), whereas the C/TG haplotype showed a protective effect (OR 0.63, 95% CI 0.45-0.87, p = 0.005). CONCLUSION: Our results suggest a potential role for the CD24 gene in the susceptibility to GCA in our population.


Assuntos
Antígeno CD24/genética , Predisposição Genética para Doença/genética , Arterite de Células Gigantes/genética , Arterite de Células Gigantes/patologia , Polimorfismo Genético/genética , Artérias Temporais/patologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , Estudos de Casos e Controles , Feminino , Genótipo , Arterite de Células Gigantes/etnologia , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Espanha
16.
Arthritis Rheum ; 58(4): 1010-9, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18383379

RESUMO

OBJECTIVE: Vasoactive intestinal peptide (VIP) has been shown to be one of the endogenous factors involved in the maintenance of immune tolerance. Administration of VIP ameliorates clinical signs in various experimental autoimmune disorders. This study was undertaken to investigate whether the exacerbated inflammatory autoimmune response in rheumatoid arthritis (RA) might result directly from altered expression and/or signaling of VIP receptors in immune cells. METHODS: The effect of specific agonists of different VIP receptors on collagen-induced arthritis in mice was investigated by clinical and histologic assessment and measurement of cytokine and chemokine production. Expression of VIP receptor type 1 (VPAC1) in synovial cells and monocytes from RA patients was determined by flow cytometry. Potential associations of VPAC1 genetic polymorphisms with RA susceptibility were investigated. RESULTS: A VPAC1 agonist was very efficient in the treatment of experimental arthritis, and deficient expression of VPAC1 in immune cells of RA patients was associated with the predominant proinflammatory Th1 milieu found in this disease. Immune cells derived from RA patients were less responsive to VIP signaling than were cells from healthy individuals and showed reduced VIP-mediated immunosuppressive activity, rendering leukocytes and synovial cells more proinflammatory in RA. A significant association between multiple-marker haplotypes of VPAC1 and susceptibility to RA was found, suggesting that the reduced VPAC1 expression in RA-derived immune cells is associated with the described VPAC1 genetic polymorphism. CONCLUSION: These findings are highly relevant to the understanding of RA pathogenesis. They suggest that VIP signaling through VPAC1 is critical to maintaining immune tolerance in RA. In addition, the results indicate that VPAC1 may be a novel therapeutic target in RA.


Assuntos
Artrite Reumatoide/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/metabolismo , Peptídeo Intestinal Vasoativo/imunologia , Adulto , Animais , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/fisiopatologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Receptores Tipo II de Peptídeo Intestinal Vasoativo/agonistas , Receptores Tipo II de Peptídeo Intestinal Vasoativo/metabolismo , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/agonistas
17.
Reumatol. clín. (Barc.) ; 4(extr.1): 1-4, mar. 2008.
Artigo em Espanhol | IBECS | ID: ibc-78083

RESUMO

Las enfermedades autoinmunitarias, entre las que se incluyen la artritis reumatoide (RA) o el lupus eritematoso sistémico (LES), se caracterizan por tener una etiología compleja, en la que varios factores genéticos de susceptibilidad y factores ambientales interaccionan y resultan en una respuesta inmunitaria alterada. Hay diversos indicios de que existen elementos genéticos comunes de predisposición a las enfermedades autoinmunitarias, como la existencia de regiones cromosómicas asociadas a numerosas enfermedades autoinmunitarias y que haya patrones de expresión génica similares en varias de ellas. La identificación de factores genéticos comunes asociados con autoinmunidad es de gran relevancia, ya que contribuiría a comprender mejor la patogenia de estas enfermedades, desarrollar nuevas estrategias de diagnóstico a escala molecular e identificar posibles nuevas dianas terapéuticas. En los últimos años se ha producido un gran avance en el conocimiento de los marcadores genéticos comunes asociados a las enfermedades autoinmunitarias. El gen PTPN22, importante regulador de la respuesta de los linfocitos T, se ha perfilado como un importante marcador genético de autoinmunidad. Este gen está implicado en la susceptibilidad a diversas enfermedades autoinmunitarias como el LES, la diabetes mellitus tipo 1 (DM1) y la RA, en la que la asociación con el gen PTPN22 se ha convertido en la más sólida y repetida después de la asociación con los genes HLA. También se han identificado como nuevos marcadores genéticos de susceptibilidad a las enfermedades autoinmunitarias genes implicados en la alteración del equilibrio de citocinas como los genes MIF e IRF5 (AU)


Autoimmune diseases (AIDs), including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) among others, are characterized by a complex etiology in which the combination of several genetic and environmental factors leads to an altered immune response. Several lines of evidence, such as the presence of chromosomal regions associated with several AIDs and the existence of similar gene expression patterns in autoimmune disorders, suggest that different AIDs share common genetic factors. The identification of common genetic factors associated with autoimmunity is of great relevance, since it will allow a better understanding of disease pathogenesis and could help for the development of molecular diagnosis tools and new therapeutic targets. In the past few years, a great progress has been made in the knowledge of the common genetic factors associated with autoimmunity. The PTPN22 gene, an important regulator of T cell response, has been identified as a relevant genetic marker for AIDs. This gene is implicated in the susceptibility to autoimmune disorders such as, RA, SLE, and type 1 diabetes (T1D). In the case of RA the association with the PTPN22 gene is the most replicated after association with HLA genes. In addition, genes implicated in the altered balance between cytokines, such as MIF and IRF5, have been identified as genetic factors predisposing to AIDs (AU)


Assuntos
Humanos , Doenças Autoimunes/genética , Autoimunidade/genética , Marcadores Genéticos , Predisposição Genética para Doença , Citocinas/isolamento & purificação , Mediadores da Inflamação/análise
18.
Reumatol Clin ; 4 Suppl 1: 1-4, 2008 Mar.
Artigo em Espanhol | MEDLINE | ID: mdl-21794545

RESUMO

Autoimmune diseases (AIDs), including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) among others, are characterized by a complex etiology in which the combination of several genetic and environmental factors leads to an altered immune response. Several lines of evidence, such as the presence of chromosomal regions associated with several AIDs and the existence of similar gene expression patterns in autoimmune disorders, suggest that different AIDs share common genetic factors. The identification of common genetic factors associated with autoimmunity is of great relevance, since it will allow a better understanding of disease pathogenesis and could help for the development of molecular diagnosis tools and new therapeutic targets. In the past few years, a great progress has been made in the knowledge of the common genetic factors associated with autoimmunity. The PTPN22 gene, an important regulator of T cell response, has been identified as a relevant genetic marker for AIDs. This gene is implicated in the susceptibility to autoimmune disorders such as, RA, SLE, and type 1 diabetes (T1D). In the case of RA the association with the PTPN22 gene is the most replicated after association with HLA genes. In addition, genes implicated in the altered balance between cytokines, such as MIF and IRF5, have been identified as genetic factors predisposing to AIDs.

19.
Arthritis Rheum ; 56(12): 3953-8, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18050210

RESUMO

OBJECTIVE: To investigate the role of the HO-1 gene as a novel functional candidate gene for rheumatoid arthritis (RA). METHODS: We performed a case-control study including 736 RA patients and 846 healthy controls of Spanish Caucasian origin. Two putative functional HO-1 promoter polymorphisms, a (GT)(n) microsatellite and a -413 A/T single-nucleotide polymorphism (SNP), were selected as genetic markers and genotyped using polymerase chain reaction-based methods. In addition, the intracellular expression of heme oxygenase 1 (HO-1) was determined in healthy individuals with different (GT)(n) genotypes. RESULTS: The distribution of HO-1 (GT)(n) short (S) alleles (< or =25 GT repeats) and long (L) alleles (>25 GT repeats) revealed a significant protective effect of S (GT)(n) alleles (P = 0.019) (odds ratio [OR] 0.8, 95% confidence interval [95% CI] 0.7-0.9) and the SS (GT)(n) genotype (P = 0.002) (OR 0.6, 95% CI 0.4-0.9). In contrast, the -413 HO-1 promoter SNP did not yield any statistically significant deviation between RA patients and controls, considering either allele or genotype frequencies. The haplotype analysis showed a strong protective effect of the S/A haplotype (P = 7 x 10(-7), corrected P [P(corr)] = 3 x 10(-6)) (OR 0.4, 95% CI 0.3-0.6), whereas the L/A haplotype showed the opposite tendency (P = 0.008, P(corr) = 0.03) (OR 1.2, 95% CI 1.0-1.4). In addition, we demonstrated that monocytes from individuals carrying the SS (GT)(n) genotype showed a significantly higher percentage of HO-1 expression than did cells from LL homozygous individuals (P = 0.0003). CONCLUSION: In this study, we identified the HO-1 (GT)(n) microsatellite as a new genetic marker involved in RA genetics in our population.


Assuntos
Artrite Reumatoide/genética , Heme Oxigenase-1/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Marcadores Genéticos/genética , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Índice de Gravidade de Doença
20.
Hum Immunol ; 68(8): 681-4, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17678723

RESUMO

Recently, a genome-wide association study identified the interleukin-23 receptor gene (IL23R) as an inflammatory bowel disease (IBD) associated gene. Given the involvement of IL23R in T-cell regulation, we decided to test whether this gene is associated with rheumatoid arthritis (RA). Eight IL23R gene polymorphisms (rs1,004,819, rs7,517,847, rs10,489,629, rs11,209,026, rs1,343,151, rs10,889,677, rs11,209,032, and rs1,495,965) were selected among the 10 most associated SNPs from the IBD study. A total of 322 RA patients and 342 healthy controls were genotyped for the selected SNPs using a Taqman 5' allelic discrimination assay. We did not find statistically significant differences when we compared allele and genotype frequencies between RA patients and controls for none of the IL23R gene polymorphisms under study. We did not observe significant differences when RA patients were stratified according to their clinical and demographic features. We conclude that the IL23R gene does not seem to be associated with RA predisposition in a Spanish population.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genética , Receptores de Interleucina/imunologia , Alelos , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Humanos , Espanha
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA