Assuntos
Anticorpos Monoclonais/uso terapêutico , Síndrome de Behçet/tratamento farmacológico , Encefalopatias/tratamento farmacológico , Osteomalacia/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Síndrome de Behçet/complicações , Encefalopatias/complicações , Tronco Encefálico/patologia , Colchicina/efeitos adversos , Feminino , Supressores da Gota/efeitos adversos , Humanos , Infliximab , Pessoa de Meia-Idade , Osteomalacia/induzido quimicamenteRESUMO
Behçet's disease (BD) is a chronic inflammatory disease characterized by oral aphthous ulcers, genital ulcers, uveitis and skin lesions. Etiology and pathogenesis of BD are not fully elucidated, but the association with human leukocyte antigen (HLA)-B51 or B*5101 has been repeatedly reported. Previous studies have shown that there are few sequence variations in the protein-coding region of B51, while there is a report on many variations in the 5'-flanking region and intron. In this study, HLA-B*5101 gene from 37 individuals including Japanese, Turkish, Jordanian and Iranian patients and healthy controls were fully sequenced to further clarify the B*5101 gene in association with BD. We found that all the patients and healthy controls carried B*510101 with no variation in the 5'-flanking region, exon and intron. However, seven polymorphisms were found in the 3'-flanking region. These polymorphisms composed of six haplotypes that were shared and stretched over the ethnic groups, suggesting that the susceptibility to BD was conferred by the B*510101 itself and not by any genes in linkage disequilibrium with B*510101. In addition, phylogenetic analyses of B*510101 showed that the 3'-flanking sequences followed an evolutional divergence differently from that of the other regions, implying that a unifying selection might operate to conserve B*510101.
Assuntos
Síndrome de Behçet/genética , Antígenos HLA-B/genética , Haplótipos/genética , Sequência de Bases , Éxons , Predisposição Genética para Doença , Antígeno HLA-B51 , Humanos , Íntrons , Dados de Sequência Molecular , Filogenia , Polimorfismo GenéticoRESUMO
BACKGROUND: Behçet's disease (BD) is a chronic multi-system inflammatory disorder of unknown aetiology, which shares many features of the inflammatory bowel diseases (IBDs). CARD15 has recently been identified as the first susceptibility gene in Crohn's disease (CD). OBJECTIVE: Given certain clinical and pathological similarities between CD and BD, and recent evidence of linkage of BD to the CARD15 genomic region, the aim of this study was to investigate the role of CARD15 variants in determining susceptibility to BD. METHODS: We studied 374 BD patients from three ethnically homogeneous cohorts (white English, Turkish, and Middle Eastern Arabs of Palestinian and Jordanian descent). Mutation detection of CARD15 was performed by direct sequencing in a subset of patients from each group and the identified variants were genotyped in the complete cohorts. Case-control analyses were carried out with additional stratification by the BD-associated allele, HLA-B*51. RESULTS: Mutation detection identified six previously described CARD15 polymorphisms at a frequency of > 3%. Additionally, two of the three CD-associated polymorphisms were present, but at low frequency. The frequency of haplotypes, constructed from nine genotyped polymorphisms, demonstrated significant variation between different ethnic groups. However, case-control analyses demonstrated no association between the CARD15 polymorphisms and susceptibility to BD, irrespective of HLA-B*51 status. CONCLUSION: CARD15 variant alleles are not associated with susceptibility to BD. Other shared loci, currently under investigation, may determine susceptibility to both CD and BD.
Assuntos
Síndrome de Behçet/genética , Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intracelular/genética , Polimorfismo Genético , Árabes/etnologia , Síndrome de Behçet/etnologia , Estudos de Casos e Controles , Análise Mutacional de DNA , Inglaterra/etnologia , Genótipo , Antígenos HLA-B/genética , Antígeno HLA-B51 , Humanos , Jordânia/etnologia , Proteína Adaptadora de Sinalização NOD2 , Turquia/etnologia , População Branca/etnologiaRESUMO
Chemokines are important determinants of the early inflammatory response. The CC chemokine receptor 5 (CCR5) Delta32 variant results in a non-functional form of the chemokine receptor, and has been implicated in a variety of immune-mediated diseases. To investigate its role in the pathogenesis of Behçet's disease, we studied 350 patients and 519 healthy controls from three ethnic groups. While significant inter-ethnic variation in allele frequency was observed, no association was identified with disease, even when data were stratified by the known susceptibility gene HLA-B*51.
Assuntos
Síndrome de Behçet/genética , Predisposição Genética para Doença , Antígenos HLA-B/genética , Polimorfismo Genético , Receptores CCR5/genética , Alelos , Árabes , Estudos de Coortes , Frequência do Gene , Variação Genética , Genótipo , Antígeno HLA-B51 , Humanos , Receptores de Quimiocinas/metabolismo , Turquia , Reino Unido , População BrancaRESUMO
Intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms have been implicated in the susceptibility to inflammatory diseases, including multiple sclerosis and inflammatory bowel disease. The expression of both soluble and tissue ICAM-1 is increased in Behçet's disease (BD) but the contribution of ICAM-1 gene polymorphisms to this disease remains unknown. Associations with BD have been reported for genes within the MHC, including HLA-B51, TNF and MICA, but the role of non-MHC genes in BD remains largely unexplored. We have investigated the frequency of the R/G 241 and K/E 469 ICAM-1 gene polymorphisms in 83 patients with BD disease and 103 healthy controls, all of Palestinian and Jordanian descent, and demonstrated an association between BD and the ICAM-1 E469 allele (Pc = 0.046, OR = 2.1). Among patients, no association was found between the presence of ocular disease and ICAM-1 polymorphisms. While the functional correlate of this polymorphism remains unclear, this finding indicates that a genetic polymorphism in the ICAM-1 gene domain, which is independent of the MHC, may contribute to disease.
Assuntos
Síndrome de Behçet/genética , Molécula 1 de Adesão Intercelular/genética , Polimorfismo Genético , Humanos , Complexo Principal de Histocompatibilidade/genéticaRESUMO
The role of HLA-B*51 and other major histocompatibility complex (MHC) genes in Behçet's disease (BD) remains unknown. We have performed HLA and tumour necrosis factor (TNF) polymorphism analysis in BD and evaluated their contribution to ocular disease. In this study, 102 patients and 115 controls of Middle Eastern descent were investigated by HLA and B*51 subtyping using novel primers, and by LT alpha NCo 1 and TNF 308 promoter polymorphism analysis. The frequency of the HLA-B*51 family of alleles was raised in patients compared to controls (66% vs. 15%, Pc=2.5x10(-12), OR=10.9). The odds ratio (OR) of this group of alleles for subgroups of patients was as follows: non-ocular patients 7.8, all ocular patients 12.6, blind patients >22. HLA-B*51 subtyping detected B*5101, 07, 08 and 09 alleles, with a similar frequency among patients and controls. HLA-Cw*1602 was associated with B*5108, but was not an independent risk factor for disease. The LT alpha (TNFB*2) allele was associated with HLA-B*51 among patients and the frequency of this allele was significantly higher among completely blind patients compared to both non-ocular patients (P=0.048, OR >3.6) and to healthy controls (P=0.022, OR >4.3). The rare TNF-2 polymorphism at the TNF -308 promoter position was associated with HLA-B*50 (not B*51), and was not associated with BD. Thus, in this population the HLA*B51 family of alleles is a strong risk factor for BD, and in particular the development of ocular disease. HLA-B*51 subtyping did not define new markers for BD. A primary role for TNF gne polymorphisms in BD was not identified, but co-expression of the TNFB*2 allele with HLA-B*51 may contribute to severity of ocular disease.
Assuntos
Síndrome de Behçet/genética , Antígenos HLA/genética , Polimorfismo Genético/genética , Fator de Necrose Tumoral alfa/genética , Adolescente , Adulto , Fatores Etários , Idoso , Feminino , Predisposição Genética para Doença , Antígenos HLA-B/genética , Antígeno HLA-B51 , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe II/genética , Teste de Histocompatibilidade , Humanos , Jordânia , Masculino , Pessoa de Meia-Idade , Oriente Médio , Polimorfismo de Fragmento de Restrição , Regiões Promotoras Genéticas/genética , Fatores de Risco , Fatores SexuaisRESUMO
PURPOSE: Behçet disease is a systemic disease of young adults characterized by venous occlusion in both the deep venous and retinal circulations. In severe ocular disease, blindness may occur despite immunosuppressive treatment. The most common inherited risk factor for the development of idiopathic venous thrombosis is the presence of the Factor V (FV Leiden) mutation, which confers resistance to activated protein C. The association of FV Leiden with Behçet disease has been reported, but its influence on ocular disease is not known. We therefore investigated the prevalence of this mutation in patients with Behçet disease to determine its contribution to the presence and severity of ocular disease. METHODS: One hundred and six Middle Eastern patients satisfying international criteria, and 120 healthy control subjects without a history of venous thrombosis were included in the study, and patients underwent standard examination by two ophthalmologists with an interest in Behçet disease. Genomic DNA was extracted from peripheral blood leukocytes and screened for the FV Leiden mutation with the polymerase chain reaction method with sequence-specific primers (PCR-SSP). RESULTS: FV Leiden was detected in 19% (23/120) of the control population compared with 27% (29/106) of all patients with Behçet disease (P = .13). However, among patients with Behçet disease who had ocular disease (75/106), the prevalence of FV Leiden was significantly higher (32%) than it was in control subjects (P = .04). Furthermore, ocular patients with Behçet disease in whom retinal occlusive disease was observed (25/75) had the highest expression of FV Leiden (44%). CONCLUSIONS: These data suggest that FV Leiden may be an additional risk factor for the development of ocular disease and, in particular, retinal vaso-occlusion, and it may contribute to the poor visual outcome in these patients.
Assuntos
Síndrome de Behçet/genética , Oftalmopatias/genética , Fator V/genética , Mutação Puntual , Adolescente , Adulto , Idoso , Síndrome de Behçet/epidemiologia , DNA/análise , Primers do DNA/química , Oftalmopatias/epidemiologia , Feminino , Humanos , Israel/epidemiologia , Jordânia/epidemiologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , PrevalênciaRESUMO
Recently a new family of non-classical MHC molecules, the MHC class I chain-related protein (MIC), encoded by genes located in the major histocompatability complex have been identified. On the basis of the location of MIC genes and the structure and expression of MIC molecules it has been postulated that MIC may be a susceptibility factor in Behçet's disease (BD). We investigated the association of the 16 described external domain alleles and the transmembrane triplet repeats of MIC-A with BD in a Middle Eastern population. DNA from ninety-five patients and 102 age- and sex-matched controls were analyzed by polymerase chain reaction using allele specific primers. Our results show an increase of MIC-A*009 in the BD patient group 44/95 (46%) compared with controls 24/102 (24%) (chi2=11.3, OR=2.8, P=0.00078). MIC-A*009 was also found to be strongly associated with HLA-B51 in the patients 39/44 (88%) when compared with controls 10/24 (42%) (chi2=4, P=0.04). MIC-A*009 was also found in linkage disequilibrium with HLA-B52, but only in controls. The A6 form of a MIC-A transmembrane triplet repeat was found to be significantly raised in the patients (80/95; 84%;) compared with controls (58/102, 57%) (chi2=17.5, OR=4, P=0.000028). Although the MIC-A associations described are highly significant, the association with HLA-B51 independently remains the most significant factor (chi2=56.8, P<10(-6)). The data suggests that as both MIC-A*009 and A6 are in strong linkage disequilibrium with HLA-B51, they are unlikely to be the susceptibility gene for BD but may be markers for additional risk factors.
Assuntos
Alelos , Síndrome de Behçet/genética , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos de Histocompatibilidade Classe I/genética , Adolescente , Adulto , Idoso , Síndrome de Behçet/imunologia , Criança , Feminino , Frequência do Gene , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Repetições de TrinucleotídeosRESUMO
A 51-year-old male patient with Behçet's disease had a large echogenic mass in the left atrium mimicking myxoma, documented by echocardiography. Postoperative pathological examination revealed left atrial thrombus, deep ulcerations of mitral valve leaflets with signs of active endocarditis. Cardiac evaluation with echocardiography should be considered in patients with Behçet's disease.