Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 38
Filtrar
1.
Clin Exp Rheumatol ; 37 Suppl 118(3): 97-106, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31464664

RESUMO

OBJECTIVES: To analyse the frequency and characterise the systemic presentation of primary Sjögren's syndrome (SS) out of the ESSDAI classification in a large international, multi-ethnic cohort of patients. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry based on world-wide data-sharing and cooperative merging of pre-existing clinical SS databases from leading centres in clinical research in SS from the five continents. A list of 26 organ-by-organ systemic features not currently included in the ESSDAI classification was defined according to previous studies; these features were retrospectively recorded. RESULTS: Information about non-ESSDAI features was available in 6331 patients [5,917 female, mean age at diagnosis 52 years, mainly White (86.3%)]. A total of 1641 (26%) patients had at least one of the ESSDAI systemic features. Cardiovascular manifestations were the most frequent organ-specific group of non-ESSDAI features reported in our patients (17% of the total cohort), with Raynaud's phenomenon being reported in 15%. Patients with systemic disease due to non-ESSDAI features had a lower frequency of dry mouth (90.7% vs. 94.1%, p<0.001) and positive minor salivary gland biopsy (86.7% vs. 89%, p=0.033), a higher frequency of anti-Ro/SSA (74.7% vs. 68.7%, p<0.001), anti-La/SSB antibodies (44.5% vs. 40.4%, p=0.004), ANA (82.7% vs. 79.5%, p=0.006), low C3 levels (17.4% vs. 9.7%, p<0.001), low C4 levels (14.4% vs. 9.6%, p<0.001), and positive serum cryoglobulins (8.6% vs. 5.5%, p=0.001). Systemic activity measured by the ESSDAI, clinESSDAI and DAS was higher in patients with systemic disease out of the ESSDAI in comparison with those without these features (p<0.001 for all comparisons). CONCLUSIONS: More than a quarter of patients with primary SS may have systemic manifestations not currently included in the ESSDAI classification, with a wide variety of cardiovascular, digestive, pulmonary, neurological, ocular, ENT (ear, nose, and throat), cutaneous and urological features that increase the scope of the systemic phenotype of the disease. However, the individual frequency of each of these non-ESSDAI features was very low, except for Raynaud's phenomenon.


Assuntos
Síndrome de Sjogren , Estudos de Coortes , Grupos Étnicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Sistema de Registros , Estudos Retrospectivos , Índice de Gravidade de Doença , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/fisiopatologia
2.
Sci Rep ; 9(1): 2777, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808881

RESUMO

Behçet's disease (BD) is an immune-mediated systemic disorder with a well-established genetic base. In a previous study, using a next generation sequencing approach, we found many rare variants and some functional polymorphisms in genes related to autoinflammatory syndromes (AID): CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A in our BD cohort. Our strategy did not allow us to establish either number of patients with variants, proportion of individuals accumulating them or relationship with other genetic factors. With the goal to answer these questions, the individual samples were sequenced. Additionally, three functional polymorphisms: NLRP3 p.Gln703Lys, NOD2 p.Arg702Trp and p.Val955Ile were genotyped using TaqMan assays. A total of 98 patients (27.6%) carried at least one rare variant and 13 of them (3.7%) accumulated two or three. Functional regression model analysis suggests epistatic interaction between B51 and MEFV (P = 0.003). A suggestive protective association of the minor allele of NOD2 p.Arg702Trp (P = 0.01) was found in both, B51 positive and negative individuals. Therefore, a high percentage of patients with BD have rare variants in AID genes. Our results suggest that the association of MEFV with BD could be modulated by the HLA molecules; whereas the protective effect of NOD2 p.Arg702Trp would be independent of HLA.

3.
PLoS One ; 13(12): e0209343, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30586461

RESUMO

BACKGROUND: The TNFSF13B (TNF superfamily member 13b) gene encodes BAFF, a cytokine with a crucial role in the differentiation and activation of B cells. An insertion-deletion variant (GCTGT→A) of this gene, leading to increased levels of BAFF, has been recently implicated in the genetic predisposition to several autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. Based on the elevated levels of this cytokine found in patients with giant cell arteritis (GCA) and systemic sclerosis (SSc), we aimed to assess whether this functional variant also represents a novel genetic risk factor for these two disorders. METHODS: A total of 1,728 biopsy-proven GCA patients from 4 European cohorts, 4,584 SSc patients from 3 European cohorts and 5,160 ethnically-matched healthy controls were included in the study. The single nucleotide polymorphism (SNP) rs374039502, which colocalizes with the genetic variant previously implicated in autoimmunity, was genotyped using a custom TaqMan assay. First, association analysis was conducted in each independent cohort using χ2 test in Plink (v1.9). Subsequently, different case/control sets were meta-analyzed by the inverse variance method. RESULTS: No statistically significant differences were found when allele distributions were compared between cases and controls for any of the analyzed cohorts. Similarly, combined analysis of the different sets evidenced a lack of association of the rs374039502 variant with GCA (P = 0.421; OR (95% CI) = 0.92 (0.75-1.13)) and SSc (P = 0.500; OR (95% CI) = 1.05 (0.91-1.22)). The stratified analysis considering the main clinical subphenotypes of these diseases yielded similar negative results. CONCLUSION: Our data suggest that the TNFSF13B functional variant does not contribute to the genetic network underlying GCA and SSc.


Assuntos
Fator Ativador de Células B/genética , Predisposição Genética para Doença , Arterite de Células Gigantes/genética , Escleroderma Sistêmico/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Estudos de Casos e Controles , Estudos de Coortes , Europa (Continente) , Feminino , Redes Reguladoras de Genes/genética , Técnicas de Genotipagem , Arterite de Células Gigantes/patologia , Humanos , Mutação INDEL , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/patologia
4.
Clin Exp Rheumatol ; 36 Suppl 112(3): 102-112, 2018 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30156539

RESUMO

OBJECTIVES: To evaluate the influence of the main immunological markers on the disease phenotype at diagnosis in a large international cohort of patients with primary Sjögren's syndrome (SjS). METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry created in 2014. As a first step, baseline clinical information from leading centres on clinical research in SjS of the 5 continents was collected. The centres shared a harmonised data architecture and conducted cooperative online efforts in order to refine collected data under the coordination of a big data statistical team. Inclusion criteria were the fulfillment of the 2002 classification criteria. Immunological tests were carried out using standard commercial assays. RESULTS: By January 2018, the participant centres had included 10,500 valid patients from 22 countries. The cohort included 9,806 (93%) women and 694 (7%) men, with a mean age at diagnosis of primary SjS of 53 years, mainly White (78%) and included from European countries (71%). The frequency of positive immunological markers at diagnosis was 79.3% for ANA, 73.2% for anti-Ro, 48.6% for RF, 45.1% for anti- La, 13.4% for low C3 levels, 14.5% for low C4 levels and 7.3% for cryoglobulins. Positive autoantibodies (ANA, Ro, La) correlated with a positive result in salivary gland biopsy, while hypocomplementaemia and especially cryoglo-bulinaemia correlated with systemic activity (mean ESSDAI score of 17.7 for cryoglobulins, 11.3 for low C3 and 9.2 for low C4, in comparison with 3.8 for negative markers). The immunological markers with a great number of statistically-significant associations (p<0.001) in the organ-by-organ ESS- DAI evaluation were cryoglobulins (9 domains), low C3 (8 domains), anti-La (7 domains) and low C4 (6 domains). CONCLUSIONS: We confirm the strong influence of immunological markers on the phenotype of primary SjS at diagnosis in the largest multi-ethnic international cohort ever analysed, with a greater influence for cryoglobulinaemic-related markers in comparison with Ro/La autoantibodies and ANA. Immunological patterns play a central role in the phenotypic expression of the disease already at the time of diagnosis, and may guide physicians to design a specific personalised management during the follow-up of patients with primary SjS.


Assuntos
Autoanticorpos/sangue , Complemento C3/análise , Complemento C4/análise , Crioglobulinas/análise , Síndrome de Sjogren/imunologia , Adulto , Idoso , Anticorpos Antinucleares/sangue , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Sistema de Registros , Fator Reumatoide/sangue , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/epidemiologia
5.
Clin Exp Rheumatol ; 36 Suppl 112(3): 121-129, 2018 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30156546

RESUMO

OBJECTIVES: To analyse the clinical features and outcomes of patients presenting with life-threatening systemic disease in a large cohort of Spanish patients with primary Sjögren's syndrome (SS). METHODS: The GEAS-SS multicentre registry was formed in 2005 with the aim of collecting a large series of Spanish patients with primary SS, and included more than 20 Spanish reference centres with substantial experience in the management of SS patients. By January 2018, the database included 1580 consecutive patients fulfilling the 2002 classification criteria for primary SS. Severe, life-threatening systemic disease was defined as an activity level scored as "high" in at least one ESSDAI domain. RESULTS: Among 1580 patients, 208 (13%) were classified as presenting a severe, potentially life-threatening systemic disease: 193 presented one ESSDAI domain classified as high, 14 presented two high scored domains and only one presented three high activity domains. The ESSDAI domains involved consisted of lymphadenopathy in 78 (37%) cases, CNS in 28 (13%), PNS in 25 (12%), pulmonary in 25 (12%), renal in 21 (10%), cutaneous in 19 (9%), articular in 18 (9%), haematological in 7 (3%) and muscular in 4 (2%). Patients with severe systemic disease were more frequently men (p=0.001) and had a higher frequency of anaemia (p<0.001), lymphopenia (p<0.001), rheumatoid factor (p=0.021), low C3 levels (p=0.015), low C4 levels (p<0.001) and cryoglobulins (p<0.001). From a therapeutic point of view, systemic patients received more frequently glucocorticoids (p<0.001), immunosuppressants (p<0.001), intravenous immunoglobulins (p=0.008) and rituximab (p<0.001). We found an overall mortality rate of 20% in severe systemic patients, a rate that reached to 33% in patients presenting two or more high systemic involvements; these patients had a higher frequency of low C4 levels (p=0.012) and cryoglobulins (p=0.001) in comparison with those with a single severe organ involved. CONCLUSIONS: 13% of patients with primary SS develop a potentially life-threatening systemic disease (mainly lymphoma, but also severe internal organ involvements including nervous system, the lungs and the kidneys). This subset of patients requires intensive therapeutic management with a mortality rate of nearly 20% of cases.


Assuntos
Síndrome de Sjogren/epidemiologia , Adulto , Idoso , Técnicas de Apoio para a Decisão , Progressão da Doença , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Sistema de Registros , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/mortalidade , Síndrome de Sjogren/terapia , Espanha/epidemiologia , Resultado do Tratamento
6.
Clin Exp Rheumatol ; 2018 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-29745871

RESUMO

OBJECTIVES: To describe the characteristics of patients with Behçet's disease (BD) who presented with venous thrombosis. In addition, we identified the factors associated with this venous involvement and those related with recurrent venous thrombosis. METHODS: Up to January 2015, 544 BD patients from 20 Spanish hospitals had been included in the REGEB (REGistro de la Enfermedad de Behçet as Spanish nomenclature). We selected those patients who presented venous thrombosis. Descriptive analysis was performed and factors related with venous thrombosis were identified. RESULTS: Overall, 99 (18.2%) BD patients had vascular thrombosis, 91 (16.7%) of them (16.7%) involving venous vessels and 18 (19.7%) suffered from venous thrombotic relapse. Lower limbs were the most common location of deep venous thrombosis present in up to 60% of patients. In 12 (13.2%) patients, venous thrombosis affected two vascular territories simultaneously and in 6 (6.6%) the venous and arterial involvement coincided in time. Overall, at the diagnosis of venous thrombosis, 97.6% of patients presented concomitantly other clinical symptoms attributable to BD. In logistic regression multivariate analysis factors associated to venous thrombosis were male sex (Odds ratio [OR] 4.3, 95% confidence interval [CI] 2.5-7.7), erythema nodosum (OR 2.4, 95%CI 1.4-4.1), fever (OR 2.0, 95%CI 1.1-3.8), and central nervous system (CNS) involvement (OR 2.5, 95%CI 1.3-4.8). Considering relapses, CNS involvement was an independent risk factor according logistic regression. However, Cox multivariate analysis did not confirm this finding. CONCLUSIONS: We identified factors related with venous involvement in patients included in the REGEB cohort.

7.
Sci Rep ; 7(1): 8453, 2017 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-28814775

RESUMO

Behçet's disease (BD) is an immune-mediated systemic disorder with a well-established association with HLA class I and other genes. BD has clinical overlap with many autoinflammatory diseases (AIDs). The aim of this study was to investigate the role of rare variants in seven genes involved in AIDs: CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A using a next generation sequencing (NGS) approach in 355 BD patients. To check global association of each gene, 4 tests: SKAT, CollapseBt, C(α) and weighted KBAC were used. Databases: 1000 Genomes Project Phase 3, Infevers, HGMD and ClinVar and algorithms: PolyPhen2 and SIFT were consulted to collect information of the 62 variants found. All the genes resulted associated using SKAT but only 3 (MVK, NOD2 and PSTPIP1) with C(α) and weighted KBAC. When all the genes are considered, 40 variants were associated to AIDs in clinical databases and 25 were predicted as pathogenic at least by one of the algorithms. Including only MVK, NOD2 and PSTPIP1, the associated to AIDs variants found in BD were 20 and the predicted as pathogenic, 12. The maxima contribution corresponds to NOD2. This study supports influence of rare variants in genes involved in AIDs in the pathogenesis of BD.

9.
Sci Rep ; 7: 43953, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28277489

RESUMO

Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) are major forms of large-vessel vasculitis (LVV) that share clinical features. To evaluate their genetic similarities, we analysed Immunochip genotyping data from 1,434 LVV patients and 3,814 unaffected controls. Genetic pleiotropy was also estimated. The HLA region harboured the main disease-specific associations. GCA was mostly associated with class II genes (HLA-DRB1/HLA-DQA1) whereas TAK was mostly associated with class I genes (HLA-B/MICA). Both the statistical significance and effect size of the HLA signals were considerably reduced in the cross-disease meta-analysis in comparison with the analysis of GCA and TAK separately. Consequently, no significant genetic correlation between these two diseases was observed when HLA variants were tested. Outside the HLA region, only one polymorphism located nearby the IL12B gene surpassed the study-wide significance threshold in the meta-analysis of the discovery datasets (rs755374, P = 7.54E-07; ORGCA = 1.19, ORTAK = 1.50). This marker was confirmed as novel GCA risk factor using four additional cohorts (PGCA = 5.52E-04, ORGCA = 1.16). Taken together, our results provide evidence of strong genetic differences between GCA and TAK in the HLA. Outside this region, common susceptibility factors were suggested, especially within the IL12B locus.


Assuntos
Predisposição Genética para Doença , Arterite de Células Gigantes/genética , Antígenos HLA/genética , Arterite de Takayasu/genética , Feminino , Genótipo , Humanos , Masculino , Polimorfismo Genético
10.
Am J Hum Genet ; 100(1): 64-74, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28041642

RESUMO

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10-54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10-10, OR = 1.28; and rs128738, p = 4.60 × 10-9, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis.


Assuntos
Alelos , Predisposição Genética para Doença/genética , Variação Genética , Estudo de Associação Genômica Ampla , Arterite de Células Gigantes/genética , Plasminogênio/genética , Prolil Hidroxilases/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Europa (Continente)/etnologia , Feminino , Humanos , Masculino , Neovascularização Fisiológica , Polimorfismo de Nucleotídeo Único/genética , Risco
11.
Ann Rheum Dis ; 76(6): 1042-1050, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27899373

RESUMO

OBJECTIVES: To analyse the influence of geolocation and ethnicity on the clinical presentation of primary Sjögren's syndrome (SjS) at diagnosis. METHODS: The Big Data Sjögren Project Consortium is an international, multicentre registry designed in 2014. By January 2016, 20 centres from five continents were participating. Multivariable logistic regression analyses were performed. RESULTS: We included 7748 women (93%) and 562 men (7%), with a mean age at diagnosis of primary SjS of 53 years. Ethnicity data were available for 7884 patients (95%): 6174 patients (78%) were white, 1066 patients (14%) were Asian, 393 patients (5%) were Hispanic, 104 patients (1%) were black/African-American and 147 patients (2%) were of other ethnicities. SjS was diagnosed a mean of 7 years earlier in black/African-American compared with white patients; the female-to-male ratio was highest in Asian patients (27:1) and lowest in black/African-American patients (7:1); the prevalence of sicca symptoms was lowest in Asian patients; a higher frequency of positive salivary biopsy was found in Hispanic and white patients. A north-south gradient was found with respect to a lower frequency of ocular involvement in northern countries for dry eyes and abnormal ocular tests in Europe (OR 0.46 and 0.44, respectively) and Asia (OR 0.18 and 0.49, respectively) compared with southern countries. Higher frequencies of antinuclear antibodies (ANAs) were reported in northern countries in America (OR=1.48) and Asia (OR=3.80) while, in Europe, northern countries had lowest frequencies of ANAs (OR=0.67) and Ro/La (OR=0.69). CONCLUSIONS: This study provides the first evidence of a strong influence of geolocation and ethnicity on the phenotype of primary SjS at diagnosis.


Assuntos
Afro-Americanos/estatística & dados numéricos , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Hispano-Americanos/estatística & dados numéricos , Sistema de Registros , Síndrome de Sjogren/etnologia , Adulto , Idoso , Anticorpos Antinucleares/sangue , Estudos Transversais , Oftalmopatias/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prevalência , Síndrome de Sjogren/sangue , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico , Análise Espacial
12.
PLoS One ; 11(8): e0161305, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27548383

RESUMO

Behcet's disease (BD) is an immuno-mediated vasculitis in which knowledge of its etiology and genetic basis is limited. To improve the current knowledge, a genetic analysis performed with the Immunochip platform was carried out in a population from Spain. A discovery cohort comprising 278 BD cases and 1,517 unaffected controls were genotyped using the Immunochip platform. The validation step was performed on an independent replication cohort composed of 130 BD cases and 600 additional controls. The strongest association signals were observed in the HLA class I region, being HLA-B*51 the highest peak (overall P = 6.82E-32, OR = 3.82). A step-wise conditional logistic regression with classical alleles identified HLA-B*57 and HLA-A*03 as additional independent markers. The amino acid model that best explained the association, includes the position 97 of the HLA-B molecule and the position 66 of the HLA-A. Among the non-HLA loci, the most significant in the discovery analysis were: IL23R (rs10889664: P = 3.81E-12, OR = 2.00), the JRKL/CNTN5 region (rs2848479: P = 5.00E-08, OR = 1.68) and IL12A (rs1874886: P = 6.67E-08, OR = 1.72), which were confirmed in the validation phase (JRKL/CNTN5 rs2848479: P = 3.29E-10, OR = 1.66; IL12A rs1874886: P = 1.62E-08, OR = 1.61). Our results confirm HLA-B*51 as a primary-association marker in predisposition to BD and suggest additional independent signals within the class I region, specifically in the genes HLA-A and HLA-B. Regarding the non-HLA genes, in addition to IL-23R, previously reported in our population; IL12A, described in other populations, was found to be a BD susceptibility factor also in Spaniards; finally, a new associated locus was found in the JRKL/CNTN5 region.


Assuntos
Síndrome de Behçet/genética , Contactinas/genética , Predisposição Genética para Doença , Antígeno HLA-B51/genética , Subunidade p35 da Interleucina-12/genética , Receptores de Interleucina/genética , Alelos , Síndrome de Behçet/imunologia , Síndrome de Behçet/patologia , Estudos de Casos e Controles , Contactinas/imunologia , Frequência do Gene , Loci Gênicos , Antígeno HLA-A3/genética , Antígeno HLA-A3/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Antígeno HLA-B51/imunologia , Humanos , Imunoensaio , Subunidade p35 da Interleucina-12/imunologia , Modelos Logísticos , Análise em Microsséries , Modelos Moleculares , Receptores de Interleucina/imunologia , Espanha
13.
Clin Exp Rheumatol ; 34(6 Suppl 102): S41-S45, 2016 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27050764

RESUMO

OBJECTIVES: The functional variant R620W of the protein tyrosine phosphatase non receptor-22 (PTPN22) gene plays an important role in susceptibility to several immuno-mediated pathologies. Behçet's disease (BD) is a complex disease related to the immune system with a demonstrated genetic base. The HLA class I genes are the most important genetic factors in BD although other genes are also involved in the susceptibility to this disease. The PTPN22 has been proposed as a candidate gene in BD but this association has not been clearly demonstrated yet. The aim of this study was to assess the association of PTPN22 with BD. METHODS: A cohort composed of 404 Spanish BD patients and 1517 unrelated healthy individuals ethnically matched was genotyped in rs2476601 (R620W). Five tag SNPs: rs1217412, rs2476599, rs3789607, rs3765598 and rs1217419 (spanning a 57 Kb region between 3'UTR and 5'UTR) and rs2488457 (located at the promoter region) were also studied in order to perform a screening of the complete gene. Genotyping was performed using TaqMan® assays. The rs2476601 data were included in a meta-analysis together with those published till the date. The rest of SNPs were used in a case-control study. RESULTS: No evidence of the association of rs2476601 with BD in the meta-analysis (P = 0.504 in the model of alleles) was found. In the case-control study, no statistically significant differences were observed when comparing the distribution of variants in patients and controls. CONCLUSIONS: Our results do not support a major role of the PTPN22 gene in BD.


Assuntos
Síndrome de Behçet/genética , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/enzimologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Masculino , Razão de Chances , Fenótipo , Regiões Promotoras Genéticas , Fatores de Risco , Espanha
14.
Clin Exp Rheumatol ; 33(6 Suppl 94): S117-22, 2015 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26486764

RESUMO

OBJECTIVES: The aim of this study was to investigate the role of the TLR8, a mediator of innate inflammatory response, in susceptibility to two immune-mediated disorders characterised by dysregulation of the immune response, Crohn's and Behçet's diseases (CD and BD). METHODS: A total of 844 CD, 371 BD patients and 1385 controls were genotyped in 8 tag single nucleotide polymorphisms (tSNPs) in the locus TLR8 (chromosome X). All these tSNPs have a minor allele frequency greater than 0.05 in the Caucasian population. RESULTS: The rs2407992 and the rs5744067 were associated with susceptibility to BD and CD, respectively (OR=1.34, 95%CI=1.10-1.62, p=0.0025 and OR=0.82, 95%CI=0.68-0.99, p=0.045, respectively). Although after stratification by gender, statistically significant differences in the distribution of the aforementioned SNPs were only observed in the females groups (BD OR=1.31, 95%CI=1.06-1.64, p=0.012 and CD OR=0.84, 95%CI=0.72-0.98, p=0.044) the trend was similar among males. Since the rs5744067 and rs2407992 are located in the same linkage disequilibrium block, we performed a haplotypic analysis by combination of the tSNPs. One haplotype (H1) was identified as a protective factor in BD (OR=0.75, 95%CI=0.62-0.90, p=0.0027) and another (H2) as a protective factor in CD (OR=0.78, 95%CI=0.64-094, p=0.0102). No statistically significant differences in the mean of the levels of expression attributable to the haplotype variants were found in the in silico analysis performed. CONCLUSIONS: Our results suggest a relationship between the TLR8 and the susceptibility to CD and BD. Nevertheless, these differences could not be imputed to the levels of expression.


Assuntos
Síndrome de Behçet/genética , Doença de Crohn/genética , Haplótipos , Polimorfismo de Nucleotídeo Único , Receptor 8 Toll-Like/genética , Adulto , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/imunologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Simulação por Computador , Doença de Crohn/diagnóstico , Doença de Crohn/imunologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Fatores de Proteção , Medição de Risco , Fatores de Risco , Fatores Sexuais , Espanha , Receptor 8 Toll-Like/imunologia , Adulto Jovem
15.
Clin Exp Rheumatol ; 33(6 Suppl 94): S96-100, 2015 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26393284

RESUMO

OBJECTIVES: Behçet's disease (BD) is an immune-mediated and complex disease associated with HLA class I and other genes. The aim of this study was to contribute to a better understanding of the relationship of the 32-bp deletion in the CCR5 gene (CCR5Δ32) and this disease by conducting a case-control study in the Spanish population and also a meta-analysis including all the studies available to date. METHODS: A cohort composed of 348 BD Spanish patients and 477 unrelated healthy and ethnically matched individuals were genotyped in CCR5Δ32 using polymerase chain reaction (PCR) and capillary electrophoresis with fluorescent detection. In the meta-analysis, data from a total of seven populations extracted from four previous studies along with data of the present study were included. RESULTS: Regarding the case-control study, no statistically significant differences were observed when the patient and control groups were compared (allelic model: 0.07 in patients vs. 0.06 in controls, p=0.303). In the meta-analysis, no evidence of association of the CCR5Δ32 polymorphism with BD was observed (pMH=0.091; OR=1.22; 95%CI 0.98 to 1.52 in the allelic model). CONCLUSIONS: The results of this meta-analysis discard a major role of the CCR5Δ32 polymorphism in BD.


Assuntos
Síndrome de Behçet/genética , Receptores CCR5/genética , Adulto , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/epidemiologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Medição de Risco , Fatores de Risco , Espanha
16.
Clin Exp Rheumatol ; 33(6 Suppl 94): S36-9, 2015 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26005883

RESUMO

OBJECTIVES: Behçet's disease (BD) is an immune-mediated and complex disease which has been associated with HLA class I molecules although other genes such as IL23R and IL10 have also been involved in the susceptibility to BD. Recently, an association of variants of the JAK1 and TNFAIP3 genes with the disease has been reported in the Chinese Han population. The aim of the present work was to asses whether the association described in Asian populations is replicated in Europeans. METHODS: This study includes a total of 1155 Spanish subjects of European origin (372 BD and 783 unrelated healthy individuals). Patients were recruited from different hospitals and controls were collected in the same geographic regions and they matched with patients in age and gender. A total of five SNPs, two in the JAK1 gene: rs2780815 and rs310241 and the other three in the TNFAIP3: rs10499194, rs9494885 and rs610604, were included in this study. The genotyping of these SNPs was performed using a real time PCR system (TaqMan® SNP Genotyping Assays). RESULTS: No statistically significant differences were found when the patient and control groups were compared. The distribution of the risk alleles was similar in patients with and without eye manifestations and in patients with and without HLA-B*51. CONCLUSIONS: The association of variants of the genes JAK1 and the TNFAIP3 with BD which has been described in the Chinese population was not replicated in Europeans.


Assuntos
Síndrome de Behçet/genética , Proteínas de Ligação a DNA/genética , Grupo com Ancestrais do Continente Europeu/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Janus Quinase 1/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Adulto , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/enzimologia , Síndrome de Behçet/etnologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Espanha/epidemiologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa
17.
Am J Hum Genet ; 96(4): 565-80, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25817017

RESUMO

We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRß1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRß1 13 (p = 4.08 × 10(-43)) and HLA-DQα1 47 (p = 4.02 × 10(-46)), 56, and 76 (both p = 1.84 × 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 × 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.


Assuntos
Genes MHC da Classe II/genética , Arterite de Células Gigantes/genética , Herança Multifatorial/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Estudos de Associação Genética , Genótipo , Humanos , Análise Multivariada , Razão de Chances
18.
J Rheumatol ; 42(4): 695-701, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25641891

RESUMO

OBJECTIVE: Behçet disease (BD) is a multifactorial disease in which infectious agents have been proposed as triggers in genetically predisposed individuals. The aim of our study was to investigate the role of innate immunity receptors, specifically the nucleic acid sensors, in susceptibility to BD. METHODS: Seventy-four tag single nucleotide polymorphisms (tSNP) selected in 9 candidate genes (DDX58, IFIH1, TLR3, TLR7, TLR8, AIM2, IFI16, ZBP1, and TLR9) were genotyped in 371 patients and 854 controls. Assays of mRNA expression and allele-specific transcript quantification (ASTQ) were performed in 110 and 50 controls, respectively. RESULTS: Patients and controls were genotyped and 2 tSNP (rs6940 in IFI16 and rs855873 in AIM2) were associated with BD. To confirm this association, these tSNP were genotyped in 850 additional controls, and the total cohort was randomly divided into 2 cohorts. The association of these 2 tSNP with the disease remained in both cohorts. One haplotype (rs6940T-rs855873G) was identified as a risk factor (OR 1.41, 95% CI 1.06-1.86, p = 0.015), and another (rs6940A-rs855873A) as a protective factor (OR 0.65, 95% CI 0.47-0.90, p = 0.009). Samples with the risk haplotype had lower IFI16 expression levels than samples with the protective (0.99 ± 0.29 vs 1.23 ± 0.50, p = 0.022). Consistently, in the ASTQ assays performed with the nonsynonymous rs6940 SNP, the risk allele had lower IFI16 expression levels than the protective (p = 0.027). CONCLUSION: Our findings suggest association of IFI16, a cytosolic sensor of dsDNA and mediator of the AIM2 inflammasome-dependent pathway, in susceptibility to BD. Differences genetically determined in the levels of this molecule could be the cause of this association.


Assuntos
Síndrome de Behçet/genética , Predisposição Genética para Doença , Proteínas Nucleares/genética , Fosfoproteínas/genética , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , Adulto , Alelos , Feminino , Genótipo , Haplótipos , Humanos , Inflamassomos/genética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Rheumatology (Oxford) ; 54(3): 424-32, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25187644

RESUMO

OBJECTIVE: The aim of this study was to describe the presentation and outcomes of patients with granulomatosis with polyangiitis (GPA) presenting with CNS involvement. METHODS: Patients were included in this nationwide retrospective study if they had GPA according to ACR criteria and/or the European Medicines Agency algorithm and CNS involvement. RESULTS: Thirty-five patients were included in the study. CNS involvement was observed in 51% of patients at GPA diagnosis. Headache (66%) was the main symptom, followed by sensory (43%) and motor impairment (31%). CNS involvement was characterized by pachymeningitis in 20, cerebral ischaemic lesions in 15 and haemorrhagic lesions in 2, with hypophyseal involvement in 2 patients. According to the clinical-radiological presentation, we distinguished granulomatous (G-CNS) and vasculitic (V-CNS) phenotypes. G-CNS patients more frequently had headaches, while V-CNS patients more frequently had motor impairment and renal involvement. Induction therapy produced clinical responses in 86% of patients. Baseline modified Rankin scale was higher for V-CNS than G-CNS patients (3 vs 2, P = 0.002). Initial spinal cord pachymeningitis was significantly associated with the need for a new induction regimen for relapsing/refractory disease (P = 0.01). Long-term neurological sequelae were noted in 51% of patients, including 35% with G-CNS and 69% with V-CNS (P = 0.08). Neurological sequelae were mainly noted in cases of spinal cord pachymeningitis (100%) and ischaemic or haemorrhagic lesions (73%). CONCLUSION: The clinical-radiological phenotype distinguished different long-term outcomes in patients with GPA and CNS involvement. Long-term neurological sequelae persisted in half of patients, mainly those with spinal cord pachymeningitis and vasculitic lesions.


Assuntos
Doenças do Sistema Nervoso Central/diagnóstico por imagem , Doenças do Sistema Nervoso Central/diagnóstico , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/diagnóstico , Fenótipo , Adolescente , Corticosteroides/uso terapêutico , Adulto , Idoso , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/tratamento farmacológico , Doenças do Sistema Nervoso Central/tratamento farmacológico , Criança , Pré-Escolar , Feminino , França , Granulomatose com Poliangiite/epidemiologia , Cefaleia/diagnóstico , Cefaleia/diagnóstico por imagem , Cefaleia/tratamento farmacológico , Humanos , Masculino , Meningite/diagnóstico , Meningite/diagnóstico por imagem , Meningite/tratamento farmacológico , Pessoa de Meia-Idade , Prevalência , Prognóstico , Radiografia , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
20.
PLoS One ; 9(11): e113476, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25409453

RESUMO

INTRODUCTION: Increased expression of IL-33 and its receptor ST2, encoded by the IL1RL1 gene, has been detected in the inflamed arteries of giant cell arteritis (GCA) patients. The aim of the present study was to investigate for the first time the potential influence of the IL33 and IL1RL1 loci on GCA predisposition. METHODS: A total of 1,363 biopsy-proven GCA patients and 3,908 healthy controls from four European cohorts (Spain, Italy, Germany and Norway) were combined in a meta-analysis. Six genetic variants: rs3939286, rs7025417 and rs7044343, within the IL33 gene, and rs2058660, rs2310173 and rs13015714, within the IL1RL1 gene, previously associated with immune-related diseases, were genotyped using predesigned TaqMan assays. RESULTS: A consistent association between the rs7025417 polymorphism and GCA was evident in the overall meta-analysis, under both allele (P(MH) = 0.041, OR = 0.88, CI 95% 0.78-0.99) and recessive (P(MH) = 3.40E-03, OR = 0.53, CI 95% 0.35-0.80) models. No statistically significant differences between allele or genotype frequencies for the other IL33 and IL1RL1 genetic variants were detected in this pooled analysis. CONCLUSIONS: Our results clearly evidenced the implication of the IL33 rs7025417 polymorphism in the genetic network underlying GCA.


Assuntos
Arterite de Células Gigantes/genética , Interleucina-33/genética , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Suscetibilidade a Doenças , Feminino , Redes Reguladoras de Genes , Loci Gênicos , Genótipo , Arterite de Células Gigantes/patologia , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1 , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/genética , Fatores de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA