RESUMO
IMPORTANCE: High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. OBJECTIVE: To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. DESIGN, SETTING, AND PARTICIPANTS: The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. INTERVENTIONS: HSCT vs intravenous pulse cyclophosphamide. MAIN OUTCOMES AND MEASURES: The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. RESULTS: A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. CONCLUSIONS AND RELEVANCE: Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN54371254.
Assuntos
Ciclofosfamida/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/administração & dosagem , Esclerodermia Difusa/tratamento farmacológico , Adulto , Autoenxertos , Ciclofosfamida/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Análise de SobrevidaRESUMO
BACKGROUND: Dyspnea may be a presenting symptom in progressive systemic sclerosis (SSc). Respiratory drive (mouth occlusion pressure, MOP, at rest and during CO2 rebreathing, 7% CO2, 93% O2) is a major determinant of dyspnea and may relate to the magnitude of dyspnea. METHODS: In a prospective design, MOP at 0.1 sec (P0.1) was measured in 73 SSc patients while breathing room air and during CO2 rebreathing. An abnormal V'E/P0.1 is defined as < 8 L/min/cm H2O. Dyspnea scores were assessed by a shortness of breath questionnaire (UCSD dyspnea scale). RESULTS: Mean P0.1 in patients with normal V'E/P0.1 (n = 45) was 1.1 ± 0.04 and 1.6 ± 0.08 cm H2O in patients with abnormal V'E/P0.1 (n = 28), p <0.001. ∆P0.1/∆PetCO2 differed significantly between these groups (0.45 versus 0.75 cm H2O/mmHg, P < 0.001), but no significant difference was present in ∆V'E/∆PetCO2. V'E/P0.1 showed the highest significant correlation with the UCSD dyspnea score (r = -0.76, p <0.001). UCSD cut-off value for abnormal V'E/P0.1 was 8.5 (sensitivity 93%, specificity 96%, area under the curve 0.98). CONCLUSIONS: In SSc patients an abnormal V'E/P0.1 better relates to the severity of dyspnea than traditional lung function parameters and can easily be assessed at first outpatient consultation.
Assuntos
Dispneia/etiologia , Escleroderma Sistêmico/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Escleroderma Sistêmico/fisiopatologia , Índice de Gravidade de DoençaRESUMO
In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.
Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 3/genética , Loci Gênicos , Predisposição Genética para Doença , Escleroderma Sistêmico/genética , Alelos , Proteína 5 Relacionada à Autofagia , Proteínas de Transporte/genética , Estudos de Casos e Controles , RNA Helicases DEAD-box/genética , Endodesoxirribonucleases/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Antígenos HLA/genética , Humanos , Subunidade p35 da Interleucina-12/genética , Desequilíbrio de Ligação , Modelos Logísticos , Masculino , Procedimentos Analíticos em Microchip , Proteínas Associadas aos Microtúbulos/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Fatores de Risco , População Branca/genéticaRESUMO
INTRODUCTION: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy. METHODS: Sixty-six non-HLA SNPs showing a P value <10â»4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. RESULTS: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10â»6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10â»6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10â»7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis. CONCLUSION: Our results suggest a role of PPARG gene in the development of SSc.
Assuntos
Predisposição Genética para Doença/genética , PPAR gama/genética , Escleroderma Sistêmico/genética , Adulto , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
This study aims to examine healthcare utilization and its determinants among patients with systemic sclerosis (SSc). A cross-sectional survey among all patients with SSc visiting an outpatient clinic of an academic hospital in the Netherlands was done. Assessments included sociodemographic characteristics and a survey on healthcare utilization including a registration of contacts with healthcare services since onset of disease, contacts, and number of visits with healthcare services over the last 12 months. A total healthcare utilization score of all visits over the last 12 months was computed and classified as high and low care utilization according to the median. In addition, the Short Form-36 and the Scleroderma Health Assessment Questionnaire (SHAQ) were administered. Logistic regression analysis was used to determine the relationship between high and low healthcare utilization as dependent variable and sociodemographic and disease characteristics as independent variables. Sixty-four patients returned the questionnaires. Over the last 12 months, 83% of the patients had had contact with one or more physicians. On average, patients reported 3.9 visits (SD, 2.9) to a rheumatologist and 6.9 visits (SD, 9.3) to other medical specialists over the last 12 months. The median total health-care utilization was six visits over the last 12 months. Multivariate regression showed that a higher SHAQ score was significantly associated with higher health-care utilization. Patients with SSc visited a considerable number of various health-care providers. Patients with more functional disability were using more healthcare.
Assuntos
Atenção à Saúde/estatística & dados numéricos , Escleroderma Sistêmico/terapia , Estudos Transversais , Pesquisas sobre Atenção à Saúde , Humanos , Análise Multivariada , Países Baixos , Qualidade de Vida , Análise de Regressão , Reprodutibilidade dos Testes , Reumatologia/métodos , Classe Social , Inquéritos e QuestionáriosRESUMO
Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are two archetypal systemic autoimmune diseases which have been shown to share multiple genetic susceptibility loci. In order to gain insight into the genetic basis of these diseases, we performed a pan-meta-analysis of two genome-wide association studies (GWASs) together with a replication stage including additional SSc and SLE cohorts. This increased the sample size to a total of 21,109 (6835 cases and 14,274 controls). We selected for replication 19 SNPs from the GWAS data. We were able to validate KIAA0319L (P = 3.31 × 10(-11), OR = 1.49) as novel susceptibility loci for SSc and SLE. Furthermore, we also determined that the previously described SLE susceptibility loci PXK (P = 3.27 × 10(-11), OR = 1.20) and JAZF1 (P = 1.11 × 10(-8), OR = 1.13) are shared with SSc. Supporting these new discoveries, we observed that KIAA0319L was overexpressed in peripheral blood cells of SSc and SLE patients compared with healthy controls. With these, we add three (KIAA0319L, PXK and JAZF1) and one (KIAA0319L) new susceptibility loci for SSc and SLE, respectively, increasing significantly the knowledge of the genetic basis of autoimmunity.
Assuntos
Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lúpus Eritematoso Sistêmico/genética , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinases/genética , Escleroderma Sistêmico/genética , Estudos de Casos e Controles , Proteínas Correpressoras , Proteínas de Ligação a DNA , Loci Gênicos , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular , Reprodutibilidade dos Testes , Fatores de Risco , Escleroderma Sistêmico/imunologiaRESUMO
Mast cells (MCs) are immune cells residing in tissues where pathogens are first encountered. It has been indicated that MCs might also be involved in setting the outcome of T-cell responses. However, little is known about the capacity of human MCs to express MHC class II and/or to capture and present antigens to CD4(+) T cells. To study the T-cell stimulatory potential of human MCs, CD34(+) stem cell derived MCs were generated. These cells expressed HLA-DR when stimulated with IFN-γ, and, importantly, presented peptide and protein for activation of antigen-specific CD4(+) T cells. The interplay between MC and T cell led to increased HLA-DR expression on MCs. MCs were present in close proximity to T cells in tonsil and expressed HLA-DR and CD80, indicating their ability to present antigens to CD4(+) T cells in T-cell areas of human LNs. Our data show that MCs can present native antigens to human CD4(+) T cells and that HLA-DR expressing MCs are present in tonsil tissue, indicating that human MCs can directly activate T cells and provide a rationale to study the potential of MCs to prime and/or skew human T-cell responses.
Assuntos
Apresentação de Antígeno/imunologia , Linfócitos T CD4-Positivos/imunologia , Ativação Linfocitária/imunologia , Mastócitos/imunologia , Antígeno B7-1/biossíntese , Antígeno B7-1/imunologia , Linfócitos T CD4-Positivos/metabolismo , Separação Celular , Citometria de Fluxo , Antígenos HLA-DR/biossíntese , Antígenos HLA-DR/imunologia , Humanos , Mastócitos/metabolismo , Tonsila Palatina/citologia , Tonsila Palatina/imunologiaRESUMO
Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P â=â1.34×10(-8), OR â=â1.22, CI 95% â=â1.14-1.30; rs2004640: P â=â4.60×10(-7), OR â=â0.84, CI 95% â=â0.78-0.90; rs10488631: P â=â7.53×10(-20), OR â=â1.63, CI 95% â=â1.47-1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P â=â0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P â=â9.04×10(-22), OR â=â1.75, CI 95% â=â1.56-1.97) better explained the observed association (likelihood P-value â=â1.48×10(-4)), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific.
Assuntos
Predisposição Genética para Doença , Haplótipos , Fatores Reguladores de Interferon/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , Alelos , Feminino , Frequência do Gene , Loci Gênicos , Humanos , Desequilíbrio de Ligação , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Fenótipo , Fatores de Risco , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/etnologia , População BrancaRESUMO
OBJECTIVE: To evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby methyl-CpG-binding protein 2 gene (MECP2). METHODS: We analysed a total of 3065 women with SSc and 2630 unaffected controls from five independent Caucasian cohorts. Four tag single-nucleotide polymorphisms of MECP2 (rs3027935, rs17435, rs5987201 and rs5945175) and the IRAK1 variant rs1059702 were genotyped using TaqMan predesigned assays. A meta-analysis including all cohorts was performed to test the overall effect of these Xq28 polymorphisms on SSc. RESULTS: IRAK1 rs1059702 and MECP2 rs17435 were associated specifically with diffuse cutaneous SSc (PFDR=4.12×10(-3), OR=1.27, 95% CI 1.09 to 1.47, and PFDR=5.26×10(-4), OR=1.30, 95% CI 1.14 to 1.48, respectively), but conditional logistic regression analysis showed that the association of IRAK1 rs1059702 with this subtype was explained by that of MECP2 rs17435. On the other hand, IRAK1 rs1059702 was consistently associated with presence of pulmonary fibrosis (PF), because statistical significance was observed when comparing SSc patients PF+ versus controls (PFDR=0.039, OR=1.30, 95% CI 1.07 to 1.58) and SSc patients PF+ versus SSc patients PF- (p=0.025, OR=1.26, 95% CI 1.03 to 1.55). CONCLUSIONS: Our data clearly suggest the existence of two independent signals within the Xq28 region, one located in IRAK1 related to PF and another in MECP2 related to diffuse cutaneous SSc, indicating that both genes may have an impact on the clinical outcome of the disease.
Assuntos
Cromossomos Humanos X/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Escleroderma Sistêmico/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Quinases Associadas a Receptores de Interleucina-1/genética , Desequilíbrio de Ligação , Proteína 2 de Ligação a Metil-CpG/genética , Polimorfismo de Nucleotídeo Único , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/genética , Esclerodermia Difusa/genética , Escleroderma Sistêmico/complicaçõesRESUMO
INTRODUCTION: A recent genome-wide association study in European systemic sclerosis (SSc) patients identified three loci (PSORS1C1, TNIP1 and RHOB) as novel genetic risk factors for the disease. The aim of this study was to replicate the previously mentioned findings in a large multicentre independent SSc cohort of Caucasian ancestry. METHODS: 4389 SSc patients and 7611 healthy controls from different European countries and the USA were included in the study. Six single nucleotide polymorphisms (SNP): rs342070, rs13021401 (RHOB), rs2233287, rs4958881, rs3792783 (TNIP1) and rs3130573 (PSORS1C1) were analysed. Overall significance was calculated by pooled analysis of all the cohorts. Haplotype analyses and conditional logistic regression analyses were carried out to explore further the genetic structure of the tested loci. RESULTS: Pooled analyses of all the analysed SNPs in TNIP1 revealed significant association with the whole disease (rs2233287 p(MH)=1.94×10(-4), OR 1.19; rs4958881 p(MH)=3.26×10(-5), OR 1.19; rs3792783 p(MH)=2.16×10(-4), OR 1.19). These associations were maintained in all the subgroups considered. PSORS1C1 comparison showed association with the complete set of patients and all the subsets except for the anti-centromere-positive patients. However, the association was dependent on different HLA class II alleles. The variants in the RHOB gene were not associated with SSc or any of its subsets. CONCLUSIONS: These data confirmed the influence of TNIP1 on an increased susceptibility to SSc and reinforced this locus as a common autoimmunity risk factor.
Assuntos
Proteínas de Ligação a DNA/genética , Proteínas/genética , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/genética , Proteína rhoB de Ligação ao GTP/genética , Europa (Continente)/epidemiologia , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , População Branca/genética , População Branca/estatística & dados numéricosRESUMO
OBJECTIVE: The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc). PATIENTS AND METHODS: The case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays. RESULTS: We observed evidence of association of the rs6822844 and rs907715 variants with global SSc (pc=6.6E-4 and pc=7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (pc=1.7E-03 and pc=8E-4, respectively). CONCLUSIONS: These results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases.
Assuntos
Interleucina-2/genética , Interleucinas/genética , Escleroderma Sistêmico/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Modelos Logísticos , Masculino , Polimorfismo de Nucleotídeo Único , Esclerodermia Difusa/etnologia , Esclerodermia Difusa/genética , Esclerodermia Limitada/etnologia , Esclerodermia Limitada/genética , Escleroderma Sistêmico/etnologia , População Branca/genéticaRESUMO
INTRODUCTION: Potassium voltage-gated channel shaker-related subfamily member 5 (KCNA5) is implicated in vascular tone regulation, and its inhibition during hypoxia produces pulmonary vasoconstriction. Recently, a protective association of the KCNA5 locus with systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) was reported. Hence, the aim of this study was to replicate these findings in an independent multicenter Caucasian SSc cohort. METHODS: The 2,343 SSc cases (179 PAH positive, confirmed by right-heart catheterization) and 2,690 matched healthy controls from five European countries were included in this study. Rs10744676 single-nucleotide polymorphism (SNP) was genotyped by using a TaqMan SNP genotyping assay. RESULTS: Individual population analyses of the selected KCNA5 genetic variant did not show significant association with SSc or any of the defined subsets (for example, limited cutaneous SSc, diffuse cutaneous SSc, anti-centromere autoantibody positive and anti-topoisomerase autoantibody positive). Furthermore, pooled analyses revealed no significant evidence of association with the disease or any of the subsets, not even the PAH-positive group. The comparison of PAH-positive patients with PAH-negative patients showed no significant differences among patients. CONCLUSIONS: Our data do not support an important role of KCNA5 as an SSc-susceptibility factor or as a PAH-development genetic marker for SSc patients.
Assuntos
Predisposição Genética para Doença/genética , Hipertensão Pulmonar/genética , Canal de Potássio Kv1.5/genética , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , Estudos de Coortes , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/etnologia , Itália , Desequilíbrio de Ligação , Países Baixos , Razão de Chances , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/etnologia , Espanha , Suécia , Reino Unido , População Branca/genéticaRESUMO
OBJECTIVE: Systemic sclerosis (SSc) is a genetically complex autoimmune disease; the genetic component has not been fully defined. Interleukin 6 (IL-6) plays a crucial role in immunity and fibrosis, both key aspects of SSc. We investigated the influence of IL6 gene in the susceptibility and phenotype expression of SSc. METHODS: We performed a large metaanalysis including a total of 2749 cases and 3189 controls from 6 white populations (Germany, The Netherlands, Norway, Spain, Sweden, and United Kingdom). Three IL6 single-nucleotide polymorphisms (SNP; rs2069827, rs1800795, and rs2069840) were selected by SNP tagging and genotyped using TaqMan(®) allele discrimination technology. RESULTS: Individual SNP metaanalysis showed no evidence of association of the 3 IL6 genetic variants with the global disease. Phenotype analyses revealed a significant association between the minor allele of rs2069840 and the limited cutaneous SSc clinical form (Bonferroni p = 0.036, OR 1.14, 95% CI 1.04-1.25). A trend of association between the minor allele of the rs1800795 and the diffuse cutaneous SSc clinical form was also evident (Bonferroni p = 0.072, OR 0.86, 95% CI 0.77-0.96). In the IL6 allelic combination analyses, the GGC allelic combination rs2069827-rs1800795-rs2069840 showed an association with overall SSc (Bonferroni p = 0.016, OR 1.13, 95% CI 1.04-1.23). CONCLUSION: Our results suggest that the IL6 gene may influence the development of SSc and its progression.
Assuntos
Predisposição Genética para Doença , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , Progressão da Doença , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Escleroderma Sistêmico/etnologia , População Branca/etnologia , População Branca/genéticaRESUMO
INTRODUCTION: The aim of the present study was to investigate the possible role of CD40 and CD40 ligand (CD40LG) genes in the susceptibility and phenotype expression of systemic sclerosis (SSc). METHODS: In total, 2,670 SSc patients and 3,245 healthy individuals from four European populations (Spain, Germany, The Netherlands, and Italy) were included in the study. Five single-nucleotide polymorphisms (SNPs) of CD40 (rs1883832, rs4810485, rs1535045) and CD40LG (rs3092952, rs3092920) were genotyped by using a predesigned TaqMan allele-discrimination assay technology. Meta-analysis was assessed to determine whether an association exists between the genetic variants and SSc or its main clinical subtypes. RESULTS: No evidence of association between CD40 and CD40LG genes variants and susceptibility to SSc was observed. Similarly, no significant statistical differences were observed when SSc patients were stratified by the clinical subtypes, the serologic features, and pulmonary fibrosis. CONCLUSIONS: Our results do not suggest an important role of CD40 and CD40LG gene polymorphisms in the susceptibility to or clinical expression of SSc.
Assuntos
Antígenos CD40/genética , Ligante de CD40/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , Genótipo , HumanosRESUMO
INTRODUCTION: CD226 genetic variants have been associated with a number of autoimmune diseases and recently with systemic sclerosis (SSc). The aim of this study was to test the influence of CD226 loci in SSc susceptibility, clinical phenotypes and autoantibody status in a large multicenter European population. METHODS: A total of seven European populations of Caucasian ancestry were included, comprising 2,131 patients with SSc and 3,966 healthy controls. Three CD226 single nucleotide polymorphisms (SNPs), rs763361, rs3479968 and rs727088, were genotyped using Taqman 5'allelic discrimination assays. RESULTS: Pooled analyses showed no evidence of association of the three SNPs, neither with the global disease nor with the analyzed subphenotypes. However, haplotype block analysis revealed a significant association for the TCG haplotype (SNP order: rs763361, rs34794968, rs727088) with lung fibrosis positive patients (PBonf = 3.18E-02 OR 1.27 (1.05 to 1.54)). CONCLUSION: Our data suggest that the tested genetic variants do not individually influence SSc susceptibility but a CD226 three-variant haplotype is related with genetic predisposition to SSc-related pulmonary fibrosis.
Assuntos
Antígenos de Diferenciação de Linfócitos T/genética , Estudos de Associação Genética , Polimorfismo de Nucleotídeo Único/genética , Fibrose Pulmonar/genética , Escleroderma Sistêmico/genética , Estudos de Coortes , Feminino , Estudos de Associação Genética/métodos , Variação Genética/genética , Genótipo , Humanos , Masculino , Fibrose Pulmonar/epidemiologia , Escleroderma Sistêmico/epidemiologiaRESUMO
Systemic sclerosis (SSc) is complex autoimmune disease affecting the connective tissue; influenced by genetic and environmental components. Recently, we performed the first successful genome-wide association study (GWAS) of SSc. Here, we perform a large replication study to better dissect the genetic component of SSc. We selected 768 polymorphisms from the previous GWAS and genotyped them in seven replication cohorts from Europe. Overall significance was calculated for replicated significant SNPs by meta-analysis of the replication cohorts and replication-GWAS cohorts (3237 cases and 6097 controls). Six SNPs in regions not previously associated with SSc were selected for validation in another five independent cohorts, up to a total of 5270 SSc patients and 8326 controls. We found evidence for replication and overall genome-wide significance for one novel SSc genetic risk locus: CSK [P-value = 5.04 × 10(-12), odds ratio (OR) = 1.20]. Additionally, we found suggestive association in the loci PSD3 (P-value = 3.18 × 10(-7), OR = 1.36) and NFKB1 (P-value = 1.03 × 10(-6), OR = 1.14). Additionally, we strengthened the evidence for previously confirmed associations. This study significantly increases the number of known putative genetic risk factors for SSc, including the genes CSK, PSD3 and NFKB1, and further confirms six previously described ones.
Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Proteínas Tirosina Quinases/genética , Escleroderma Sistêmico/genética , Proteína Tirosina Quinase CSK , Estudos de Coortes , Europa (Continente) , Seguimentos , Genótipo , Humanos , Fatores Reguladores de Interferon/genética , Metanálise como Assunto , Subunidade p50 de NF-kappa B/genética , Razão de Chances , Fatores de Risco , beta Carioferinas/genética , Quinases da Família srcRESUMO
PURPOSE: The aim of this study was to investigate the use of the electrocardiogram-derived ventricular gradient, projected on the x-axis (VGx), for detection of pulmonary hypertension (PH) and for prediction of all-cause mortality in PH patients. METHODS: In patients referred for PH screening (n = 216), the VGx was calculated semiautomatically from the electrocardiogram and was defined as abnormal when less than 24 mV · ms. The VGx of PH patients was compared with the VGx of patients without PH. The association between a reduced VGx and mortality was investigated in PH patients. RESULTS: Patients with PH (n = 117) had a significantly reduced VGx: 14 ± 27 vs 45 ± 23 mV · ms, P < .001. Furthermore, a severely reduced VGx (<0 mV · ms) was associated with increased mortality in PH patients: hazard ratio, 1.025 (95% confidence interval, 1.006-1.045; P = .012) per mV·ms VGx decrease. CONCLUSION: Reduced VGx is associated with the presence of PH and, more importantly, within PH patients, a severely reduced VGx predicts mortality.
Assuntos
Eletrocardiografia/métodos , Eletrocardiografia/estatística & dados numéricos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/mortalidade , Disfunção Ventricular/diagnóstico , Disfunção Ventricular/mortalidade , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Prevalência , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Análise de Sobrevida , Taxa de SobrevidaRESUMO
A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [P(MH)= 1.92 × 10(-5) odds ratio (OR) = 1.19] as the genetic variant with the firmest independent association observed in the analyzed GWAS peak of association. After the first follow-up phase, only the association of rs3790567 was consistent (P(MH)= 4.84 × 10(-3) OR = 1.12). The second follow-up phase confirmed this finding (P(χ2) = 2.82 × 10(-4) OR = 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (P(MH)= 2.82 × 10(-9) OR = 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.
Assuntos
Predisposição Genética para Doença/genética , Receptores de Interleucina-12/genética , Escleroderma Sistêmico/genética , População Branca/genética , Europa (Continente)/etnologia , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos/etnologiaRESUMO
OBJECTIVE: Systemic sclerosis (SSc) is a connective tissue disease characterized by vascular inflammation and fibrosis. Visceral involvement, including cardiac manifestations, can lead to severe clinical complications, such as congestive heart failure, arrhythmias, and sudden death. Conventional echocardiography parameters have limited sensitivity to detect subtle myocardial dysfunction in patients with SSc. The aim of this study was to assess, using novel speckle-tracking strain analysis, the presence of myocardial dysfunction in patients with SSc, and to investigate its relationship to functional capacity and ventricular arrhythmias. METHODS: A total of 104 patients with SSc (mean ± SD age 54 ± 12 years, 77% female) were included and underwent cardiopulmonary exercise testing, 24-hour electrocardiography (EKG) Holter monitoring, and transthoracic echocardiography. For comparison, 37 matched healthy control subjects were included. RESULTS: The total patient population consisted of 51 patients with limited cutaneous SSc and 53 with diffuse cutaneous SSc. Peak VO(2) was a mean ± SD 91 ± 20% predicted, and 28 patients had abnormal findings (ventricular tachycardia or ventricular ectopics >100/day) on EKG Holter monitoring. Patients with SSc, as compared with controls, had impaired global longitudinal and circumferential strains (mean ± SD -18.2 ± 1.8% versus -21.3 ± 1.7% and -18.2 ± 2.3% versus -21.3 ± 2.1%, respectively; each P < 0.01), but there was no difference in the left ventricular ejection fraction between patients and controls (mean ± SD 63.5 ± 7.2% versus 64.6 ± 4.4%; P = 0.20). In patients with SSc, global longitudinal and circumferential strains each correlated with the peak VO(2) (r = -0.46 and r = -0.41, respectively; both P < 0.01), and multivariate analysis confirmed the independent association of each strain measure with the peak VO(2). Compared to SSc patients with normal results on EKG Holter monitoring, SSc patients with abnormal results showed impaired global longitudinal strains (-18.5 ± 1.5% versus -17.1 ± 2.1%; P < 0.01) and circumferential strains (-18.7 ± 2.0% versus -17.3 ± 2.5%; P = 0.01), and each strain measure was independently associated with abnormal Holter findings. CONCLUSION: Speckle-tracking strain analysis can detect subtle myocardial dysfunction in patients with SSc. Importantly, decreased global longitudinal and circumferential strains are associated with lower functional capacity and rhythm disturbances in patients with SSc.