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1.
Nat Commun ; 10(1): 4955, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31672989

RESUMO

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

2.
Ann Rheum Dis ; 78(7): 979-987, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30967395

RESUMO

OBJECTIVE: To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice. METHODS: We performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab. RESULTS: 254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47-5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)>10% (OR: 1.03 [0.55-1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56-3.53], p<0.0001). Patients treated concomitantly with mycophenolate mofetil had a trend for better outcomes as compared with patients receiving rituximab alone (delta FVC: 5.22 [0.83-9.62]; p=0.019 as compared with controls vs 3 [0.66-5.35]; p=0.012). CONCLUSION: Rituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial.

3.
J Rheumatol ; 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30936287

RESUMO

OBJECTIVE: Scleroderma renal crisis (SRC) is a severe life-threatening manifestation in patients with systemic sclerosis (SSc). However, the knowledge about risk factors for SRC is limited. We determined here the frequency of SRC and identified risk factors for the prediction of SRC. METHODS: Based on regular followup data from the German Network for Systemic Scleroderma, we used univariate and multivariate generalized estimating equations to analyze the association between clinical variables, SSc subsets, therapy [i.e., angiotensin-converting enzyme inhibitors (ACEi), corticosteroids], and the occurrence of SRC. RESULTS: Data of 2873 patients with 10,425 visits were available for analysis with a mean number of registry visits of 3.6 ± 2.8 and a mean time of followup of 3.6 ± 3.8 years. In total, 70 patients developed SRC (70/2873, 2.4%). Of these patients, 57.1% (40/70) were diagnosed with diffuse cutaneous SSc, 31.4% (22/70) with limited cutaneous SSc, and 11.4% (8/70) with SSc-overlap syndromes. Predictive independent factors with the highest probability for SRC were positive anti-RNA polymerase antibodies (RNAP), a history of proteinuria prior to SRC onset, diminished DLCO, and a history of hypertension. Interestingly, positive antitopoisomerase autoantibodies did not predict a higher risk for SRC. Further, patients with SRC were significantly more frequently treated with ACEi and corticosteroids without being independently associated with SRC. CONCLUSION: In this cohort, SRC has become a rare complication. By far the highest risk for SRC was associated with the detection of anti-RNAP and proteinuria.

4.
Semin Arthritis Rheum ; 48(4): 686-693, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29706243

RESUMO

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune chronic disease characterized by vascular impairment, immune dysfunction and collagen deposition. Raynaud's phenomenon (RP) and digital ulcers (DU) are prominent features of SSc. Intravenous (IV) iloprost (ILO), according to the recently updated EULAR recommendations, is indicated for RP after failure of oral therapy. Moreover, IV ILO could be useful in DU healing. IV ILO is currently available mainly on the European market approved for RP secondary to SSc with 3-5 days infusion cycle. Unfortunately, data published varies regarding regimen (dosage, duration and frequency). Up to now, ILO has been studied in small cohorts of patients and in few randomized controlled trials. METHODS: A systematic review of studies on IV ILO in patients with SSc complicated by DU and RP was performed. Insufficient data were available to perform a meta-analysis according to the GRADE system. We performed a three-stage internet-based Delphi consensus exercise. RESULTS: Three major indications were identified for IV ILO usage in SSc: RP non-responsive to oral therapy, DU healing, and DU prevention. IV ILO should be administered between 0.5 and 2.0ng/kg/min according to patient tolerability with a frequency depending on the indication. CONCLUSIONS: Although these suggestions are supported by this expert group to be used in clinical setting, it will be necessary to formally validate the present suggestions in future clinical trials.


Assuntos
Iloprosta/uso terapêutico , Doença de Raynaud/tratamento farmacológico , Escleroderma Sistêmico/complicações , Úlcera Cutânea/tratamento farmacológico , Vasodilatadores/uso terapêutico , Consenso , Dedos , Humanos , Iloprosta/administração & dosagem , Injeções Intravenosas , Úlcera Cutânea/etiologia , Vasodilatadores/administração & dosagem
5.
Clin Drug Investig ; 38(11): 1061-1069, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30238433

RESUMO

BACKGROUND AND OBJECTIVE: Raynaud's phenomenon (RP) is characterized by transient digital ischemia and is commonly associated with connective tissue disease. Treatment remains unsatisfactory. Here we evaluate the efficacy, safety, and pharmacokinetics of a single dose of the soluble guanylate cyclase stimulator riociguat in RP. METHODS: DIGIT was a double-blind, randomized, placebo-controlled pilot study. Patients with primary or secondary RP were randomized to a single oral dose of riociguat 2 mg or placebo in a cross-over design (7 ± 3 days). Efficacy was assessed as placebo-corrected change in digital blood flow 2 h post-dose at room temperature (RT) or following cold exposure (CE), measured by laser-speckle contrast analysis. Patients were regarded as responders if placebo-corrected digital blood flow increased by ≥ 10% from baseline at RT or after CE. RESULTS: Of 20 eligible patients, 17 (85%) were female and mean [standard deviation (SD)] age was 52 (13.8) years. Placebo-corrected changes in digital blood flow were + 46% [90% confidence interval (CI) - 6 to + 98] at RT and - 9% (90% CI - 63 to + 44) after CE, with high inter-individual variability. Eight patients (40%) were responders at RT, and 12 (60%) after CE. Riociguat increased mean (SD) digital blood flow in responders at RT by + 136% (114) and in responders following CE by + 39% (53). Riociguat was well tolerated, with few adverse events. CONCLUSION: In this pilot study, single-dose riociguat was well tolerated in patients with RP and resulted in improved digital blood flow in some patient subsets, with high inter-individual variability. Long-term evaluation is warranted.


Assuntos
Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Ativadores de Enzimas/administração & dosagem , Dedos/irrigação sanguínea , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Doença de Raynaud/tratamento farmacológico , Administração Oral , Adulto , Idoso , Velocidade do Fluxo Sanguíneo/fisiologia , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Doença de Raynaud/diagnóstico , Doença de Raynaud/fisiopatologia , Resultado do Tratamento
6.
Hautarzt ; 69(11): 901-907, 2018 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-30143809

RESUMO

Systemic sclerosis (scleroderma) is a severe, chronic inflammatory connective tissue disease involving the skin, musculoskeletal system, and several internal organs. The heterogeneity of its presentation and course are a particular challenge for the treating physician. As therapeutic options have improved considerably during recent years, various working groups have published consensus recommendations for the treatment of SSc. The aim of this overview is to present major aspects of these recommendations and embed them in a concept of modern interdisciplinary care for this often still devastating disease.


Assuntos
Escleroderma Sistêmico , Humanos
9.
Rheumatology (Oxford) ; 57(3): 441-450, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28499034

RESUMO

Objectives: The multisystem manifestations of SSc can greatly impact patients' quality of life. The aim of this study was to identify factors associated with disability in SSc. Methods: SSc patients from the prospective DeSScipher cohort who had completed the scleroderma health assessment questionnaire (SHAQ), a disability score that combines the health assessment questionnaire and five visual analogue scales, were included in this analysis. The effect of factors possibly associated with disability was analysed with multiple linear regressions. Results: The mean SHAQ and HAQ scores of the 944 patients included were 0.87 (s.d. = 0.66) and 0.92 (s.d. = 0.78); 59% of the patients were in the mild to moderate difficulty SHAQ category (0 ⩽ SHAQ < 1), 34% in the moderate to severe disability category (1 ⩽ SHAQ < 2) and 7% in the severe to very severe disability category (2 ⩽ SHAQ ⩽ 3). The means of the visual analogue scales scores were in order of magnitude: overall disease severity (37 mm), RP (31 mm), pulmonary symptoms (24 mm), gastrointestinal symptoms (20 mm) and digital ulcers (19 mm). In multiple regression, the main factors associated with high SHAQ scores were the presence of dyspnoea [modified New York Heart Association (NYHA) class IV (regression coefficient B = 0.62), modified NYHA class III (B = 0.53) and modified NYHA class II (B = 0.21; all vs modified NYHA class I)], FM (B = 0.37), muscle weakness (B = 0.27), digital ulcers (B = 0.20) and gastrointestinal symptoms (oesophageal symptoms, B = 0.16; stomach symptoms, B = 0.15; intestinal symptoms, B = 0.15). Conclusion: SSc patients perceive dyspnoea, pain, digital ulcers, muscle weakness and gastrointestinal symptoms as the main factors driving their level of disability, unlike physicians who emphasize objective measures of disability.


Assuntos
Atividades Cotidianas , Avaliação da Deficiência , Qualidade de Vida , Escleroderma Sistêmico/fisiopatologia , Perfil de Impacto da Doença , Europa (Continente) , Gastroenteropatias/etiologia , Gastroenteropatias/fisiopatologia , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/fisiopatologia , Estudos Longitudinais , Debilidade Muscular/etiologia , Debilidade Muscular/fisiopatologia , Medição da Dor , Estudos Prospectivos , Análise de Regressão , Fatores de Risco , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/psicologia , Índice de Gravidade de Doença , Úlcera Cutânea/etiologia , Úlcera Cutânea/fisiopatologia
10.
Front Med (Lausanne) ; 4: 120, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28868289

RESUMO

Sclerosing skin diseases represent a large number of distinct disease entities, which include systemic sclerosis, localized scleroderma, and scleredema adultorum. These pathologies have a common clinical appearance and share histological features. However, the specific interplay between cytokines and growth factors, which activate different mesenchymal cell populations and production of different extracellular matrix components, determines the biomechanical properties of the skin and the clinical features of each disease. A better understanding of the mechanisms underlying these events is prerequisite for developing novel targeted therapeutic approaches.

11.
Ann Rheum Dis ; 76(11): 1897-1905, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28835464

RESUMO

OBJECTIVES: To determine the causes of death and risk factors in systemic sclerosis (SSc). METHODS: Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation. RESULTS: We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile. CONCLUSION: Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients' survival.


Assuntos
Escleroderma Sistêmico/mortalidade , Idoso , Causas de Morte , Bases de Dados Factuais , Atestado de Óbito , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores de Tempo
12.
J Rheumatol ; 44(10): 1453-1457, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28668810

RESUMO

OBJECTIVE: Systemic sclerosis (SSc) is a fibrotic immune-mediated disease of unknown etiology. Among its clinical manifestations, pulmonary involvement is the leading cause of mortality in patients with SSc. However, the genetic factors involved in lung complication are not well defined. We aimed to review the association of the MIF gene, which encodes a cytokine implicated in idiopathic pulmonary hypertension among other diseases, with the susceptibility and clinical expression of SSc, in addition to testing the association of this polymorphism with SSc-related pulmonary involvement. METHODS: A total of 4392 patients with SSc and 16,591 unaffected controls from 6 cohorts of European origin were genotyped for the MIF promoter variant rs755622. An inverse variance method was used to metaanalyze the data. RESULTS: A statistically significant increase of the MIF rs755622*C allele frequency compared with controls was observed in the subgroups of patients with diffuse cutaneous SSc (dcSSc) and with pulmonary arterial hypertension (PAH) independently (dcSSc: p = 3.20E-2, OR 1.13; PAH: p = 2.19E-02, OR 1.32). However, our data revealed a stronger effect size with the subset of patients with SSc showing both clinical manifestations (dcSSc with PAH: p = 6.91E-3, OR 2.05). CONCLUSION: We reviewed the association of the MIF rs755622*C allele with SSc and described a phenotype-specific association of this variant with the susceptibility to develop PAH in patients with dcSSc.


Assuntos
Predisposição Genética para Doença , Hipertensão Pulmonar/genética , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Esclerodermia Difusa/genética , Alelos , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Hipertensão Pulmonar/etiologia , Esclerodermia Difusa/complicações
15.
Ann Rheum Dis ; 76(6): 1150-1158, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28314753

RESUMO

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease characterised by skin and systemic fibrosis culminating in organ damage. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Transethnic meta-analyses have successfully expanded the list of susceptibility genes and deepened biological insights for other autoimmune diseases. METHODS: We performed transethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4436 cases and 14 751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighbouring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes. RESULTS: We identified two significant SNP in two loci, GSDMA and PRDM1, both of which are related to immune functions and associated with other autoimmune diseases (p=1.4×10-10 and 6.6×10-10, respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3. PRDM1 encodes BLIMP1, a transcription factor regulating T-cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighbouring genes, and this could explain the association in this locus. We found different human leukocyte antigen (HLA) association patterns between the two populations. Enrichment analysis suggested the importance of CD4-naïve primary T cell. CONCLUSIONS: GSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.


Assuntos
Proteínas de Neoplasias/genética , Proteínas Repressoras/genética , Escleroderma Sistêmico/genética , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos HLA/genética , Humanos , Japão/epidemiologia , Polimorfismo de Nucleotídeo Único , Fator 1 de Ligação ao Domínio I Regulador Positivo , Escleroderma Sistêmico/etnologia
17.
Ann Rheum Dis ; 76(8): 1327-1339, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27941129

RESUMO

The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.


Assuntos
Gastroenteropatias/terapia , Hipertensão Pulmonar/terapia , Nefropatias/terapia , Doença de Raynaud/terapia , Escleroderma Sistêmico/terapia , Úlcera/terapia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Técnica Delfos , Antagonistas dos Receptores de Endotelina/uso terapêutico , Europa (Continente) , Dedos , Fluoxetina/uso terapêutico , Gastroenteropatias/etiologia , Glucocorticoides/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Humanos , Hipertensão Pulmonar/etiologia , Nefropatias/etiologia , Pneumopatias/etiologia , Pneumopatias/terapia , Inibidores da Fosfodiesterase 5/uso terapêutico , Prostaglandinas I/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Doença de Raynaud/etiologia , Reumatologia , Escleroderma Sistêmico/complicações , Inibidores de Captação de Serotonina/uso terapêutico , Úlcera/etiologia
18.
Int J Cardiol ; 223: 385-389, 2016 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-27543715

RESUMO

OBJECTIVES: Cardiovascular involvement is a major contributor to mortality in systemic sclerosis (SSc). We examined whether N-terminal pro-brain natriuretic peptide (NT-proBNP) is a reliable predictor of mortality in SSc. METHODS AND RESULTS: This multicentre prospective cohort study included 523 patients presenting with SSc, whose mean age was 54±13years, mean disease duration 8±9years, and diffuse cutaneous form in 168. Plasma NT-proBNP was measured at baseline and the patients were followed yearly. Overall mortality was measured at 3years. At baseline, cardiovascular involvement was present in 37 patients, including 17 with pulmonary artery hypertension (PAH) and 20 with a left ventricular ejection fraction (LVEF) <55%. At 3years, 32 (7%) patients had died. The median [25th-75th percentile] NT-proBNP concentration was 203ng/l [129-514] in patients who died within 3years, versus 88ng/l [47-167] in survivors (P<0.001). NT-proBNP was an independent predictor of 3-years mortality in multivariate analysis (P=0.046). The optimal cut-off derived from the ROC curve was 129ng/l; sensitivity and specificity to predict 3y mortality were 78.1 and 66.7%. Using the previously recommended 125-ng/l concentration as threshold value, NT-proBNP reliably and independently predicted 3year mortality, with a sensitivity of 78.1 and a negative predictive value of 97.6%, respectively (P=0.006). The consideration of SSc patients without PAH or LVEF<55% at baseline yielded similar results. CONCLUSION: NT-proBNP appears as a reliable and independent predictor of mortality in patients with SSc.


Assuntos
Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/mortalidade , Idoso , Biomarcadores/sangue , Feminino , Seguimentos , França/epidemiologia , Alemanha/epidemiologia , Humanos , Hungria/epidemiologia , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Curva ROC , Taxa de Sobrevida/tendências , Fatores de Tempo
19.
Arthritis Rheumatol ; 68(9): 2338-44, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27111665

RESUMO

OBJECTIVE: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc-RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc-RA loci through an interdisease meta-genome-wide association (meta-GWAS) strategy. METHODS: The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case-control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. RESULTS: This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P < 5 × 10(-6) ) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these 2 diseases (Pcombined = 3.29 × 10(-12) ). Analysis of the biologic relevance of the known SSc-RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors. CONCLUSION: This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.


Assuntos
Artrite Reumatoide/genética , Estudo de Associação Genômica Ampla , Fatores Reguladores de Interferon/genética , Escleroderma Sistêmico/genética , Loci Gênicos , Predisposição Genética para Doença , Humanos , Fatores de Risco
20.
Can J Cardiol ; 32(8): 1008.e11-7, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26927854

RESUMO

BACKGROUND: Vein graft disease is a major and yet unsolved problem in cardiac revascularization surgery. Although accumulation of extracellular matrix is characteristic for vein graft disease, detailed analysis of the fibrotic material is lacking. Because alterations of collagen cross-links are typical for organ fibrosis, we performed a comprehensive analysis of collagen and elastin in vein graft disease. METHODS: Collagen, elastin, and their respective cross-links were analyzed using histology and amino acid analysis. The expression of collagen-modifying enzymes was analyzed using SYBR Green quantitative real-time polymerase chain reaction. Fibrillin expression was analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction. RESULTS: Diseased vein grafts showed a marked increase of collagen and of intermediate collagen cross-links, which are markers for newly synthesized collagen. Furthermore, we identified in vein graft disease increased levels of mature hydroxylysine aldehyde-derived cross-links typical for skeletal tissues. This was accompanied by upregulation of lysyl hydroxylase 2 and lysyl oxidase expression. Furthermore, vein graft disease showed a reduction of the elastin/collagen ratio, using elastin cross-links as a marker of elastin content, which was accompanied by an increase of fibrillin-1. CONCLUSIONS: Vein graft disease was accompanied by marked alterations in the composition of the extracellular matrix. The altered collagen cross-link pattern and the reduced elastin/collagen ratio might synergistically increase the stiffness in diseased vein grafts. Furthermore, hydroxylysine aldehyde-derived cross-links can cause a decreased degradability of collagens by matrix-metalloproteinases. Our data suggest collagen cross-links as a therapeutic target in vein graft disease.


Assuntos
Colágeno/metabolismo , Elastina/metabolismo , Oclusão de Enxerto Vascular/metabolismo , Idoso , Estudos de Casos e Controles , Colágeno/genética , Ponte de Artéria Coronária , Dipeptídeos/metabolismo , Feminino , Fibrilina-1/metabolismo , Oclusão de Enxerto Vascular/diagnóstico , Oclusão de Enxerto Vascular/patologia , Humanos , Masculino , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/genética , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/metabolismo , Proteína-Lisina 6-Oxidase/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima
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