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1.
Intern Med ; 58(2): 293-295, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30146600

RESUMO

Takayasu arteritis (TAK) is a large-vessel vasculitis affecting the aorta and its main branches. Hemoptysis can be experienced as the respiratory manifestation, but origination from a bronchial artery is rare. Ulcerative colitis (UC) shares genetic similarities with TAK; HLA-B52*01 is associated with TAK and UC. We herein report a patient who presented with hemoptysis from the right bronchial artery and was diagnosed with TAK during the follow-up of UC. Transcatheter embolization was performed, and prednisolone and tocilizumab induced remission. Complication of TAK should be considered in the clinical course of HLA-B52-positive UC patients, and tocilizumab may be a treatment option.


Assuntos
Artérias Brônquicas , Colite Ulcerativa/complicações , Hemoptise/etiologia , Arterite de Takayasu/complicações , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Colite Ulcerativa/genética , Embolização Terapêutica , Antígeno HLA-B52/genética , Hemoptise/terapia , Humanos , Masculino , Prednisolona/uso terapêutico , Indução de Remissão , Arterite de Takayasu/genética , Adulto Jovem
2.
Clin Rheumatol ; 38(1): 143-148, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30171380

RESUMO

Takayasu arteritis (TA) is a chronic inflammatory disease. Interleukin (IL)-6 and IL-10 are important cytokines involved in the immune response of TA in some ethnicities. We investigated whether the single-nucleotide polymorphism (SNP) of IL-6 and IL-10 genes and their expressions were associated with TA in a Chinese Han population. One hundred eighty-four TA patients and 235 healthy controls (HC) were recruited. DNA and RNA were extracted from peripheral blood cells. Genotyping of IL-6 and -10 was performed using polymerase chain reaction-ligase detection reaction (PCR-LDR). The mRNA levels of IL-6 and IL-10 were semi-quantified using reverse transcription polymerase chain reaction (RT-PCR) and real-time polymerase chain reaction (real-time PCR). Plasma levels of them were examined by enzyme-linked immunosorbent assay (ELISA). The mRNA levels of IL-6 in active phase of TA were higher than those in stable phase (p = 0.015); the IL-10 in active phase was lower compared with stable phase (p = 0.046). Plasma levels of IL-6 in TA were higher than those in HC (p = 0.024). Plasma levels of IL-10 showed no difference between the two groups (p = 0.264). Plasma levels of IL-6 in active phase were increased than those in stable phase (p = 0.043) while those of IL-10 were decreased in active phase (p = 0.041). We found no significant differences between TA and HC in the frequency of any of the variations in the SNPs of IL-6 and IL-10 genes. The expression levels of both cytokines were associated with the disease status, indicating that they may serve as potential biomarkers for monitoring disease activity.


Assuntos
Interleucina-10/sangue , Interleucina-6/sangue , Arterite de Takayasu/sangue , Arterite de Takayasu/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores/sangue , Estudos de Casos e Controles , China , Feminino , Humanos , Interleucina-10/genética , Interleucina-6/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/análise , Adulto Jovem
3.
Inflamm Res ; 68(3): 195-201, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30470857

RESUMO

OBJECTIVES: Takayasu's arteritis (TA) represents a rare autoimmune disease (AD) characterized by systemic vasculitis that primarily affects large arteries, especially the aorta and the aortic arch and its main branches. Genetic components in TA are largely unknown. PTPN22 is a susceptibility loci for different ADs; however, the role of different PTPN22 single-nucleotide polymorphisms (SNPs) in the susceptibility to TA is not clear. METHODS: We evaluated the PTPN22 R620W (C1858T), R263Q (G788A), and - 123G/C SNPs in a group of patients with TA and in healthy individuals from Mexico. Our study included 111 patients with TA and 314 healthy individuals. Genotyping was performed with the 5' exonuclease (TaqMan®) assay. RESULTS: Our data showed that the PTPN22 R620W polymorphism is a risk factor for TA (CC vs. CT: OR 4.3, p = 0.002, and C vs. T: OR 4.1, p = 0.003); however, the PTPN22 R263Q and - 1123G/C polymorphisms are not associated with this AD. In addition, the PTPN22 CGT haplotype, which carries the minor allele of the PTPN22 C1858T variant, was also associated with TA susceptibility. CONCLUSION: This is the first report documenting an association between PTPN22 R620W and TA.


Assuntos
Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Arterite de Takayasu/genética , Adulto , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , México , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
4.
Proc Natl Acad Sci U S A ; 115(51): 13045-13050, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30498034

RESUMO

Takayasu arteritis (TAK) is a systemic vasculitis with severe complications that affects the aorta and its large branches. HLA-B*52 is an established susceptibility locus to TAK. To date, there are still only a limited number of reports concerning non-HLA susceptibility loci to TAK. We conducted a genome-wide association study (GWAS) and a follow-up study in a total of 633 TAK cases and 5,928 controls. A total of 510,879 SNPs were genotyped, and 5,875,450 SNPs were imputed together with HLA-B*52. Functional annotation of significant loci, enhancer enrichment, and pathway analyses were conducted. We identified four unreported significant loci, namely rs2322599, rs103294, rs17133698, and rs1713450, in PTK2B, LILRA3/LILRB2, DUSP22, and KLHL33, respectively. Two additional significant loci unreported in non-European GWAS were identified, namely HSPA6/FCGR3A and chr21q.22. We found that a single variant associated with the expression of MICB, a ligand for natural killer (NK) cell receptor, could explain the entire association with the HLA-B region. Rs2322599 is strongly associated with the expression of PTK2B Rs103294 risk allele in LILRA3/LILRB2 is known to be a tagging SNP for the deletion of LILRA3, a soluble receptor of HLA class I molecules. We found a significant epistasis effect between HLA-B*52 and rs103294 (P = 1.2 × 10-3). Enhancer enrichment analysis and pathway analysis suggested the involvement of NK cells (P = 8.8 × 10-5, enhancer enrichment). In conclusion, four unreported TAK susceptibility loci and an epistasis effect between LILRA3 and HLA-B*52 were identified. HLA and non-HLA regions suggested a critical role for NK cells in TAK.


Assuntos
Epistasia Genética , Antígeno HLA-B52/genética , Polimorfismo de Nucleotídeo Único , Receptores Imunológicos/genética , Arterite de Takayasu/genética , Estudos de Casos e Controles , Células Cultivadas , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Arterite de Takayasu/patologia
5.
Circ Genom Precis Med ; 11(10): e002296, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30354298

RESUMO

BACKGROUND: Takayasu arteritis (TAK) is an autoimmune systemic arteritis of unknown pathogenesis. Genome-wide association studies revealed that single-nucleotide polymorphisms in the MLX gene encoding the MLX (Max-like protein X) transcription factor are significantly associated with TAK in Japanese patients. MLX single-nucleotide polymorphism rs665268 is a missense mutation causing the Q139R substitution in the DNA-binding site of MLX. METHODS: To elucidate the hypothesis that the single-nucleotide polymorphism of the MLX gene plays a critical role in the development of TAK, we conducted clinical and laboratory analyses. RESULTS: We show that rs665268 significantly correlated with the severity of TAK, including the number of arterial lesions and morbidity of aortic regurgitation; the latter may be attributed to the fact that MLX mRNA expression was mostly detected in the aortic valve. Furthermore, the Q139R mutation caused structural changes in MLX, which resulted in enhanced formation of a heterodimer with MondoA, upregulation of TXNIP (thioredoxin-interacting protein) expression, and increase in the activity of the NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome and cellular oxidative stress. Furthermore, autophagy, which negatively regulates inflammasome activation, was suppressed by the Q139R mutation in MLX. The MLX-Q139R mutant significantly induced macrophage proliferation and macrophage-endothelium interaction, which was abolished by the treatment with SBI-477, an inhibitor of MondoA nuclear translocation. Our findings suggest that the Q139R substitution in MLX plays a crucial role in the pathogenesis of TAK. CONCLUSIONS: MLX-Q139R mutation plays a crucial role in the pathogenesis of TAK through promoting inflammasome formation.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Inflamassomos , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Arterite de Takayasu , Substituição de Aminoácidos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Inflamassomos/genética , Inflamassomos/metabolismo , Masculino , Pessoa de Meia-Idade , Arterite de Takayasu/genética , Arterite de Takayasu/metabolismo , Arterite de Takayasu/patologia
6.
Ann Rheum Dis ; 77(4): 589-595, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29374629

RESUMO

OBJETIVE: Systemic vasculitides represent a heterogeneous group of rare complex diseases of the blood vessels with a poorly understood aetiology. To investigate the shared genetic component underlying their predisposition, we performed the first cross-phenotype meta-analysis of genetic data from different clinically distinct patterns of vasculitis. METHODS: Immunochip genotyping data from 2465 patients diagnosed with giant cell arteritis, Takayasu's arteritis, antineutrophil cytoplasmic antibody-associated vasculitis or IgA vasculitis as well as 4632 unaffected controls were analysed to identify common susceptibility loci for vasculitis development. The possible functional consequences of the associated variants were interrogated using publicly available annotation data. RESULTS: The strongest association signal corresponded with an intergenic polymorphism located between HLA-DQB1 and HLA-DQA2 (rs6932517, P=4.16E-14, OR=0.74). This single nucleotide polymorphism is in moderate linkage disequilibrium with the disease-specific human leucocyte antigen (HLA) class II associations of each type of vasculitis and could mark them. Outside the HLA region, we identified the KDM4C gene as a common risk locus for vasculitides (highest peak rs16925200, P=6.23E-07, OR=1.75). This gene encodes a histone demethylase involved in the epigenetic control of gene expression. CONCLUSIONS: Through a combined analysis of Immunochip data, we have identified KDM4C as a new risk gene shared between systemic vasculitides, consistent with the increasing evidences of the crucial role that the epigenetic mechanisms have in the development of complex immune-mediated conditions.


Assuntos
Loci Gênicos/genética , Histona Desmetilases com o Domínio Jumonji/genética , Fenótipo , Vasculite Sistêmica/genética , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Estudos de Casos e Controles , Epigênese Genética , Feminino , Loci Gênicos/imunologia , Predisposição Genética para Doença , Arterite de Células Gigantes/genética , Arterite de Células Gigantes/imunologia , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Cadeias beta de HLA-DQ/genética , Cadeias beta de HLA-DQ/imunologia , Humanos , Histona Desmetilases com o Domínio Jumonji/imunologia , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , Análise Serial de Proteínas , Vasculite Sistêmica/imunologia , Arterite de Takayasu/genética , Arterite de Takayasu/imunologia
7.
Int J Rheum Dis ; 21(2): 532-540, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28425192

RESUMO

AIM: Disease activity assessment in Takayasu arteritis (TA) is challenging. Human leukocyte antigen E (HLA-E) is shed from endothelium into serum as a soluble molecule (sHLA-E) in response to inflammation. We aimed to study: (i) utility of sHLA-E as a biomarker of disease activity; and (ii) association of HLA-E polymorphism rs1264457 with clinical disease in Asian-Indian TA patients. MATERIALS AND METHODS: In phase-1, sHLA-E levels were estimated in sera of 50 consecutive TA patients at baseline visit and 27 healthy controls. Serial estimations were performed in 27 of them. In phase-2, DNA of 150 TA patients and 264 healthy controls were genotyped for rs1264457 polymorphism. RESULTS: At baseline visit, disease was classified as active, stable and grumbling in 23, 18 and nine patients, respectively. sHLA-E levels were higher in active TA (43; interquartile range [IQR]: 25.3-64.6) pg/mL) than stable disease (12.9; IQR: 7.6-21.6 pg/mL) (P = 0.001). At first follow-up visit, sHLA-E levels were numerically higher in active disease than stable disease (P = 0.06) but this trend was blunted at second follow-up. sHLA-E levels increased in 54% versus 25% of patients with persistently active/relapsing and persistent stable course, respectively. rs1264457 polymorphism was not associated with susceptibility to TA and did not affect sHLA-E levels. CONCLUSION: sHLA-E level is useful as a biomarker of disease activity and course in TA patients. rs1264457 polymorphism is neither associated with susceptibility nor did it influence sHLA-E levels in TA.


Assuntos
Antígenos de Histocompatibilidade Classe I/sangue , Arterite de Takayasu/sangue , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Índia/epidemiologia , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Arterite de Takayasu/diagnóstico , Arterite de Takayasu/etnologia , Arterite de Takayasu/genética , Adulto Jovem
8.
Int J Rheum Dis ; 21(3): 732-739, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29024426

RESUMO

BACKGROUND/PURPOSE: Normal C-reactive protein (CRP) in active Takayasu arteritis (TA) is a dilemma. We attempted to validate our pilot study finding of rs1205 in CRP gene being protective against TA. METHODS: Genomic DNA of 104 patients and 185 sex-matched healthy controls were genotyped for rs1205 by Taqman assay. Clinical details, demography, angiographic and activity scores (Indian Takayasu arteritis score 2010) were recorded prospectively at baseline and during follow-up visits for 12 months. Minor allele frequency (MAF) and genotype distribution between patients and controls as well as patient subgroups were compared using χ2 test with Bonferroni correction (pc ) and logistic regression was performed to determine independent associations. RESULTS: The majority of patients (n = 84) and controls (n = 166) were females. MAF of T allele of rs1205 was less frequent in patients (27%) as compared to controls (37.6%), P = 0.013, pc = 0.026 with an odds ratio of 0.632 irrespective of gender. Frequency of CC genotype was higher in cases (53.8%) than controls (37.3%), P = 0.006, pc = 0.018. A dominant model of genotype-phenotype association revealed CC to be associated with more frequent coronary arterial and ascending aorta involvement than the other genotypes clubbed together (P = 0.01 and P = 0.014, respectively). Blunted CRP response seems to be less frequent in patients with CC genotype (P = 0.064). CONCLUSION: T allele of rs1205 in CRP gene was less frequent in TA. CC genotype was associated with involvement of coronary arteries and ascending aorta. CC genotype was less commonly associated with blunted CRP response (CT + TT > CC).


Assuntos
Proteína C-Reativa/genética , Polimorfismo de Nucleotídeo Único , Arterite de Takayasu/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Índia/epidemiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Fenótipo , Fatores de Proteção , Fatores de Risco , Arterite de Takayasu/diagnóstico , Arterite de Takayasu/etnologia , Adulto Jovem
9.
Int J Rheum Dis ; 21(1): 271-277, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28261975

RESUMO

AIM: Takayasu arteritis (TA) is a rare autoimmune disease with ethnic differences. Genome-wide association studies (GWAS) showed novel genetic variants in the human leukocyte antigen (HLA) region were associated with TA. The present study aimed to investigate the linkage between these single nucleotide polymorphisms (SNP) and TA in a Chinese Han population. METHODS: Four hundred and twelve patients from multiple centers and 597 healthy controls were genotyped using the Sequenom MassArray iPLEX platform. The association between these SNPs and various clinical symptom of TA was also investigated. RESULTS: Our study showed a higher risk allele frequency of rs12524487 in TA patients compared to healthy controls (26.6% vs. 21.7%, odds ratio [OR] 1.31, 95% CI 1.06-1.61). The other SNP rs9366782 in HLA-B/MICA (major histocompatibility complex class I polypeptide-related sequence A) showed association with TA ischemic brain disease (OR: 1.78, 95% CI: 1.16-2.73, Pc = 0.03). However, rs3763288 and rs114202986 in MICA were negatively related to TA either as a whole or in any clinical features. Meanwhile, ATGT(rs9366782, rs12524487, rs3763288 and rs114202986) were the risk haplotypes (Pc = 2.48 × 10-10 ). CONCLUSIONS: Our findings indicated that rs12524487 in HLA-B/MICA was a genetic risk factor for TA in a Chinese Han population and rs9366782 in this region was associated with ischemic brain disease in TA but not TA susceptibility.


Assuntos
Antígenos HLA-B/genética , Antígenos de Histocompatibilidade Classe I/genética , Polimorfismo de Nucleotídeo Único , Arterite de Takayasu/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/etnologia , Isquemia Encefálica/genética , Isquemia Encefálica/imunologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , China/epidemiologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Antígenos HLA-B/imunologia , Haplótipos , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fenótipo , Fatores de Risco , Arterite de Takayasu/diagnóstico , Arterite de Takayasu/etnologia , Arterite de Takayasu/imunologia , Adulto Jovem
10.
Indian Heart J ; 70 Suppl 3: S167-S172, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30595251

RESUMO

BACKGROUND: Takayasu arteritis (TA) is an idiopathic chronic inflammatory disease of the aorta and its branches, leading to stenosis, occlusion, and aneurysmal dilatation. Tumor necrosis factor-alpha (TNF-α) is a cytokine with pleomorphic actions and plays a pivotal role in inflammation; the serum level of TNF-α is genetically determined. However, the literature lacks adequate information on the association of TNF-α polymorphisms with TA. Hence, the present study investigates the contribution of TNF-α polymorphism toward the complex etiology of TA. METHODS: A cross-sectional study was performed in 87 patients with TA and 90 controls. A promoter region polymorphism of TNF-α, rs1800629 G/A, or -308G/A was genotyped in all the study subjects followed by a case-control association study. Furthermore, to understand the biomarker profile, levels of specific markers such as erythrocyte sedimentation rate, serum high-sensitivity C-reactive protein, interleukin-18, interleukin-6, and TNF-α were measured in all the study subjects. RESULTS: All the inflammatory markers were significantly higher in the TA patients than in the controls. The genetic study (available for 57 TA patients and 36 controls) revealed that the TNF-α -308A allele was overrepresented in the TA patients (12% vs 7%). The TNF-α -308A allele correlated with the increased TNF-α levels, but it could not attain significance because of a small sample size. CONCLUSION: The TNF-α -308G/A polymorphism is associated with TNF-α levels in Indian population, which might have implications for clinical risk stratification and treatment. The different TNF-α gene promoter polymorphism might contribute to the molecular pathogenesis of TA. However, further study of the underlying mechanism is warranted.


Assuntos
DNA/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Arterite de Takayasu/genética , Fator de Necrose Tumoral alfa/genética , Adolescente , Adulto , Alelos , Biomarcadores/metabolismo , Criança , Estudos Transversais , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Arterite de Takayasu/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
11.
Cardiol Young ; 28(3): 354-361, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29233197

RESUMO

Takayasu arteritis is an idiopathic chronic granulomatous panarteritis predominantly affecting the aorta and its main branches. Although idiopathic, genetic contribution to disease susceptibility is being increasingly recognised. Rare in children, Takayasu arteritis is a worldwide disease with significant morbidity and mortality. Its diagnosis is a challenge and requires awareness of the condition as clinical features at presentation are non-specific and assessing disease activity is difficult. In the inflammatory stage, treatment is essential to prevent the insidious course and vascular damage: stenotic, occlusive lesions, aneurysms, and aortic regurgitation. New imaging modalities, such as CT scan, MRI, and 18F-fluorodeoxyglucose positron emission tomography, have expanded the possibilities for non-invasive diagnosis and monitoring; however, digital subtraction arteriography remains the gold standard for the diagnosis of Takayasu arteritis. Steroids are the first-line medical treatment. The combined use of methotrexate, cyclophosphamide, azathioprine, mycophenolate mofetil, and biological agents is common. Revascularisation therapy should be considered in uncontrolled hypertension secondary to renal artery stenosis, symptomatic coronary ischaemia, cerebrovascular disease, severe aortic regurgitation, limb ischaemia, and aneurysms at risk of rupture, using surgical or endovascular procedures and taking into consideration that complications, especially restenosis, are frequent. Disease activity increases the likelihood of complications after revascularisation. Surgical intervention has shown better long-term outcomes, although the endovascular approach is evolving. The aim of this review was to describe key points of the diagnosis, treatment, and follow-up of Takayasu arteritis in childhood.


Assuntos
Angiografia , Aorta/diagnóstico por imagem , Esteroides/uso terapêutico , Arterite de Takayasu/diagnóstico , Arterite de Takayasu/terapia , Aorta/patologia , Fatores Biológicos/uso terapêutico , Criança , Diagnóstico Diferencial , Procedimentos Endovasculares/efeitos adversos , Humanos , Hipertensão/etiologia , Pediatria , Arterite de Takayasu/genética
12.
Arthritis Res Ther ; 19(1): 197, 2017 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-28874185

RESUMO

BACKGROUND: A previous study revealed the association between susceptibility to Takayasu arteritis (TAK) and a single nucleotide polymorphism (SNP) rs6871626 located in IL12B, which encodes interleukin (IL)-12p40, a common component of IL-12p70 and IL-23. We investigated the expression of these cytokines in patients with TAK, stratifying them into those with or without the risk allele at the rs6871626 SNP. METHODS: Plasma levels of IL-12p40, IL-12p70, and IL-23 were quantified in 44 patients with TAK and 19 healthy controls (HCs) by enzyme-linked immunosorbent assays. Monocytes were obtained from 20 patients with TAK and 14 HCs, treated with interferon-γ (IFN-γ) and lipopolysaccharide, and then supernatant cytokines were quantified. In addition, the ratio of IFN-γ+ or IL-17A+ cells to CD4+ T cells was measured by flow cytometric analysis of peripheral blood mononuclear cells. RESULTS: The levels of plasma IL-12p40, plasma IL-12p70, and supernatant IL-12p70 were significantly higher in patients with TAK than in HCs, whereas there were no significant differences in the levels of plasma IL-23, supernatant IL-23, or supernatant IL-12p40. The levels of plasma IL-12p70, supernatant IL-12p40, and supernatant IL-12p70 were significantly higher in patients with the risk allele than in those without. The ratio of CD4+IFN-γ+ cells was significantly higher in patients with the risk allele, whereas CD4+IL-17A+ cells showed no differences. CONCLUSIONS: The rs6871626 SNP in IL12B may influence the increased expression of IL-12p40 and IL-12p70. These enhanced cytokines might play roles in the pathophysiology of TAK.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença/genética , Subunidade p40 da Interleucina-12/genética , Interleucina-12/genética , Arterite de Takayasu/genética , Adulto , Biomarcadores/sangue , Feminino , Humanos , Interleucina-12/sangue , Subunidade p40 da Interleucina-12/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Arterite de Takayasu/sangue , Arterite de Takayasu/fisiopatologia
13.
Rheumatol Int ; 37(10): 1643-1649, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28801814

RESUMO

Assessment of disease activity in Takayasu arteritis (TA) is challenging. We aimed to study utility of serum amyloid A (SAA) to assess disease activity and its association with SAA gene polymorphisms, if any, in our TA patients. Serum of 99 consecutive adult TA patients and 40 healthy controls were assayed for SAA. Depending on the ITAS2010 and ITAS-CRP score, patients were designated as having active disease if ITAS2010 ≥ 2 or ITAS-CRP ≥ 3 and stable disease if ITAS2010 = 0 or ITAS-CRP is ≤1. Clinical ITAS of 0 with raised inflammatory markers scoring a ITAS-CRP of 2 was considered as indeterminate for disease activity assessment. Repeat SAA levels for active group was measured after 6 months from baseline. SAA levels between active and stable disease as well as serial levels were compared. DNA of 40 patients and controls were genotyped for SAA polymorphisms (rs12218, rs2468844) and the allele frequencies were compared. At baseline, SAA levels were higher in patients as compared to controls (137.4 vs 100.8 ng/ml, p = 0.001) and higher in patients with active disease (166.4 ng/ml) than those with stable disease (98.2 ng/ml), p = 0.001. SAA decreased during follow-up in treatment responders (189.9 ng/ml at baseline vs 119.0 ng/ml at follow-up, p = 0.008); in contrast, there was no significant change among non-responders during follow-up. Allelic frequencies of SAA gene polymorphisms did not differ between cases and controls. SAA may be a reliable biomarker to assess disease activity and treatment response in TA.


Assuntos
Imunossupressores/uso terapêutico , Proteína Amiloide A Sérica/metabolismo , Arterite de Takayasu/sangue , Adulto , Biomarcadores/sangue , Progressão da Doença , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Proteína Amiloide A Sérica/genética , Índice de Gravidade de Doença , Arterite de Takayasu/diagnóstico , Arterite de Takayasu/tratamento farmacológico , Arterite de Takayasu/genética , Resultado do Tratamento , Adulto Jovem
14.
Presse Med ; 46(7-8 Pt 2): e197-e203, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28756072

RESUMO

Takayasu arteritis (TA), a granulomatous large vessel vasculitis involves mostly the aorta and its proximal branches and occurs most commonly in young females. The data on the epidemiology of TA is limited, probably due to the rarity of the disease. Although the disease has a worldwide distribution, it is generally thought to be much more common among Asian populations. The incidences of TA were estimated to be 1-2 per million in Japan and 2.2 per million in Kuwait. Recent epidemiologic studies suggest that TA is being increasingly recognized in Europe with reported incidence estimates varying from 0.4 to 1.5 per million. The highest ever prevalence of TA at 40 per million was estimated in Japan and the lowest ever one at 0.9 per million in US. The reported prevalences in the European populations vary between the ranges of 4.7 per million and 33 per million. These variations between the studies may be derived from geographical and genetic differences between the populations, but also may be due to the methodological differences.


Assuntos
Arterite de Takayasu/epidemiologia , Idade de Início , Feminino , Predisposição Genética para Doença , Antígeno HLA-B52/genética , Humanos , Incidência , Masculino , Prevalência , Prognóstico , Distribuição por Sexo , Arterite de Takayasu/diagnóstico , Arterite de Takayasu/genética
15.
Presse Med ; 46(7-8 Pt 2): e179-e187, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28756073

RESUMO

Takayasu arteritis (TAK) is a rare systemic vasculitis that is characterized by granulomatous inflammation of the aorta and its major branches. The cellular and biochemical processes involved in the pathogenesis of TAK are beginning to be elucidated, and implicate both cell and antibody-mediated autoimmune mechanisms. In addition, the underlying etiology to TAK may be explained, at least in part, by a complex genetic contribution. The most well-recognized genetic susceptibility locus for the disease is the classical HLA allele, HLA-B*52, which has been confirmed in several ethnicities. The genetic susceptibility with HLA-B*52, as well as additional classical alleles and loci, implicate both HLA class I and class II involvement in TAK. Furthermore, genetic associations with genes encoding immune response regulators, pro-inflammatory cytokines and mediators of humoral immunity may directly relate to disease mechanisms. Non-HLA susceptibility loci that have been recently established for TAK with a genome-wide level of significance include FCGR2A/FCGR3A, IL12B, IL6, RPS9/LILRB3, and a locus on chromosome 21 near PSMG1. In this review, we present the complex genetic predisposition to TAK and discuss how recent findings identified potential targets in the pathogenesis and treatment of the disease.


Assuntos
Arterite de Takayasu/genética , Alelos , Antígenos CD/genética , Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Subunidade p40 da Interleucina-12/genética , Interleucina-6/genética , Receptores de IgG/genética , Receptores Imunológicos/genética
16.
Hum Immunol ; 78(7-8): 515-520, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28438554

RESUMO

OBJECTIVES: To assess genetic association between single nucleotide polymorphisms (SNPs) in genes encoding T-helper cytokines and Takayasu Arteritis (TA) susceptibility in Asian Indian population. METHODS: In Phase-1, the genomic DNA of 120 TA patients and 119 healthy controls were genotyped for SNPs rs1800795 (interleukin (IL)-6), rs763780 (IL-17F), rs1800871, rs1800872, rs1800896 (IL-10) and rs1800468, rs1800469, rs1800470 (transforming growth factor-ß). Allele frequencies between cases and controls were compared using chi-squared test and also reassessed empirically (pe) by 10,000 permutations. In Phase-2, additional 98 TA patients and 101 controls were genotyped for replicating the significant associations noted in Phase-1 of the study. RESULTS: All 8 SNPs in Phase 1 were in Hardy-Weinberg proportions. The G allele at rs763780 (IL-17F) was significantly associated with TA (p=0.014). We also found that rs1800795 (IL-6) was associated with tuberculosis (p=0.001) under a dominant model. In Phase-2 replication part of the study, the rs763780 showed a trend towards association with TA (p=0.08), and the magnitude and direction of the odds ratio (OR) also were consistent with results of Phase-1. In the combined analysis, protective association of the G allele of rs763780 with TA was again significant [OR (95% CI)=0.44 (0.25-0.77); p=0.0029]. The G allele was also significantly associated (p<0.05) with underlying tuberculosis (TB) and occurrence of syncope in TA. CONCLUSION: G allele of rs763780 in IL-17F gene was protectively associated against susceptibility to TA. GG genotypes of rs1800795 in IL-6 was also associated with occurrence of tuberculosis in our patients with TA.


Assuntos
Genótipo , Interleucina-17/genética , Interleucina-6/genética , Linfócitos T Auxiliares-Indutores/fisiologia , Arterite de Takayasu/genética , Adulto , Grupo com Ancestrais do Continente Asiático , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Adulto Jovem
17.
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
18.
Rheumatol Int ; 37(4): 547-555, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28160070

RESUMO

Takayasu arteritis (TA) is a rare autoimmune disease of unknown etiology. Genome-wide association studies (GWAS) have demonstrated association between genetic variants of IL12B and IL6 and TA. Since TA has been reported with ethnic heterogeneity, we sought to investigate whether the single-nucleotide-polymorphisms (SNPs) reported in these studies are associated with TA in the Chinese Han population. A multi-center study involving 412 patients with TA and 597 healthy controls was conducted. Sequenom MassArray iPLEX platform was used to determine the frequencies of SNPs in the IL12B and IL6 region. We demonstrated a allele association between the four SNPs of IL12B and TA (rs6871626: OR 1.52, 95% CI 1.26-1.83; rs4921492: OR 1.46, 95% CI 1.21-1.75; rs60689680: OR 1.41, 95% CI 1.17-1.69; rs4921493: OR 1.45, 95% CI 1.21-1.75, all P c  < 10- 3 ). A meta-analysis consist of four populations showed rs6871626 was a susceptible locus of TA. Its OR was 1.51, and 95% CI was 1.31-1.74. The four SNPs were in strong linkage disequilibrium and two haplotypes were significantly different between patients and controls. Conditional analysis shows that these SNPs were not independent factors contributing to TA. Nevertheless, neither genotype nor allele frequencies of rs2069837 in IL6 showed significant between-group differences. Thus SNP of IL12B may be considered a high-risk factor for TA in Chinese Han population and provide further clues for research into the pathogenesis of TA.


Assuntos
Predisposição Genética para Doença , Subunidade p40 da Interleucina-12/genética , Polimorfismo de Nucleotídeo Único , Arterite de Takayasu/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Oncotarget ; 8(10): 17239-17245, 2017 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-27769046

RESUMO

Takayasu arteritis (TA) is a chronic large-vessel vasculitis of unclear pathogenesis. A recent genome-wide association study (GWAS) has revealed that the FCGR2A/FCGR3A, EEFSEC, RPS9/LILRB3, RIPPLY2 and MLX genes confer susceptibility to TA. We investigated the linkage between presumptive TA-related genes (FCGR2A/FCGR3A, EEFSEC, RPS9/LILRB3, RIPPLY2 and MLX) and TA in the Han Chinese population.We performed a large case-control multi-center study of 412 Han Chinese TA patients and 597 ethnically matched healthy controls. Five single nucleotide polymorphisms (SNPs) were assessed and genotyped using Sequenom MassArray system (iPLEX assay, Sequenom, San Diego, CA, USA).The frequency of the rs2099684 variant G allele in the FCGR2A/FCGR3A gene was significantly higher in the TA patients than in the controls (37.5% compared with 25.4%, OR =1.77, 95% CI: 1.46-2.14, Pc =1.5×10-8). Similar results were observed in genotype distribution analysis and logistic regression analyses conducted using three genetic models. The allele and genotype distributions for the other polymorphisms were not significantly associated with TA among the Han Chinese patients.The SNP rs2099684 in FCGR2A/FCGR3A can be considered a genetic risk factor for TA in the Chinese Han population. These findings provide further insights into the etiopathogenesis of TA.


Assuntos
Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Receptores de IgG/genética , Arterite de Takayasu/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , China , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Arterite de Takayasu/etnologia , Adulto Jovem
20.
Clin Rheumatol ; 36(1): 173-181, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27815653

RESUMO

We performed a meta-analysis to determine whether combined evidence shows an association between HLA-B*51 and HLA-B*52 alleles and TNF-α-308A/G polymorphism and the susceptibility to Takayasu arteritis (TA). Relevant articles dated November 2015 were acquired from the PubMed, Embase and Cochrane databases. The number of genotypes and/or alleles for HLA-B*51 and HLA-B*52 alleles and TNF-α-308 A/G polymorphism in cases and control subjects was extracted, and statistical analysis was conducted using STATA 11.2 software. We included 20 studies with 1864 TA patients and 6973 controls. The HLA-B*52 allele was found to be associated with TA (pooled OR 3.91, 95 % CI 3.22-4.74, P < 0.0001). The meta-analysis of TNF-α-308 A/G polymorphism for the A allele vs. G allele (P = 0.006) and AA + AG vs. GG (P = 0.023) revealed a significant association with TA. However, we did not find that the HLA-B*51 allele was associated with TA. This meta-analysis demonstrated that the HLA-B*52 allele and TNF-α-308 A/G polymorphism may contribute to TA susceptibility.


Assuntos
Antígeno HLA-B51/genética , Antígeno HLA-B52/genética , Polimorfismo Genético , Arterite de Takayasu/genética , Fator de Necrose Tumoral alfa/genética , Alelos , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Humanos , Inflamação , Sensibilidade e Especificidade
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