RESUMO
OBJECTIVE: To determine if SARS-CoV-2 mRNA vaccination has an impact on the clinical course of systemic lupus erythematosus (SLE). METHODS: Puerto Ricans with SLE who received mRNA COVID-19 vaccines were studied. Demographic parameters, clinical manifestations, disease activity (per Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), disease damage (per Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index), emergency room visits, hospitalizations, and pharmacologic therapy were determined. Baseline variables (prior to vaccination) were compared between patients with and without exacerbation after SARS-CoV-2 vaccination. Among those with exacerbation, clinical outcomes were determined up to 1 year after vaccination. RESULTS: Of the entire cohort (n = 247), 14 (5.7%) had post-vaccination exacerbations. Photosensitivity, oral ulcers, anti-Ro antibodies, higher SLEDAI score, and corticosteroids exposure were associated with post-vaccination flares. Among those with post-vaccination flares, 10 (71.4%) had major organ involvement. No significant differences were observed for mean SLEDAI scores, emergency room visits, hospitalizations, disease damage, and exposure to immunosuppressive drugs before and after SARS-CoV-2 mRNA vaccination. At 12 months of follow-up, all patients were fully controlled without evidence of active disease. CONCLUSION: In our group of SLE patients, 5.7% had a disease flare after SARS-CoV-2 mRNA vaccination. Most had exacerbations involving major organs/systems. Mucocutaneous manifestations, anti-Ro antibodies, disease activity, and corticosteroids were associated with flares. Awareness of these factors and the possibility of a major lupus flare after vaccination with COVD-19 vaccines is critical to provide timely and effective therapy.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Lúpus Eritematoso Sistêmico , Humanos , Estudos de Coortes , COVID-19/prevenção & controle , COVID-19/complicações , Vacinas contra COVID-19/efeitos adversos , Progressão da Doença , Lúpus Eritematoso Sistêmico/complicações , Porto Rico , RNA Mensageiro , SARS-CoV-2 , Índice de Gravidade de Doença , Exacerbação dos Sintomas , Vacinação/efeitos adversosRESUMO
BACKGROUND: Hydroxychloroquine (HCQ) use is associated with less disease activity, flares, damage and improved survival in Systemic Lupus Erythematosus (SLE). However, its effect on patient reported health outcomes (PROs) such as quality of life (QOL) is not known. METHODS: International data from Study on Outcomes of Lupus (SOUL) from 2,161 SLE patients were compared by HCQ use. Disease activity and damage were assessed using SELENA-SLEDAI and SLICC-ACR/SDI. QOL was evaluated using LupusPRO and Lupus Impact Tracker (LIT). Linear regression analyses were performed with LupusPRO summary scores health related HRQOL, non-health related NHRQOL and LIT as dependent and HCQ use as independent variable. Analyses were undertaken to test mediation of effects of HCQ use on QOL through disease activity. RESULTS: Mean age was 40.5 ± 12.8 years, 93% were women. Sixty-three (1363/2161) percent were on HCQ. On univariate analysis, HCQ use was associated with (a) better QOL (LupusPRO-HRQOL: ß 6.19, 95% CI 4.15, 8.24, P ≤ 0.001, LupusPRO NHRQOL: ß 5.83, 95% CI 4.02, 7.64, P ≤ 0.001) and less impact on daily life (LIT: ß -9.37, 95% CI -12.24, -6.50, P ≤ 0.001). On multivariate and mediational analyses, the effects of HCQ on QOL were indirectly and completely mediated through disease activity. CONCLUSIONS: HCQ use in SLE is associated with better patient reported health outcomes (LupusPRO-HRQOL and NHRQOL and impact on daily life), and the effects are mediated through disease activity. This information can facilitate patients and physician's communication with decision-making regarding the use of HCQ for SLE management.
Assuntos
Antirreumáticos , Hidroxicloroquina , Lúpus Eritematoso Sistêmico , Medidas de Resultados Relatados pelo Paciente , Adulto , Antirreumáticos/uso terapêutico , Estudos Transversais , Bases de Dados Factuais , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Qualidade de VidaRESUMO
Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared with the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.
Assuntos
Alelos , Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético , Locos de Características Quantitativas , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT4/genética , Feminino , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , Fatores de RiscoRESUMO
OBJECTIVE: The aim of this study was to determine the association of demographic parameters, clinical manifestations, disease activity, and pharmacologic therapy with disease damage in a group of Puerto Ricans with primary Sjögren syndrome (pSS). METHODS: A cross-sectional study was conducted in 100 Hispanics of Puerto Rico with pSS. Patients were 21 years or older and fulfilled the 2012 American College of Rheumatology classification criteria for pSS. Demographic factors, lifestyle behaviors, extraglandular manifestations, serologic tests, comorbidities, pharmacologic therapy, disease activity (per European League Against Rheumatism Sjögren Syndrome Disease Activity Index), and disease damage (per Sjögren Syndrome Disease Damage Index [SSDDI]) were assessed. Patients with disease damage (SSDDI ≥1) and without damage (SSDDI = 0) were compared using bivariate analysis and multivariate regression analysis adjusted for age, sex, and disease duration. RESULTS: The mean age of patients was 52.8 years; 94% were women. The mean disease duration was 5.9 years. Thirty-nine patients had disease damage. Disease damage was mainly attributed to pulmonary fibrosis and peripheral neuropathy. In the bivariate analysis, disease damage was associated with low C3 and C4, coronary artery disease, infections, and higher activity index and was more frequently treated corticosteroids and azathioprine. In the multivariate analysis, low C3, disease activity, and corticosteroid exposure retained significance. CONCLUSIONS: In this population of Puerto Ricans with pSS, C3 and C4 hypocomplementemia, coronary artery disease, infections, and exposure to corticosteroids and azathioprine were associated with damage accrual. Clinicians should be aware of these factors to identify those who may require close follow-up and early therapeutic intervention.
Assuntos
Reumatologia , Síndrome de Sjogren , Estudos Transversais , Feminino , Hispânico ou Latino , Humanos , Masculino , Pessoa de Meia-Idade , Porto Rico/epidemiologia , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/tratamento farmacológicoRESUMO
Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. Several recent studies have implicated ETS1 as a critical driver of immune cell function and differentiation, and mice deficient in ETS1 develop an SLE-like autoimmunity. We performed a fine-mapping study of 14,551 subjects from multi-ancestral cohorts by starting with genotyped variants and imputing to all common variants spanning ETS1. By constructing genetic models via frequentist and Bayesian association methods, we identified 16 variants that are statistically likely to be causal. We functionally assessed each of these variants on the basis of their likelihood of affecting transcription factor binding, miRNA binding, or chromatin state. Of the four variants that we experimentally examined, only rs6590330 differentially binds lysate from B cells. Using mass spectrometry, we found more binding of the transcription factor signal transducer and activator of transcription 1 (STAT1) to DNA near the risk allele of rs6590330 than near the non-risk allele. Immunoblot analysis and chromatin immunoprecipitation of pSTAT1 in B cells heterozygous for rs6590330 confirmed that the risk allele increased binding to the active form of STAT1. Analysis with expression quantitative trait loci indicated that the risk allele of rs6590330 is associated with decreased ETS1 expression in Han Chinese, but not other ancestral cohorts. We propose a model in which the risk allele of rs6590330 is associated with decreased ETS1 expression and increases SLE risk by enhancing the binding of pSTAT1.
Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Proteína Proto-Oncogênica c-ets-1/genética , Fator de Transcrição STAT1/genética , Alelos , Animais , Povo Asiático , Teorema de Bayes , Genótipo , Haplótipos , Humanos , Camundongos , Ligação Proteica , Proteína Proto-Oncogênica c-ets-1/metabolismo , Fator de Transcrição STAT1/metabolismoRESUMO
Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.
Assuntos
Lúpus Eritematoso Sistêmico/genética , Regiões Promotoras Genéticas , Transcrição Gênica , Quinases da Família src/genética , Alelos , Cromossomos Humanos Par 8 , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
OBJECTIVE: Maximum diameter (MD) is the established rupture predictor for abdominal aortic aneurysm (AAA). However, biomechanical markers from finite element analysis (FEA) could be more accurate predictors for these patients. In this study, the association between peak wall stress (PWS) and MD with symptoms of AAA was evaluated. METHODS: Patients diagnosed with infrarenal non-ruptured AAA at the centre between 2009 and 2015 were included. Clinical data, morphological variables (including MD), and the biomechanical variables PWS and diameter normalised PWS (dnPWS) in symptomatic (sAAA) and asymptomatic AAA patients (aAAA) were included. RESULTS: A total of 170 patients were analysed, 153 aAAA and 17 sAAA. MD was significantly greater in sAAA patients than in aAAA patients (70.4 mm, 95% CI 66.4-86.0 vs. 59.1 mm, 95% CI 53.7-67.8, respectively; p = .002). PWS was also significantly higher in the sAAA group (324.6 kPa, 95% CI 217.4-399.5 vs. 199.2 kPa, 95% CI 165.6-239.5; p < .01). No differences in MD were found in patients with an AAA ≥ 65 mm (43 aAAA and 14 sAAA); however, both PWS (327.4 kPa, 95% CI 239.0-473.3 vs. 229.4 kPa, 95% CI 210.0 to 289.4; p = .020) and dnPWS (4.3, 95% CI 3.17-4.67 vs. 3.03, 95% CI 2.8-3.49; p = .004) were higher in sAAA than in aAAA. CONCLUSIONS: This study suggests that MD and the biomechanical parameters obtained by finite element analysis are greater in sAAA than in aAAA. However, considering patients with MD ≥ 65 mm alone, only PWS, and particularly dnPWS, were able to differentiate sAAA from aAAA.
Assuntos
Aneurisma da Aorta Abdominal/complicações , Ruptura Aórtica/etiologia , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/fisiopatologia , Feminino , Análise de Elementos Finitos , Humanos , Masculino , Curva ROC , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Resistência ao Cisalhamento , Resistência à TraçãoRESUMO
OBJECTIVES: Systemic lupus erythematosus (SLE; OMIM 152700) is characterised by the production of antibodies to nuclear antigens. We previously identified variants in complement receptor 2 (CR2/CD21) that were associated with decreased risk of SLE. This study aimed to identify the causal variant for this association. METHODS: Genotyped and imputed genetic variants spanning CR2 were assessed for association with SLE in 15 750 case-control subjects from four ancestral groups. Allele-specific functional effects of associated variants were determined using quantitative real-time PCR, quantitative flow cytometry, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR. RESULTS: The strongest association signal was detected at rs1876453 in intron 1 of CR2 (pmeta=4.2×10(-4), OR 0.85), specifically when subjects were stratified based on the presence of dsDNA autoantibodies (case-control pmeta=7.6×10(-7), OR 0.71; case-only pmeta=1.9×10(-4), OR 0.75). Although allele-specific effects on B cell CR2 mRNA or protein levels were not identified, levels of complement receptor 1 (CR1/CD35) mRNA and protein were significantly higher on B cells of subjects harbouring the minor allele (p=0.0248 and p=0.0006, respectively). The minor allele altered the formation of several DNA protein complexes by EMSA, including one containing CCCTC-binding factor (CTCF), an effect that was confirmed by ChIP-PCR. CONCLUSIONS: These data suggest that rs1876453 in CR2 has long-range effects on gene regulation that decrease susceptibility to lupus. Since the minor allele at rs1876453 is preferentially associated with reduced risk of the highly specific dsDNA autoantibodies that are present in preclinical, active and severe lupus, understanding its mechanisms will have important therapeutic implications.
Assuntos
Anticorpos Antinucleares/sangue , Lúpus Eritematoso Sistêmico/genética , Receptores de Complemento 3d/genética , Adolescente , Adulto , Subpopulações de Linfócitos B/imunologia , Estudos de Casos e Controles , DNA/imunologia , Predisposição Genética para Doença , Variação Genética , Genótipo , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores de Complemento 3b/biossíntese , Medição de Risco/métodos , Fatores de Transcrição/metabolismo , Adulto JovemRESUMO
OBJECTIVES: Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of NMNAT2 at rs2022013, we fine-mapped its 150â kb flanking regions containing NMNAT2 and SMG7 in a 15â 292 case-control multi-ancestry population and tested functions of identified variants. METHODS: We performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA. RESULTS: We confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (p=2.4×10-8, OR=1.23 (95% CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with SMG7 mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased SMG7 mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1×10-3 and 6.8×10-8, respectively) and conferred reduced transcription activity in transfected HEK-293 (human embryonic kidney cell line) and Raji cells (p=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including ribonucleoprotein (RNP) and Smith (Sm). We showed SMG7 mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=-0.31, p=0.01), and SMG7 knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0×10-5 and 2.0×10-4, respectively). CONCLUSION: We confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk allele-associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis.
Assuntos
Anticorpos Antinucleares/metabolismo , Proteínas de Transporte/genética , Leucócitos Mononucleares/imunologia , Lúpus Eritematoso Sistêmico/genética , Nicotinamida-Nucleotídeo Adenililtransferase/genética , Alelos , Indígena Americano ou Nativo do Alasca/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Células HEK293 , Hispânico ou Latino/genética , Humanos , Desequilíbrio de Ligação , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Linhagem , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , População Branca/genéticaRESUMO
Prostacyclin (PGI2 ) plays a role in cancer progression but the mechanism is currently poorly understood. Additionally, no data are available about the prognostic value of the PGI2 pathway in head and neck squamous cell carcinoma (HNSCC) therapy. We evaluated the expression of the PGI2 pathway in HNSCC patients. PGI2 production and PGI synthase (PGIS) expression, in terms of mRNA (RT-PCR) and protein (immunoblotting), were lower in tumour samples than in non-tumoural mucosa, whereas, as expected, COX-2 expression was increased in HNSCC tumour samples. Using local control of the tumour after radiotherapy or chemoradiotherapy as a dependent variable, patients were classified into two categories of PGIS transcript levels. The high-PGIS group had a significantly lower frequency of local and distant failure than the low-PGIS group, and the 5-year cancer-specific survival was higher [90.2% (95% CI 81.0-99.4%) versus 60.5% (95% CI 44.4-76.6%)]. None of the four HNSCC cell lines analysed expressed PGIS and therefore they did not produce PGI2 . However, HNSCC-conditioned media enhanced PGI2 production in endothelial cells (ECs). The stable analogue of PGI2 , carbaprostacyclin (cPGI2 ), exerted little effect on HNSCC cell line migration, and no effect on cell cycle distribution or proliferation rate after radiation injury was observed. Nevertheless, cPGI2 promoted EP-4-dependent in vitro angiogenesis. Von Willebrand factor expression (EC marker) and capillary density were significantly higher in the group of patients with high expression of PGIS. Our results indicate that PGIS expression was associated with radiotherapy efficiency. Although we do not provide direct evidence of a relationship between tumour vascularization and radiotherapy efficiency, our results suggest that the effect of PGI2 is related to its ability to promote vascularization. These results also support the concept that co-adjuvant therapy with PGIS enhancers, such as retinoids, could have therapeutic value for HNSCC treatment.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/radioterapia , Sistema Enzimático do Citocromo P-450/metabolismo , Endotélio Vascular/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/radioterapia , Oxirredutases Intramoleculares/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD=6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P(meta) = 5.20×10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08×10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16×10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.
Assuntos
Negro ou Afro-Americano/genética , RNA Helicases DEAD-box/genética , Lúpus Eritematoso Sistêmico/genética , Alelos , Antígenos Nucleares/genética , Antígenos Nucleares/imunologia , Apoptose/genética , Autoanticorpos/genética , Autoanticorpos/imunologia , Mapeamento Cromossômico , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Predisposição Genética para Doença , Genoma Humano , Haplótipos , Humanos , Inflamação/genética , Helicase IFIH1 Induzida por Interferon , Autoantígeno Ku , Lúpus Eritematoso Sistêmico/imunologia , Polimorfismo de Nucleotídeo Único , Ligação Proteica , População Branca/genéticaRESUMO
We previously reported that the G allele of rs3853839 at 3'untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [Pâ=â6.5×10(-10), odds ratio (OR) (95%CI)â=â1.27 (1.17-1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmetaâ=â7.5×10(-11), ORâ=â1.24 [1.18-1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3'UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R(2)â=â0.255, Pâ=â0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3'UTR segment bearing the C allele (Pâ=â0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta â=â2.0×10(-19), ORâ=â1.25 [1.20-1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.
Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , MicroRNAs/genética , Receptor 7 Toll-Like , Regiões 3' não Traduzidas , Negro ou Afro-Americano/genética , Alelos , Povo Asiático/genética , Regulação da Expressão Gênica/genética , Células HEK293 , Hispânico ou Latino/genética , Humanos , Lúpus Eritematoso Sistêmico/metabolismo , Polimorfismo de Nucleotídeo Único , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismo , População BrancaRESUMO
Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (Pâ=â2.7×10â»8, ORâ=â1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.
Assuntos
Predisposição Genética para Doença , Interleucina-10/genética , Lúpus Eritematoso Sistêmico/genética , Proteínas Elk-1 do Domínio ets/genética , Alelos , Povo Asiático , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Hispânico ou Latino , Humanos , Interleucina-10/biossíntese , Íntrons , Lúpus Eritematoso Sistêmico/patologia , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Regulação para Cima , População Branca/genética , Proteínas Elk-1 do Domínio ets/biossínteseRESUMO
Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE.
Assuntos
Predisposição Genética para Doença/genética , Leptina/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Genótipo , HumanosRESUMO
Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; p(meta-Euro) = 2.08 × 10(-10)), transmembrane protein 39A (TMEM39A; rs1132200; p(meta-all) = 8.62 × 10(-9)), and 17q21 (rs1453560; p(meta-all) = 3.48 × 10(-10)) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 × 10(-8) < p(meta-Euro) < 9.99 × 10(-5)) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4, FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation.
Assuntos
Proteínas do Ovo/genética , Predisposição Genética para Doença , Fator de Transcrição Ikaros/genética , Fatores Reguladores de Interferon/genética , Lúpus Eritematoso Sistêmico/genética , Proteínas de Membrana/genética , Povo Asiático/genética , População Negra/genética , Mapeamento Cromossômico , Feminino , Haplótipos/genética , Hispânico ou Latino/genética , Humanos , Indígenas Norte-Americanos/genética , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA , População Branca/genéticaRESUMO
Chikungunya virus (CHIKV) infection is a common cause of febrile arthritis. The most common manifestations of acute infection are fever, symmetrical polyarthralgias or polyarthritis, myalgias, and maculopapular rash. Up to 80% of patients may develop musculoskeletal manifestations that persist longer than 3 months, causing impairment in their quality of life. The most common chronic manifestations are persistent or relapsing-remitting polyarthralgias, polyarthritis, and myalgias. Fingers, wrists, knees, ankles, and toes are the most frequently involved, but proximal joints and axial involvement can occur in the chronic stage. Chronic manifestations of CHIKV infection may resemble those of some autoimmune connective tissue diseases. Furthermore, CHIKV infection can cause cryoglobulinemia and may induce rheumatoid arthritis and seronegative spondyloarthropathies in genetically susceptible individuals. The Centers for Disease Control and Prevention recommend acetaminophen and non steroidal anti-inflammatory drugs for the acute rheumatic manifestations of CHIKV infection. However, some studies suggest that low-dose corticosteroids for about 1-2 months (depending on clinical course) are beneficial in relieving acute rheumatic symptoms. Conversely, hydroxychloroquine in combination with corticosteroids or other disease modifying anti-rheumatic drugs (DMARDs) has been successful in treating chronic rheumatic manifestations. Methotrexate and sulfasalazine (alone or in combination) have also been effective for chronic CHIKV arthritis. Patients with CHIKV infection should be closely monitored to identify those with chronic arthritis who would benefit from a rheumatologic evaluation and early treatment with DMARDs.
Assuntos
Febre de Chikungunya/complicações , Doenças Reumáticas/virologia , Febre de Chikungunya/diagnóstico , Febre de Chikungunya/tratamento farmacológico , Humanos , Doenças Reumáticas/diagnóstico , Doenças Reumáticas/tratamento farmacológicoRESUMO
Systemic lupus erythematosus (SLE) is considered to be the prototypic autoimmune disease, with a complex genetic architecture influenced by environmental factors. We sought to replicate a putative association at 11p13 not yet exceeding genome-wide significance (p < 5 × 10(-8)) identified in a genome-wide association study (GWAS). Our GWA scan identified two intergenic SNPs located between PDHX and CD44 showing suggestive evidence of association with SLE in cases of European descent (rs2732552, p = 0.004, odds ratio [OR] = 0.78; rs387619, p = 0.003, OR = 0.78). The replication cohort consisted of >15,000 subjects, including 3562 SLE cases and 3491 controls of European ancestry, 1527 cases and 1811 controls of African American (AA) descent, and 1265 cases and 1260 controls of Asian origin. We observed robust association at both rs2732552 (p = 9.03 × 10(-8), OR = 0.83) and rs387619 (p = 7.7 × 10(-7), OR = 0.83) in the European samples with p(meta) = 1.82 × 10(-9) for rs2732552. The AA and Asian SLE cases also demonstrated association at rs2732552 (p = 5 × 10(-3), OR = 0.81 and p = 4.3 × 10(-4), OR = 0.80, respectively). A meta-analysis of rs2732552 for all racial and ethnic groups studied produced p(meta) = 2.36 × 10(-13). This locus contains multiple regulatory sites that could potentially affect expression and functions of CD44, a cell-surface glycoprotein influencing immunologic, inflammatory, and oncologic phenotypes, or PDHX, a subunit of the pyruvate dehydrogenase complex.
Assuntos
Cromossomos Humanos Par 11/genética , Loci Gênicos , Predisposição Genética para Doença , Receptores de Hialuronatos/genética , Lúpus Eritematoso Sistêmico/genética , Complexo Piruvato Desidrogenase/genética , Negro ou Afro-Americano/genética , Indígena Americano ou Nativo do Alasca/genética , Povo Asiático/genética , Estudos de Coortes , Feminino , Haplótipos , Hispânico ou Latino/genética , Humanos , Desequilíbrio de Ligação , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
OBJECTIVE: To examine the prevalence of isolated IgA anti-ß2 -glycoprotein I (anti-ß2 GPI) positivity and the association of these antibodies, and a subgroup that bind specifically to domain IV/V of ß2 GPI, with clinical manifestations of the antiphospholipid syndrome (APS) in 3 patient groups and to evaluate the pathogenicity of IgA anti-ß2 GPI in a mouse model of thrombosis. METHODS: Patients with systemic lupus erythematosus (SLE) from a multiethnic, multicenter cohort (LUpus in MInorities, NAture versus nurture [LUMINA]) (n = 558), patients with SLE from the Hopkins Lupus Cohort (n = 215), and serum samples referred to the Antiphospholipid Standardization Laboratory (APLS) (n = 5,098) were evaluated. IgA anti-ß2 GPI titers and binding to domain IV/V of ß2 GPI were examined by enzyme-linked immunosorbent assay (ELISA). CD1 mice were inoculated with purified IgA anti-ß2 GPI antibodies, and surgical procedures and ELISAs were performed to evaluate thrombus development and tissue factor (TF) activity. RESULTS: A total of 198 patients were found to be positive for IgA anti-ß2 GPI isotype, and 57 patients were positive exclusively for IgA anti-ß2 GPI antibodies. Of these, 13 of 23 patients (56.5%) in the LUMINA cohort, 17 of 17 patients (100%) in the Hopkins cohort, and 10 of 17 patients (58.9%) referred to APLS had at least one APS-related clinical manifestation. Fifty-four percent of all the IgA anti-ß2 GPI-positive serum samples reacted with domain IV/V of anti-ß2 GPI, and 77% of those had clinical features of APS. Isolated IgA anti-ß2 GPI positivity was associated with an increased risk of arterial thrombosis (P < 0.001), venous thrombosis (P = 0.015), and all thrombosis (P < 0.001). The association between isolated IgA anti-ß2 GPI and arterial thrombosis (P = 0.0003) and all thrombosis (P = 0.0003) remained significant after adjusting for other risk factors for thrombosis. In vivo mouse studies demonstrated that IgA anti-ß2 GPI antibodies induced significantly larger thrombi and higher TF levels compared to controls. CONCLUSION: Isolated IgA anti-ß2 GPI-positive titers may identify additional patients with clinical features of APS. Testing for these antibodies when other antiphospholipid tests are negative and APS is suspected is recommended. IgA anti-ß2 GPI antibodies directed to domain IV/V of ß2 GPI represent an important subgroup of clinically relevant antiphospholipids.
Assuntos
Anticorpos Anti-Idiotípicos/sangue , Síndrome Antifosfolipídica/diagnóstico , Autoanticorpos/sangue , Imunoglobulina A/sangue , beta 2-Glicoproteína I/imunologia , Animais , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/imunologia , Humanos , Estudos Longitudinais , Camundongos , Prevalência , Trombose/diagnóstico , Trombose/imunologiaRESUMO
OBJECTIVE: The increased risk of thrombosis in systemic lupus erythematosus (SLE) may be partially explained by interrelated genetic pathways for thrombosis and SLE. The present study was undertaken to investigate whether 33 established and novel single-nucleotide polymorphisms (SNPs) in 20 genes involved in hemostasis pathways that have been associated with deep venous thrombosis (DVT) in the general population are risk factors for SLE among Asian subjects. METHODS: Patients in the discovery cohort were enrolled in 1 of 2 North American SLE cohorts. Patients in the replication cohort were enrolled in 1 of 4 Asian or 2 North American cohorts. We first genotyped 263 Asian patients with SLE and 357 healthy Asian control subjects for 33 SNPs in the discovery phase, and then genotyped 5 SNPs in up to an additional 1,496 patients and 993 controls in the replication phase. Patients were compared to controls for bivariate association with minor alleles. Principal components analysis was used to control for intra-Asian ancestry in the replication cohort. RESULTS: Two genetic variants in the gene VKORC1 were highly significant in both the discovery and replication cohorts: rs9934438 (in the discovery cohort, odds ratio [OR] 2.45, P=2×10(-9); in the replication cohort, OR 1.54, P=4×10(-6)) and rs9923231 (in the discovery cohort, OR 2.40, P=6×10(-9); in the replication cohort, OR 1.53, P=5×10(-6)). These associations were significant in the replication cohort after adjustment for intra-Asian ancestry: for rs9934438, OR 1.34, P=0.0029; for rs9923231, OR 1.34, P=0.0032. CONCLUSION: Genetic variants in VKORC1, which are involved in vitamin K reduction and associated with DVT, correlate with SLE development in Asian subjects. These results suggest that there may be intersecting genetic pathways for the development of SLE and thrombosis.
Assuntos
Hemostasia/genética , Lúpus Eritematoso Sistêmico/genética , Oxigenases de Função Mista/genética , Trombose Venosa/genética , Adulto , Povo Asiático , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Vitamina K Epóxido RedutasesRESUMO
BACKGROUND: The cyclooxygenase- (COX-) 2/microsomal PGE-synthase- (mPGES-) 1/PGE-receptor- (EP-) 4 axis could play a key role in the physiopathology of abdominal aortic aneurysm (AAA) in humans. In this study, we investigated the influence of cardiovascular risk factors on the expression of the PGE2 pathway in human AAA. METHODS: Aortic (n = 89) and plasma (n = 79) samples from patients who underwent AAA repair were collected. Patients were grouped according to risk factors. COX-isoenzymes, mPGES-1, EPs, α-actin, and CD45 and CD68 transcripts levels were quantified by QRT-PCR and plasma PGE2 metabolites by EIA. RESULTS: Current smoking (CS) patients compared to no-CS had significantly higher local levels of mPGES-1 (P = 0.009), EP-4 (P = 0.007), and PGE2 metabolites plasma levels (P = 0.008). In the multiple linear regression analysis, these parameters remained significantly enhanced in CS after adding confounding factors. Results from association studies with cell type markers suggested that the increased mPGES-1/EP-4 levels were mainly associated with microvascular endothelial cells. CONCLUSIONS: This study shows that elements of the PGE2 pathway, which play an important role in AAA development, are increased in CS. These results provide insight into the relevance of tobacco smoking in AAA development and reinforce the potential of mPGES-1 and EP-4 as targets for therapy in AAA patients.