RESUMO
The major pathological hallmark of the systemic sclerosis (SSc) is skin and internal organ fibrosis, which results from normal tissue architecture alterations and extracellular matrix (ECM) protein deposition. ECM components are degraded by matrix metalloproteinases (MMP). Promoter region polymorphisms in MMP genes may influence gene expression, resulting in an imbalance between ECM protein production and degradation. Here, we analyzed MMP1 -1607 1G/2G (rs1799750), MMP3 -1171 5A/6A (rs3025058), and MMP9 -1562 C/T (rs3918242) polymorphisms in relation to susceptibility to SSc and its clinical features. The patient group included 98 individuals with longstanding or recently diagnosed disease, meeting the American College of Rheumatology or LeRoy and Medsger criteria for SSc; the control group included 100 healthy blood donors. All participants were of European descent. Genotyping was performed by polymerase chain reaction followed by restriction digestion. Genotype and allele frequencies of MMP polymorphisms were similar between the two groups. In secondary analyses, significantly higher frequency of 1G/2G genotype from MMP1 polymorphism was observed for patients testing positive for antinuclear autoantibodies (P = 0.007), while 1G/1G genotype was associated with interstitial lung disease development (P = 0.018). The 6A/6A genotype from MMP3 polymorphism was absent in patients with calcinosis (P = 0.011), while the MMP3 5A/5A genotype correlated with the presence of anti-topoisomerase I antibodies (P = 0.009) and reduced diffusing capacity for carbon monoxide (P = 0.024). These results suggest that MMP polymorphisms are not associated with SSc susceptibility, although MMP1 and MMP3 variants are associated with specific SSc clinical and laboratory features.
Assuntos
Metaloproteinase 1 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Escleroderma Sistêmico/patologiaRESUMO
OBJECTIVE: The ovarian reserve of patients with systemic lupus erythematosus (SLE) may be affected by disease activity and medication use. Studies have found that patients with SLE have similar fertility rates as healthy women of the same age. The goal of the present study was to investigate the ovarian reserve of patients with SLE by measuring anti-Müllerian hormone (AMH) levels, and compare it to that of healthy controls. METHOD: This was a case-control study performed on 80 premenopausal women, of whom 40 fulfilled the 1997 American College of Rheumatology (ACR) criteria for SLE and 40 healthy controls paired by oral contraceptive use. Serum concentrations of AMH in peripheral venous blood were measured using a human AMH ELISA kit (CUSABIO, Wuhan, China). RESULTS: AMH serum levels did not differ between patients with SLE and controls (22.79 ± 17.32 ng/ml versus 21.41 ± 16.22 ng/ml, respectively, p = 0.7), even after adjusting for age (21.03 ± 2.074 ng/ml versus 23.97 ± 2.71 ng/ml; p = 0.5). AHM levels were not significantly correlated with disease duration (r = 0.2; p = 0.3), body mass index (r = 0.2; p = 0.2) and disease activity (SLEDAI (r = 0.1; p = 0.7)) and damage indices (SLICC (r = 0.1; p = 0.7)). No associations were found between AMH and ethnicity, current smoking, as well as current or prior use of cyclophosphamide and other immunosuppressants. CONCLUSION: In this cross-sectional study, women with SLE demonstrated similar AMH levels as healthy controls, suggesting preserved ovarian reserve in this population.
Assuntos
Hormônio Antimülleriano/sangue , Lúpus Eritematoso Sistêmico/sangue , Reserva Ovariana , Pré-Menopausa/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/fisiopatologiaRESUMO
In this study, we sought to investigate the genetic influence of two HLA-G 3'-untranslated region (3'-UTR) polymorphisms - 14 bp (rs66554220) and +3142C>G (rs1063320) and their compounding haplotypes in susceptibility to rheumatoid arthritis (RA) in a two-region Brazilian study comprising of 539 patients and 489 controls. All subjects were polymerase chain reaction (PCR) genotyped for the referred polymorphisms and logistic regression models controlling for sex, city and age were performed. Homozygozity for the +3142G allele was associated with an increased risk of RA [odds ratio (OR) = 1.45, 95% confidence interval (CI) = 1.075-1.959, P(Bonf) = 0.030], whereas no association was observed for the 14 bp polymorphism. Haplotype comparisons between patients and controls showed a decreased frequency of the delC haplotype in patients (OR = 0.70, 95% CI = 0.521-0.946, P(Bonf) = 0.040), which remained significant in the rheumatoid factor (RF)-positive group (OR = 0.66, 95% CI = 0.482-0.900, P(Bonf) = 0.018), but not in the RF-negative group. These results corroborate the hypothesis of an involvement of HLA-G in the susceptibility of RA. The +3142G allele is associated with haplotype lineages that share high identity and are regarded as low producers. The presence of the G allele in homozygosis could be responsible for a low HLA-G expression profile that could favor the triggering of RA.
Assuntos
Regiões 3' não Traduzidas , Alelos , Artrite Reumatoide/genética , Frequência do Gene , Antígenos HLA-G/genética , Polimorfismo Genético , Adulto , Idoso , Brasil , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseRESUMO
The aim of this study was to analyze the allelic and genotypic frequencies of the CCR5delta32 polymorphism in systemic lupus erythematosus (SLE) patients and to investigate a possible association of this allele with SLE susceptibility and clinical outcome. A total of 367 SLE patients and 435 healthy controls were genotyped for the CCR5delta32 polymorphism. We observed that, in European-derived individuals, the frequency of the CCR5delta32 allele was smaller in patients than in controls (2.7% vs. 7.5%, OR 0.34, 95% CI 0.17-0.65, p Bonf=0.002), suggesting that this allele could be considered a protective factor for the disease. Regarding clinical manifestations, we observed that CCR5delta32 female African-derived carrier patients presented a higher predisposition to class IV nephritis when compared with absent nephritis/other class group (13.8% vs. 3.8%, OR 37.1, 95% CI 2.8-1854.7, p Bonf=0.030). A multivariate analysis including all female patients and controlling for the presence or absence of anti-dsDNA antibodies, ethnicity and age at diagnosis showed an increased relative risk of 3.9 times for patients carrying the CCR5delta32 allele to develop class IV nephritis as compared with noncarriers. Our data suggest that the CCR5delta32 allele is a protective factor for the disease in European-derived patients and a susceptibility factor to class IV nephritis in African-derived female patients.
Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Nefrite Lúpica/genética , Receptores CCR5/genética , Adulto , Alelos , População Negra , Brasil , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polimorfismo Genético , Fatores Sexuais , População BrancaRESUMO
SUMMARY: We investigated vitamin D status in Brazilian cities located at different latitudes. Insufficiency (<50 nmol/L) was common (17 %), even in those living in a tropical climate. Vitamin D insufficiency increased as a function of latitude. Mean 25-hydroxyvitamin D (25(OH)D) levels in each site and latitude correlation were very high (r = -0.88; p=0.02). [corrected]. INTRODUCTION: Inadequate vitamin D, determined by low levels of 25(OH)D, has become very common despite the availability of sunlight at some latitudes. National data from a country that spans a wide range of latitudes would help to determine to what extent latitude or other factors are responsible for vitamin D deficiency. We investigated vitamin D status in cities located at different latitudes in Brazil, a large continental country. METHODS: The source is the Brazilian database from the Generations Trial (1,933 osteopenic or osteoporotic postmenopausal women (60 to 85 years old) with 25(OH)D measurements). 25(OH)D below 25 nmol/L (10 ng/mL) was an exclusion criterion. Baseline values were between fall and winter. The sites included Recife, Salvador, Rio de Janeiro, São Paulo, Curitiba, and Porto Alegre. Mean and standard deviation of 25(OH)D, age, spine and femoral neck T-score, calcium, creatinine, and alkaline phosphatase were calculated for each city. Pearson correlation was used for 25(OH)D and latitude. RESULTS: Insufficiency (<50 or <20 ng/mL) was common (329 subjects, 17 %). Vitamin D insufficiency increased as a function of latitude, reaching 24.5 % in the southernmost city, Porto Alegre. The correlation between mean 25(OH)D levels in each site and latitude was very high (r = -0.88, p < 0.0001). CONCLUSION: There is a high percentage of individuals with vitamin D insufficiency in Brazil, even in cities near the equator, and this percentage progressively increases with more southern latitudes.
Assuntos
Pós-Menopausa/sangue , Deficiência de Vitamina D/epidemiologia , Vitamina D/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Brasil/epidemiologia , Bases de Dados Factuais , Feminino , Humanos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/sangue , Prevalência , Pigmentação da Pele , Luz Solar , Saúde da População Urbana/estatística & dados numéricos , Vitamina D/sangue , Deficiência de Vitamina D/sangueRESUMO
Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrotic, immunological and vascular abnormalities. Nuclear factor-kB (NFKB), as a key transcription factor involved in the regulation of immune responses, appears to be a good candidate for studies on the pathogenesis of autoimmune diseases, as well as the interleukin-10 (IL-10) polymorphism, which other studies have suggested an association with SSc. Our objective was to study the association of NFKB and IL-10 gene polymorphisms with SSc. One hundred and fifty-one SSc patients and 147 healthy bone marrow donors were enrolled in a case-control study. Blood was collected for DNA extraction; typing of IL-10 genes was made by polymerase chain reaction with sequence-specific primers (PCR-SSP), and NFKB gene typing was made by restriction fragment length polymorphism (RFLP). Patients underwent clinical evaluation, serology, Doppler echocardiography and chest high-resolution computed tomography. The frequency of IL-10 (-1082) GG genotype was found to be significantly higher in SSc patients (36.4%) as compared to healthy controls (22.4%) (P = 0.012). The frequency of heterozygous genotype GA was significantly lower (P = 0.004) in patients (38.4%) in comparison with control subjects (55.8%). A predominance of the high-producing IL-10 phenotype (GCC(+) /GCC(+) ) was observed in SSc patients compared with healthy controls (37.7% versus 24.5%, respectively; OR: 1.87, 95% CI: 1.10-3.19, P = 0.019). No significant difference was found in the allelic and genotype distribution of the NFKB promoter polymorphism between patients and controls. No statistically significant associations were found between IL-10 or NFKB polymorphisms clinical and laboratory features of SSc. Our results confirmed the association of the high-producing phenotype (GCC(+) /GCC(+) ) with increased risk for SSc, but found no correlation with NFKB polymorphisms.
Assuntos
Interleucina-10/genética , Subunidade p50 de NF-kappa B/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Escleroderma Sistêmico/genética , Alelos , Estudos de Casos e Controles , Epistasia Genética , Frequência do Gene , Genótipo , Haplótipos , Humanos , Fenótipo , Escleroderma Sistêmico/diagnósticoRESUMO
OBJECTIVES: To evaluate the prevalence of metabolic syndrome (MetS) in patients with rheumatoid arthritis (RA) vs. controls, and to verify possible associations of MetS with specific disease-related factors. METHODS: The subjects were 283 RA patients and 226 healthy controls, frequency matched by age and sex. MetS was defined according to National Cholesterol Education Program (NCEP) criteria. Disease activity was evaluated with the Disease Activity Score using 28 joints (DAS28). A standardized clinical evaluation was performed and cardiovascular risk factors were assessed. RESULTS: The criteria for MetS were met by 39.2% RA patients vs. 19.5% in the control group (p < 0.001). Increased waist circumference, elevated blood pressure (BP), and fasting glucose were more frequent in RA patients than controls (p < 0.001 for all associations). By multiple logistic regression analysis (adjusted for age, sex, and years at school), the risk of having MetS was significantly higher for RA patients than for controls [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.17-3.00, p = 0.009]. The DAS28 was significantly higher in RA patients with MetS than in those without MetS (3.59 ± 1.27 vs. 3.14 ± 1.53; p = 0.01). Disease duration, the presence of rheumatoid factor, and extra-articular manifestations were similar for patients with and without MetS. CONCLUSIONS: MetS frequency was higher in RA patients than in controls. Among RA patients, MetS was associated with disease activity. The higher prevalence of cardiovascular risk factors in RA suggests that inflammatory processes play a notable role in the development of cardiovascular disease (CVD), and indicates that tight control of systemic inflammatory activity and CVD modifiable risk factors should be recommended.
Assuntos
Artrite Reumatoide/epidemiologia , Síndrome Metabólica/epidemiologia , Índice de Gravidade de Doença , Adulto , Idoso , Artrite Reumatoide/fisiopatologia , Glicemia/análise , Pressão Sanguínea/fisiologia , Brasil/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Circunferência da CinturaRESUMO
Vitamin D deficiency has been described in systemic lupus erythematosus (SLE). BsmI VDR (vitamin D receptor) gene polymorphism was associated with SLE in Asian patients. Studies in Brazilian populations have not been realized. A case-control study with 195 SLE patients and 201 healthy controls was conducted to investigate the influence of BsmI and FokI VDR gene polymorphisms on susceptibility to SLE. In addition, 25-hydroxyvitamin D [25(OH)D] was measured in SLE patients to evaluate possible associations with VDR polymorphic variants and clinical and laboratory expressions of disease. Genotyping was performed by RFLP-PCR. The measurement of 25(OH)D was performed by chemiluminescence. There was no statistically significant difference in genotype and allelic frequencies of BsmI and FokI polymorphisms between European-derived cases and controls. The mean serum levels of 25(OH)D were 25.51 ± 11.43 ng/ml in SLE patients. According to genotype distribution, 25(OH)D concentrations were significantly higher in patients carrying the FokI f/f genotype compared with patients carrying the F/F genotype (31.6 ± 14.1 ng/ml versus 23.0 ± 9.2 ng/ml, p = 0.004), reinforcing its role in the functional activity of VDR. This feature may be considered in future clinical and experimental studies involving vitamin D measurements. Therefore, genetic-specific definitions of ideal levels of vitamin D in SLE need to be established in future studies.
Assuntos
Desoxirribonucleases de Sítio Específico do Tipo II/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético , Receptores de Calcitriol/genética , Vitamina D/análogos & derivados , Adulto , Brasil , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Vitamina D/sangue , População BrancaRESUMO
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and can affect several organs and systems. It is characterized by high production of autoantibodies against nuclear compounds. TLR7/8/9 are responsible for nucleic acid recognition and they trigger proinflammatory responses through activation of NK-kappaB and Type I IFN production, making a bridge between the innate and the adaptative immune systems. We analyzed the frequency of TLR7 rs179008, TLR8 rs3764880, TLR9 rs5743836 and rs352140 in 370 patients with SLE and 415 healthy controls from southern Brazil. All analyses were conducted with regard to gender and ethnicity. Genotypic and allelic frequencies were different for TLR7 rs179008 (0.253 vs. 0.163, p = 0.020 and p = 0.003, OR for T allele: 1.74 CI 95% 1.12-2.70) and TLR9 rs5743836 (0.174 vs. 0.112, p = 0.045 and p = 0.017, OR for C allele: 1.59, CI 95% 0.99-2.57) between European-derived female groups. A higher frequency was observed for the presence of Anti-SSa/Ro for TRL9 rs5743836 C allele carriers (0.228 vs 0.126, Bonferroni corrected p = 0.06). No statistical differences were found for TLR9 haplotypic analyses. We suggest that TLR7 rs179008 and TLR9 rs5743836 can be considered SLE susceptibility factors for women of European descent in our population.
Assuntos
Lúpus Eritematoso Sistêmico/genética , Receptor 7 Toll-Like/genética , Receptor 8 Toll-Like/genética , Receptor Toll-Like 9/genética , Alelos , População Negra/genética , Brasil , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Polimorfismo Genético , Fatores Sexuais , População Branca/genéticaRESUMO
OBJECTIVE: To evaluate the antiinflammatory effects of RC-3095 in 2 experimental models of arthritis, collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA), and to determine the mechanisms of action involved. METHODS: RC-3095 was administered daily to mice with CIA and mice with AIA, after induction of disease with methylated bovine serum albumin. Disease incidence and severity were assessed using a clinical index and evaluation of histologic features, respectively. In mice with CIA, gastrin-releasing peptide receptor (GRPR) was detected by immunohistochemical analysis, while in mice with AIA, migration of neutrophils, presence of glycosaminoglycans, and lymphocyte proliferation, determined using the MTT assay, were assessed. Expression of cytokines interleukin-17 (IL-17), IL-1ß, and tumor necrosis factor α (TNFα) was evaluated in all mouse knees using enzyme-linked immunosorbent assay. Treg cell production was assessed by flow cytometry in the joints of mice with AIA. RESULTS: In mice with AIA, administration of RC-3095 reduced neutrophil migration, mechanical hypernociception, and proteoglycan loss. These findings were associated with inhibition of the levels of all 3 proinflammatory cytokines, decreased lymphocyte proliferation, and increased Treg cell numbers. In the CIA model, treatment with RC-3095 led to a significant reduction in arthritis clinical scores and the severity of disease determined histologically. Synovial inflammation, synovial hyperplasia, pannus formation, and extensive erosive changes were all dramatically reduced in the arthritic mice treated with RC-3095. Furthermore, arthritic mice treated with RC-3095 showed a significant reduction in the concentrations of IL-17, IL-1ß, and TNFα, and showed a diminished expression of GRPR. CONCLUSION: These findings suggest that the GRP pathway has a significant role in chronic arthritis, and its inhibition can be explored as a possible therapeutic strategy in rheumatoid arthritis.