RESUMO
Rheumatoid arthritis is an autoimmune and inflammatory disease that predominantly affects the diarthrodial joints. In this pathology, environmental or behavioral factors can act in synergy with genetic predisposition, accelerating the onset and severity of the disease. This link between the environment and the genome is mediated by epigenetic marks on deoxyribonucleic acid, including its methylation, histone modification, and noncoding ribonucleic acid-mediated regulation. Epigenetics can generate heritable phenotypic changes, which are not determined by modifications in the deoxyribonucleic acid sequence and are therefore reversible. Therefore, diet, medications and other environmental factors would have the ability to modulate them. The identification of a specific epigenetic dysregulation can offer a better understanding of the pathophysiology of the disease and positively influence the prevention, diagnosis and development of new therapeutic targets.
La artritis reumatoide es una enfermedad autoinmune e inflamatoria que afecta de manera predominante a las articulaciones diartrodiales. En esta patología los factores ambientales o conductuales pueden actuar en sinergia con la predisposición genética, acelerando el inicio y la gravedad de la enfermedad. Este vínculo entre el medio ambiente y el genoma está mediado por marcas epigenéticas en el ácido desoxirribonucleico, incluyendo su metilación, la modificación de histonas y la regulación mediada por ácido ribonucleico no codificante. La epigenética puede generar cambios fenotípicos hereditarios, que no están determinados por modificaciones en la secuencia del ácido desoxirribonucleico y, en consecuencia, son reversibles. Por lo tanto la dieta, los medicamentos y otros factores ambientales, tendrían la capacidad de modularlos. La identificación de una desregulación epigenética específica, puede ofrecer una mayor comprensión de la fisiopatología de la enfermedad e influenciar positivamente en la prevención, diagnóstico y desarrollo de nuevas dianas terapéuticas.
Assuntos
Artrite Reumatoide , Metilação de DNA , Humanos , Histonas/genética , Histonas/metabolismo , Epigênese Genética , DNARESUMO
La artritis reumatoide es una enfermedad autoinmune e inflamatoria que afecta de manera predominante a las articulaciones diartrodiales. En esta patología los factores ambientales o conductuales pueden actuar en sinergia con la predisposición genética, acelerando el inicio y la gravedad de la enfermedad. Este vínculo entre el medio ambiente y el genoma está mediado por marcas epigenéticas en el ácido desoxirribonucleico, incluyendo su metilación, la modificación de histonas y la regulación mediada por ácido ribonucleico no codificante. La epigenética puede generar cambios fenotípicos hereditarios, que no están determinados por modificaciones en la secuencia del ácido desoxirribonucleico y, en consecuencia, son reversibles. Por lo tanto la dieta, los medicamentos y otros factores ambientales, tendrían la capacidad de modularlos. La identificación de una desregulación epigenética específica, puede ofrecer una mayor comprensión de la fisiopatología de la enfermedad e influenciar positivamente en la prevención, diagnóstico y desarrollo de nuevas dianas terapéuticas.
Rheumatoid arthritis is an autoimmune and inflammatory disease that predominantly affects the diarthrodial joints. In this pathology, environmental or behavioral factors can act in synergy with genetic predisposition, accelerating the onset and severity of the disease. This link between the environment and the genome is mediated by epigenetic marks on deoxyribonucleic acid, including its methylation, histone modification, and noncoding ribonucleic acid-mediated regulation. Epigenetics can generate heritable phenotypic changes, which are not determined by modifications in the deoxyribonucleic acid sequence and are therefore reversible. Therefore, diet, medications and other environmental factors would have the ability to modulate them. The identification of a specific epigenetic dysregulation can offer a better understanding of the pathophysiology of the disease and positively influence the prevention, diagnosis and development of new therapeutic targets.
Assuntos
Humanos , Artrite Reumatoide , Metilação de DNA , DNA , Histonas/genética , Histonas/metabolismo , Epigênese GenéticaRESUMO
Objetivo: Evaluar el polimorfismo TLR2 Arg753Gln como posible marcador de riesgo para el desarrollo de sepsis Materiales y métodos: Estudio de asociación, el cual incluyó 183 individuos venezolanos no relacionados, agrupados en individuos sépticos (n=50), hospitalizados en el área de emergencia del Hospital Central del Instituto Venezolano de los Seguros Sociales -Dr. Miguel Pérez Carreño-, e individuos aparentemente sanos (n=133). El polimorfismo TLR2 Arg753Gln se determinó utilizando la técnica reacción en cadena de la polimerasa con iniciadores de secuencias específicas. Resultados: Se observó en el grupo de pacientes con escala SOFA en el rango entre 6-9 una mayor frecuencia de fallecimientos con respecto al grupo de pacientes con escala SOFA en el rango entre 0-5 (OR: 8.5; IC 95%: 2.33-30.90, p= 0,000357). El polimorfismo Arg753Gln del gen TLR2 está ausente en los pacientes con diagnóstico de sepsis. Conclusión: Se verificó que la escala SOFA es un sistema que permite predecir la mortalidad. La ausencia del polimorfismo Arg753Gln del gen TLR2 en el grupo de pacientes sépticos y una baja frecuencia del mismo en los individuos aparentemente sanos, sugiere la rareza de este polimorfismo en la población venezolana. Consecuentemente, se requiere incrementar el tamaño de la muestra para poder comprobar si es un marcador de riesgo para el desarrollo de sepsis en nuestra población.
Objective: To evaluate the TLR2 Arg753Gln polymorphism as a possible risk marker for sepsis development. Materials and Methods: Association study which included 183 unrelated Venezuelan individuals, divided into two groups: patients with sepsis (n = 50), hospitalized in the emergency area of the Central Hospital of the Venezuelan Institute of Social Security "Dr. Miguel Pérez Carreño", and apparently healthy individuals (n = 133). The TLR2 Arg753Gln polymorphism was determined using the polymerase chain reaction technique with specific sequence primers. Results: A higher death rate was observed among the group of patients with the SOFA scale range between 6-9, compared to the group of patients with the SOFA scale range between 0-5 (OR: 8.5; 95% CI: 2.33-30.90, p = 0.000357). The Arg753Gln polymorphism of the TLR2 gene is absent in patients diagnosed with sepsis. Conclusion: It was verified that the SOFA scale is a useful system to predict the mortality rate associated with sepsis. The absence of the Arg753Gln polymorphism of the TLR2 gene among the group of patients with sepsis diagnosis and its low frequency in apparently healthy individuals suggests the rarity of this polymorphism in the Venezuelan population. Consequently, it is necessary to increase the size of the sample to be able to evaluate whether it can be considered as a risk marker for sepsis development in our population.
RESUMO
Chagas disease is one of the parasitic infections with the greatest socio-economic impact in Latin America. In Venezuela, epidemiological data has shown different sources of infection, such as the vectorial route by oral transmission. Given the importance of the TLR4 gene in the innate immune response triggered by infection with Trypanosoma cruzi, this work analyses the role of TLR4 polymorphisms and its possible effect on cytokine expression. Genomic DNA was extracted from the peripheral blood of patients from the main outbreak of oral Chagas disease in Venezuela (n = 90), as well as from a group of healthy individuals (n = 183). Subsequently, peripheral blood was also extracted from individuals with different TLR4 haplotypes and then stimulated with LPS to determine the cytokine concentration by ELISA. The internalization of TLR4 was evaluated by flow cytometry. In comparison to healthy individuals, the analysis showed a significantly increased frequency of the Asp/Gly genotype in symptomatic patients. Also, observed a correlation of the 299/399 haplotype with a significant decrease in cytokine concentration and disease severity. Finally, the parasites' trypomastigotes cause the internalization or negative regulation of TLR4. The variants of TLR4 associated with low production of cytokines may be a risk factor for chronicity and severity (cardiac involvement) in oral vectorial Chagas disease.
Assuntos
Doença de Chagas , Receptor 4 Toll-Like , Doença de Chagas/genética , Doença de Chagas/imunologia , Citocinas/imunologia , Humanos , Fatores de Risco , Receptor 4 Toll-Like/genética , Trypanosoma cruziRESUMO
Resumen Objetivo: Examinar si los polimorfismos de los genes IL6, TNFA e IL10 representan un marcador de riesgo de infarto agudo de miocardio (IAM) y analizar su correlación con los factores de riesgo, la edad de ocurrencia y el tipo de IAM. Método: Estudio de asociación que incluyó 310 individuos venezolanos, no relacionados, agrupados en 190 pacientes con IAM y 120 controles con o sin factores de riesgo cardiovascular. Los polimorfismos IL6-174 G/C (rs1800795), TNFA-308 G/A (rs1800629) e IL10-1082 A/G (rs1800896), -819 C/T (rs1800871) y -592 C/A (rs1800872) se determinaron utilizando la técnica reacción en cadena de la polimerasa con iniciadores de secuencias específicas. Resultados: La comparación de frecuencias genotípicas y alélicas, mediante el análisis de regresión logística ajustado para los factores de riesgo, mostró una frecuencia significativamente incrementada de la combinación de genotipos G/G-A/A de la variante TNFA-308 G/A (odds ratio [OR]: 3.8; p = 0.00007), GG/-C/C de la variante IL6-174 G/C (OR: 2.3; p = 0.009), A/G-G/G de la variante IL10-1082 A/G (OR: 3.8; p = 0.00001) y del haplotipo GCC de IL10 (OR: 3.71; p = 0.0053) en los pacientes con IAM con respecto a los controles. Se observaron interacciones entre los polimorfismos IL10-1082 A/G y TNFA-308 G/A e hipertensión. Conclusiones: La asociación de las variantes de los genes TNFA, IL6 e IL10 con IAM sugiere que el desbalance en la producción de citocinas promueve un proceso inflamatorio exacerbado, apoyando el papel fundamental de la inflamación en todas las etapas del proceso aterosclerótico.
Abstract Objective: To examine whether the polymorphisms of the IL6, TNFA and IL10 genes represent a risk marker for acute myocardial infarction (AMI) and to analyze their correlation with risk factors, age of occurrence and type of AMI. Method: Association study that included 310 unrelated Venezuelan individuals, grouped in 190 patients with AMI and 120 controls with or without cardiovascular risk factors. The IL6-174 G/C (rs1800795), TNFA -308 G/A (rs1800629), and IL10-1082 A/G (rs1800896), -819 C/T (rs1800871) and -592 C/A (rs1800872) polymorphisms were determined using the polymerase chain reaction technique with sequence-specific primers. Results: Comparison of genotypic and allelic frequencies, using adjusted logistic regression analysis for risk factors, showed a significantly increased frequency of the genotype combination G/G-A/A of TNFA-308 G/A (odds ratio [OR]: 3.8; p = 0.00007), GG/-C/C of IL6-174 G/C (OR: 2.3; p = 0.009), A/G-G/G of IL10-1082 A/G (OR: 3.8; p = 0.00001) and the GCC haplotype of IL10 (OR: 3.71; p = 0.0053) in infarcted patients compared to controls. Interactions between the IL10-1082 A/G and TNFA-308 G/A polymorphisms and hypertension were observed. Conclusions: The association of the variants of the TNFA, IL6 and IL10 genes with AMI suggest that the imbalance in the production of cytokines promotes an exacerbated inflammatory process, supporting the fundamental role of inflammation in all stages of the atherosclerotic process.
RESUMO
Objective: To examine whether the polymorphisms of the IL6, TNFA and IL10 genes represent a risk marker for acute myocardial infarction (AMI) and to analyze their correlation with risk factors, age of occurrence and type of AMI. Method: Association study that included 310 unrelated Venezuelan individuals, grouped in 190 patients with AMI and 120 controls with or without cardiovascular risk factors. The IL6-174 G/C (rs1800795), TNFA -308 G/A (rs1800629), and IL10-1082 A/G (rs1800896), -819 C/T (rs1800871) and -592 C/A (rs1800872) polymorphisms were determined using the polymerase chain reaction technique with sequence-specific primers. Results: Comparison of genotypic and allelic frequencies, using adjusted logistic regression analysis for risk factors, showed a significantly increased frequency of the genotype combination G/G-A/A of TNFA-308 G/A (odds ratio [OR]: 3.8; p = 0.00007), GG/-C/C of IL6-174 G/C (OR: 2.3; p = 0.009), A/G-G/G of IL10-1082 A/G (OR: 3.8; p = 0.00001) and the GCC haplotype of IL10 (OR: 3.71; p = 0.0053) in infarcted patients compared to controls. Interactions between the IL10-1082 A/G and TNFA-308 G/A polymorphisms and hypertension were observed. Conclusions: The association of the variants of the TNFA, IL6 and IL10 genes with AMI suggest that the imbalance in the production of cytokines promotes an exacerbated inflammatory process, supporting the fundamental role of inflammation in all stages of the atherosclerotic process.
Objetivo: Examinar si los polimorfismos de los genes IL6, TNFA e IL10 representan un marcador de riesgo de infarto agudo de miocardio (IAM) y analizar su correlación con los factores de riesgo, la edad de ocurrencia y el tipo de IAM. Método: Estudio de asociación que incluyó 310 individuos venezolanos, no relacionados, agrupados en 190 pacientes con IAM y 120 controles con o sin factores de riesgo cardiovascular. Los polimorfismos IL6-174 G/C (rs1800795), TNFA-308 G/A (rs1800629) e IL10-1082 A/G (rs1800896), -819 C/T (rs1800871) y -592 C/A (rs1800872) se determinaron utilizando la técnica reacción en cadena de la polimerasa con iniciadores de secuencias específicas. Resultados: La comparación de frecuencias genotípicas y alélicas, mediante el análisis de regresión logística ajustado para los factores de riesgo, mostró una frecuencia significativamente incrementada de la combinación de genotipos G/G-A/A de la variante TNFA-308 G/A (odds ratio [OR]: 3.8; p = 0.00007), GG/-C/C de la variante IL6-174 G/C (OR: 2.3; p = 0.009), A/G-G/G de la variante IL10-1082 A/G (OR: 3.8; p = 0.00001) y del haplotipo GCC de IL10 (OR: 3.71; p = 0.0053) en los pacientes con IAM con respecto a los controles. Se observaron interacciones entre los polimorfismos IL10-1082 A/G y TNFA-308 G/A e hipertensión. Conclusiones: La asociación de las variantes de los genes TNFA, IL6 e IL10 con IAM sugiere que el desbalance en la producción de citocinas promueve un proceso inflamatorio exacerbado, apoyando el papel fundamental de la inflamación en todas las etapas del proceso aterosclerótico.
RESUMO
Macrophages are the primary host cell for Leishmania parasites, by Toll like receptors (TLR-MyD88) that are central components of the innate and adaptive immunity against leishmania infection. The CD40/CD40L interaction has also been shown to be important in resistance to various protozoa. In this context, one of the most important properties of suppressors of cytokine signalling (SOCS) proteins, especially SOCS1 and SOCS3, is the regulation of macrophages cell for Leishmania parasites. In the present study we evaluated variants of molecules involved in activation and modulation of leishmanicidal signaling cascades and the possible associations between polymorphisms present in the TLR2, TLR4, MyD88, CD40, SOCS1, SOCS3 genes with susceptibility/resistent to Leishmania. The results suggest the absence of any association between TLR2 and TLR4 variants and susceptibility to Leishmaniasis. Analysis of the nucleotide sequence encoding the TIR recognition domain of the MyD88 molecule showed that it is highly conserved when compared to the reference sequences. In contrast, heterozygous rs 12953258, which reflects a decrease in the expression of SOCS3, suggesting that it may be involved in the leishmaniasis susceptibility. This study is a first advance in the analysis of polymorphisms of genes involved in the signaling pathway of the macrophage and their relationship with leishmaniases infection and disease progression.
Assuntos
Variação Genética , Leishmaniose Cutânea/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD40/genética , Antígenos CD40/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Doenças Endêmicas , Feminino , Frequência do Gene , Humanos , Leishmaniose Cutânea/etiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , População Rural , Alinhamento de Sequência , Proteína 1 Supressora da Sinalização de Citocina/genética , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Venezuela , Adulto JovemRESUMO
Objective: To identify if the absence of the GSTM1 and / or GSTT1 genes is correlated with the response to cyclophosphamide and the presence of anti DNA in a patient with SLE. Methodology: An correlational cross study that included 46 patients with a diagnosis of systemic lupus erythematosus. (LES), who attended the rheumatology clinic of the Venezuelan Institute of Social Security- Central Hospital "Dr. Miguel Pérez Carreño ", during the period June 2016 - June 2017. Patients with SLE were classified according to the presence or absence of renal involvement (lupus nephritis). Each individual was extracted 5 mL of peripheral blood, from which the genomic DNA was extracted. The presence or absence of the GSTM1 and GSTT1 genes was determined using the multiplex polymerase chain reaction method with specific primers. Results: In the studied population (n = 46), 95.7% were women and only 4.3% men. The average age was 31 years, being mostly young women of childbearing age. The treatment of patients included the use of chloroquine (78%), mycophenolate (69.6%) and corticoids (38.7%). The GST genes were present, the GSTM1 gene with a frequency.
Objetivo: Identificar si la ausencia de los genes GSTM1 y/o GSTT1 está correlacionada con la respuesta a ciclofosfamida y con la presencia de anti DNA en paciente con LES. Metodología: Estudio transversal correlacional, que incluyó 46 pacientes con diagnóstico de lupus eritematoso sistémico (LES), que acudieron a la consulta de reumatología del Instituto Venezolano del Seguro Sociales- Hospital Central "Dr. Miguel Pérez Carreño", durante el período septiembre 2016 junio de 2017. Los pacientes con LES se clasificaron de acuerdo a la presencia o no de afectación renal (nefritis lúpica). A cada individuo se le extrajo 5 mL de sangre periférica, a partir de la cual se extrajo el ADN genómico. La presencia o ausencia de los genes GSTM1 y GSTT1 se determinó utilizando el método de reacción en cadena de la polimerasa múltiplex con iniciadores específicos. Resultados: En la población estudiada (n= 46), 95,7% eran mujeres y sólo 4,3% hombres. La edad media fue de 31 años, siendo en su mayoría mujeres jóvenes en edad fértil. El tratamiento de los pacientes, comprendió el uso de cloroquina (78%), micofenolato (69,6 %) y corticoides (38,7%). Los genes GST estuvieron presentes, el gen GSTM1 con una frecuencia del 100 % y GSTT1 del 93,5%. Solo un 6,5% de los pacientes no presentaron el gen GSTT1. Conclusión: No se observó una correlación entre la presencia y/o ausencia de los genes GSTM1 y GSTT1 con la respuesta al tratamiento con Ciclofosfamida ni a la presencia de anti-DNA
Assuntos
Humanos , Polimorfismo Genético , DNA , Análise de Mediação , NefriteRESUMO
BACKGROUND: Prostate cancer is the third cause of cancer death in men in the Western hemisphere and the second cause of cancer death in Zulian men from Venezuela. OBJECTIVE: To determine whether polymorphisms 308 and 238 of the tumor necrosis factor alpha (TNF-α) gene are associated with prostate cancer. METHODS: The DNA that was extracted from the peripheral blood of 40 patients with prostatic specific antigen and 40 controls was amplified by PCR plus digestion with enzymes NcoI and MspI. RESULTS: In the patients, genotypes of the TNF-α-238 polymorphism were observed in 90% GG and 10% GA; in controls, in 97.5% GG and 2.5% GA, odds ratio (OR) = 4,000 for GA. In the patients, genotypes of TNF-α-308 polymorphism were identified in 85% GG and 15% GA, and in controls in 72.5% GG and 27.5% GA, OR = 0.545 for GA and 1.172 for GG. The allelic frequencies for TNF-α-238 in patients were 95% for G and 5% for A; in controls, 98.75% for G and 1.25% for A, with OR = 4,000 for A. The allelic frequencies for TNF-α-308 in the patients were 92.5% for G and 7.5% for A. CONCLUSIONS: There weren't any statistically significant associations. The allele A of the TNF-α-238 polymorphism resulted in a considerable risk factor for prostate cancer.
Antecedentes: El cáncer de próstata es la tercera causa de muerte por cáncer en hombres del hemisferio occidental y la segunda en zulianos de Venezuela. Objetivo: Determinar si los polimorfismos 308 y 238 del gen TNFα están asociados con cáncer de próstata. Métodos: El ADN extraído de sangre periférica de 40 pacientes con antígeno prostático específico y 40 controles fue amplificado por reacción en cadena de la polimerasa más digestión con enzimas NcoI y MspI. Resultados: Respecto al polimorfismo 238 del gen TNFα, en los pacientes se observó 90 % de genotipo GG y 10 % de GA; en los controles, 97.5 % de GG y 2.5 % de GA, razón de momios (RM) = 4.000 para GA. En cuanto al polimorfismo 308, en los pacientes se identificó 85 % de genotipo GG y 15 % de GA; y en los controles, 72.5 % de GG y 27.5 % de GA, RM = 0.545 para GA y 1.172 para GG. Las frecuencias alélicas de TNFα-238 en los pacientes fue de 95 % de G y 5 % de A; en los controles, 98.75 % de G y 1.25 % de A, con RM = 4.000 para A. Las frecuencias alélicas para TNFα-308 en los pacientes fueron 92.5 % de G y 7.5 % de A. Conclusiones: No existieron asociaciones estadísticamente significativas. El alelo A del polimorfismo 238 del gen TNF-α resultó de riesgo para cáncer de próstata.
Assuntos
Polimorfismo Genético , Neoplasias da Próstata/genética , Fator de Necrose Tumoral alfa/genética , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Purpose: Fasting or postprandial hypertriglyceridemia is considered an independent cardiovascular disease (CVD) risk factor. The intestinal fatty acid binding protein (FABP2) is involved in the intracellular transport and metabolism of fatty acids. The presence of the Ala54Thr polymorphism of the FABP2 gene appears to be involved in postprandial hypertriglyceridemia. We explored the possible association of the Ala54Thr polymorphism with fat intolerance in apparently healthy, fasting, normolipidemic subjects with normal body-mass index and without diabetes. Methodology: A total of 158 apparently healthy individuals were classified as fat tolerant (n = 123) or intolerant (n = 35) according to their response (plasma triglycerides) to an oral abbreviated tolerance test with blood samples taken at 0, 2 and 4 h. At 0 h, all subjects ingested 26.3 g of fats. Presence of the Ala54Thr polymorphism of the FABP2 gene was evaluated by polymerase chain reactionâ»restriction fragment length (PCRâ»RFLP). Results: The group with fat intolerance (postprandial hypertriglyceridemia group) showed an increased frequency of the Thr54Thr genotype when compared with the group with normal fat tolerance (control group) (23% vs. 4%, respectively, OR: 16.53, 95% CI: 4.09â»66.82, p: 0.0001, pc: 0.0003). Carriers of at least one Thr54 allele were up to six times more prevalent in the fat intolerant group than in the non-carriers. (OR: 6.35; 95% CI: 1.86â»21.59, p: 0.0003, pc: 0.0009). The levels of plasma triglycerides (Tg) at 4 h after the test meal were higher in carriers of at least one 54Thr allele than in carriers of the Ala54 allele (p < 0.05). Conclusions: There is a significant association between postprandial hypertriglyceridemia and the presence of at least one 54Thr allele of the FABP2 gene. In addition, subjects with this genotype showed an increased ratio of Tg/HDL-cholesterol. This parameter is a marker of increased CVD risk and insulin resistance.