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OBJECTIVES: B-cell depleting monoclonal antibodies are associated with increased COVID-19 severity and impaired immune response to vaccination. We aimed to assess the humoral and cell mediated (CMI) immune response after SARS-CoV-2 vaccination in rituximab (RTX)-treated rheumatic patients. METHODS: Serum and whole blood samples were collected from RTX-treated rheumatic patients 3-6 months after last vaccination against SARS-CoV-2. Serum was tested by ELISA for quantitative detection of anti-spike SARS-CoV-2 IgG. Cell-mediated variant-specific SARS-CoV-2 immunity (CMI) was assessed by interferon-γ release assay Covi-FERON FIA. Patients were interviewed for breakthrough COVID-19 infection (BTI) 3 months post sampling. RESULTS: Sixty patients were studied after a median (IQR) of 179 (117-221.5) days from last vaccine to sampling. Forty (66.7%) patients had positive Covi-FERON and 23 (38.3%) had detectable anti-spike IgG. Covi-FERON positive patients had lower median RTX cumulative dose [6 (4-10.75) vs 11 (6.75-14.75) grams, (P = 0.019)]. Patients with positive anti-spike IgG had received fewer RTX cycles [2 (2-4) vs 6 (4-8), P = 0.002] and cumulative dose [4 (3-7) vs 10 (6.25-13) grams, P = 0.002] and had shorter time from last vaccination to sampling [140 (76-199) vs 192 (128-230) days, P = 0.047]. Thirty-seven percent were positive only for Covi-FERON and 7% only for anti-spike IgG. Twenty (33.3%) BTI occurred post sampling, exclusively during Omicron variant predominance. The proportion of patients with CMI response against Delta variant was lower in patients who experienced BTI (25% vs 55%, P = 0.03). CONCLUSIONS: Four out of ten RTX-treated vaccinated patients show lasting cell-mediated immune response despite undetectable anti-spike antibodies. Cumulative RTX dose affects both humoral and cell-mediated responses to SARS-CoV-2 vaccines. Cell-mediated immune responses call for attention as a vaccine efficacy marker against SARS-CoV-2.
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Infección Irruptiva , COVID-19 , Humanos , Rituximab/uso terapéutico , COVID-19/prevención & control , SARS-CoV-2 , Vacunas contra la COVID-19 , Vacunación , Anticuerpos Antivirales , Inmunoglobulina GRESUMEN
We determined whether plasma concentrations of the receptor for advanced glycation end products (RAGE) and the soluble (s) form of RAGE (sRAGE) in healthy individuals and patients with type 2 diabetes (T2D) modulate vascular remodeling. Healthy individuals and patients with T2D were divided into two age groups: young = <35 years old or middle-aged (36-64 years old) and stratified based on normal glucose tolerance (NGT), impaired (IGT), and T2D. Plasma titers of sRAGE, the RAGE ligands, AGEs, S100B, S100A1, S100A6, and the apoptotic marker Fas ligand Fas(L) were measured by enzyme-linked immunosorbent assay (ELISA). The apoptotic potential of the above RAGE ligands and sRAGE were assessed in cultured adult rat aortic smooth muscle cells (ASMC). In NGT individuals, aging increased the circulating levels of AGEs and S100B and decreased sRAGE, S100A1 and S100A6. Middle-aged patients with T2D presented higher levels of circulating S100B, AGEs and FasL, but lower levels of sRAGE, S100A1 and S100A6 than individuals with NGT or IGT. Treatment of ASMC with either AGEs or S100B at concentrations detected in T2D patients increased markers of inflammation and apoptosis. Responses attenuated by concomitant administration of sRAGE. In middle-aged patients with T2D, lower circulating plasma levels of sRAGE may limit decoy and exogenous trapping of deleterious pro-apoptotic/pro-inflammatory RAGE ligands AGEs and S100B, increasing the risk for diabetic complications.
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Apoptosis , Diabetes Mellitus Tipo 2/sangre , Ligandos , Receptor para Productos Finales de Glicación Avanzada/sangre , Receptor para Productos Finales de Glicación Avanzada/química , Adulto , Factores de Edad , Anciano , Animales , Antropometría , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Endotelio Vascular/metabolismo , Proteína Ligando Fas/metabolismo , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Músculo Liso Vascular/citología , Miocitos del Músculo Liso , Ratas , Proteína A6 de Unión a Calcio de la Familia S100/metabolismo , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismo , Proteínas S100/metabolismo , Transducción de Señal , Receptor fas/metabolismoRESUMEN
BACKGROUND: Secreted frizzled-related protein (Sfrp)5 improves insulin sensitivity, but impairs beta-cell function in rodents. However, the relationship between Sfrp5, insulin sensitivity and secretion in humans is currently unclear. Therefore, the aim of the study was to characterize the associations between serum Sfrp5 and indices of insulin sensitivity and beta-cell function from dynamic measurements using oral glucose tolerance tests (OGTT) in humans. MATERIAL AND METHODS: This study enrolled 194 individuals with nonalcoholic fatty liver disease (NAFLD), who were diagnosed based on ultrasound and liver transaminases and underwent a frequent sampling 75-g OGTT. Fasting serum Sfrp5 was measured by ELISA. Associations were assessed with several indices of insulin sensitivity and beta-cell function derived from glucose, insulin and C-peptide concentrations during the OGTT. RESULTS: Circulating Sfrp5 associated inversely with the insulinogenic index based on C-peptide (rs = -0·244, P = 0·001), but not with the insulinogenic index based on insulin levels (rs = -0·007, P = 0·926) after adjustment for age, sex and body mass index. Sfrp5 inversely correlated only with QUICKI as a marker of insulin sensitivity in the model adjusted for age and sex (rs = -0·149, P = 0·039). These associations were not influenced by the additional adjustment for hepatic steatosis index. CONCLUSIONS: The inverse association of serum Sfrp5 with beta-cell function suggests a detrimental role of Sfrp5 for insulin secretion also in humans. The severity of NAFLD does not appear to affect this relationship. The weak association between serum Sfrp5 and insulin sensitivity was partially explained by body mass.
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Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Proteínas del Ojo/sangre , Intolerancia a la Glucosa/sangre , Resistencia a la Insulina , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Proteínas de la Membrana/sangre , Enfermedad del Hígado Graso no Alcohólico/sangre , Proteínas Adaptadoras Transductoras de Señales , Adulto , Anciano , Péptido C/sangre , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Intolerancia a la Glucosa/complicaciones , Prueba de Tolerancia a la Glucosa , Humanos , Secreción de Insulina , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Obesidad/sangre , Obesidad/complicacionesRESUMEN
OBJECTIVE: Women with polycystic ovary syndrome (PCOS) have higher circulating levels of C-reactive protein, but the relationship between inflammation and endocrine function in PCOS remains poorly understood. Thus, this study aimed to investigate the association between low-grade inflammation and sex hormones in women with PCOS. DESIGN AND PATIENTS: A comprehensive panel of biomarkers of inflammation was measured in serum of 63 women with PCOS using proximity extension assay technology. Associations of 65 biomarkers with sex hormones were assessed without and with adjustment for age and body mass index (BMI). RESULTS: In the unadjusted analysis, 20 biomarkers were positively correlated with 17-OH-progesterone (17-OH-P), 14 with prolactin and 6 with free testosterone, whereas inverse associations were found for 16 biomarkers with sex hormone-binding globulin (SHBG), 6 with luteinizing hormone (LH) and 6 with estrogen (all p<0.05). Among the positive associations, correlations were mainly found for five chemokines (CXCL11, CCL4, MCP-4/CCL13, CXCL5, CXCL6) and for VEGF-A, LAP-TGFß1, TNFSF14 and MMP-1. Inverse associations with sex hormones were mainly present for two chemokines (CXCL1, MCP-2/CCL8), CDCP1, CST5 and CSF-1. Adjustment for age and BMI reduced the number of biomarker associations for SHBG and estrogen, but had hardly any impact on associations with 17-OH-P, prolactin, free testosterone and LH. CONCLUSION: Women with PCOS feature BMI-independent associations between biomarkers of inflammation and certain sex steroid and hypophyseal hormones. Most of these inflammation-related biomarkers were chemokines, which may be relevant as potential mediators of the increased cardiometabolic risk of women with PCOS.
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Índice de Masa Corporal , Quimiocinas/sangre , Hormonas Esteroides Gonadales/sangre , Inflamación/sangre , Síndrome del Ovario Poliquístico/sangre , Adulto , Estrógenos/sangre , Femenino , Humanos , Hormona Luteinizante/sangre , Progesterona/sangre , Prolactina/sangre , Globulina de Unión a Hormona Sexual/metabolismo , Testosterona/sangreRESUMEN
Immunological abnormalities have been implicated in schizophrenia. On the other hand, antipsychotics may exert immunomodulatory effects, by triggering pro-inflammatory and anti-inflammatory agents through complex homeostatic mechanisms, which seem to be implicated in medication responsiveness and in the presence or not of adverse effects. There is evidence that olanzapine, a second generation antipsychotic, may increase synapse formation and neurogenesis through alterations in the levels of cytokines and neurotrophic factors. In the present study, we recruited 14 drug-naive inpatients with first-episode schizophrenia (male:female ratio, 7:7) with a mean age of 26.5 years. The positive and negative syndrome scale (PANSS) scores and serum levels of a broad spectrum of cytokines and of brain-derived neurotrophic factor (BDNF) were recorded twice, once at baseline prior to the initiation of olanzapine treatment and 8 weeks later, once the dose of olanzapine had stabilized. Subsequently, the associations between the PANSS scores and the measured markers were examined. Correlation analyses revealed that follow-up PANSSnegative positively correlated with baseline interleukin (IL)-6 (ρ=0.685, P=0.007) and baseline IL-27 levels (ρ=0.785, P=0.001). Furthermore, the percentage change in PANSSnegative [(PANSS-follow-up - PANSS-baseline)/PANSS-baseline; ΔPANSSnegative%)] positively correlated with baseline IL-27 (ρ=0.785, P=0.001) and baseline IL-6 levels (ρ=0.685, P=0.007). Finally, linear regression revealed that follow-up PANSSnegative was associated with baseline IL-27 (R2=0.301, P=0.042), ΔPANSSnegative% was associated with baseline IL-6 (R2=0.301, P=0.042) and baseline IL-27 levels (R2=0.446, P=0.009). Thus, these findings indicate that IL-27 and IL-6 may be trait markers in patients being administered olanzapine monotherapy at the onset of schizophrenia. However, further studies are warranted in order to replicate these associations and to confirm their potential use as biomarkers of treatment effectiveness and safety, as well as to explore novel immunomodulatory strategies for the treatment of schizophrenia.
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Several lines of evidence indicate a causal role of the cytokine interleukin (IL)-6 in the development of type 2 diabetes in humans. Two common polymorphisms in the promoter of the IL-6 encoding gene IL6, -174G>C (rs1800795) and -573G>C (rs1800796), have been investigated for association with type 2 diabetes in numerous studies but with results that have been largely equivocal. To clarify the relationship between the two IL6 variants and type 2 diabetes, we analyzed individual data on >20,000 participants from 21 published and unpublished studies. Collected data represent eight different countries, making this the largest association analysis for type 2 diabetes reported to date. The GC and CC genotypes of IL6 -174G>C were associated with a decreased risk of type 2 diabetes (odds ratio 0.91, P = 0.037), corresponding to a risk modification of nearly 9%. No evidence for association was found between IL6 -573G>C and type 2 diabetes. The observed association of the IL6 -174 C-allele with a reduced risk of type 2 diabetes provides further evidence for the hypothesis that immune mediators are causally related to type 2 diabetes; however, because the association is borderline significant, additional data are still needed to confirm this finding.
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Diabetes Mellitus Tipo 2/genética , Interleucina-6/genética , Polimorfismo Genético , Regiones Promotoras Genéticas , Estudios de Casos y Controles , Genética de Población , Humanos , Oportunidad Relativa , RiesgoRESUMEN
The novel adipokine chemerin has been related to insulin-resistant states such as obesity and non alcoholic fatty liver disease (NAFLD). However, its association with insulin resistance and beta cell function remains controversial. The main objective was to examine whether serum chemerin levels associate with insulin sensitivity and beta cell function independently of body mass index (BMI), by studying consecutive outpatients of the hepatology clinics of a European university hospital. Individuals (n=196) with NAFLD were stratified into persons with normal glucose tolerance (NGT; n=110), impaired glucose tolerance (IGT; n=51) and type 2 diabetes (T2D; n=35) and the association between serum chemerin and measures of insulin sensitivity and beta cell function as assessed during fasting and during oral glucose tolerance test (OGTT) was measured. Our results showed that serum chemerin positively associated with BMI (P=0.0007) and C peptide during OGTT (P<0.004), but not with circulating glucose, insulin, lipids or liver enzymes (all P>0.18). No BMI independent relationships of chemerin with fasting and OGTT derived measures of insulin sensitivity were found (P>0.5). Chemerin associated positively with fasting beta cell function as well as the OGTT derived insulinogenic index IGI_cp and the adaptation index after adjustment for age, sex and BMI (P=0.002-0.007), and inversely with the insulin/C peptide ratio (P=0.007). Serum chemerin neither related to the insulinogenic index IGI_ins nor the disposition index. In conclusion, circulating chemerin is likely linked to enhanced beta cell function but not to insulin sensitivity in patients with NAFLD.
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Quimiocinas/sangre , Resistencia a la Insulina , Células Secretoras de Insulina/patología , Péptidos y Proteínas de Señalización Intercelular/sangre , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/patología , Factores de Edad , Antropometría , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
BACKGROUND: Increased adiposity in patients with newly diagnosed type 2 diabetes mellitus (DM), as well as in patients who do not have DM, affects the regulation of insulin sensitivity and the metabolic effects of adiponectin. OBJECTIVE: The goal of this study was to investigate the relationship between plasma adiponectin levels and obesity in patients developing DM mainly due to an early decline in ß-cell function. METHODS: We studied 29 patients with latent autoimmune diabetes in adults (LADA), 38 patients with type 1 DM, and 55 healthy volunteers. RESULTS: Plasma adiponectin levels, adjusted for body mass index (BMI), were higher in patients with type 1 DM than in controls (P < 0.001) and similar to those in patients with LADA (P = 0.464). Plasma adiponectin levels were higher in LADA patients compared with controls (P < 0.001). In LADA patients, plasma adiponectin levels, adjusted for BMI, correlated significantly with insulin resistance (ß coefficient, -6.453 [2.772]; P = 0.028). Interestingly, this relationship in LADA patients was significant in more overweight patients (ß coefficient, -7.142 [3.249]; P = 0.048) but not in leaner patients (P = 0.571), a finding that was not confirmed through the results in the controls (P = 0.520 and P = 0.992, respectively). CONCLUSIONS: In patients with LADA, increases in plasma adiponectin levels, after adjustment for BMI, could act as a mediator for improvement in insulin sensitivity and thus compensate for the primary secretory defect. This effect seems more profound in more overweight subjects than in leaner subjects.
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Adiponectina/sangre , Diabetes Mellitus Tipo 1/sangre , Resistencia a la Insulina , Obesidad/sangre , Adiponectina/metabolismo , Adulto , Índice de Masa Corporal , Diabetes Mellitus Tipo 1/inmunología , Femenino , Humanos , Insulina/sangre , Interleucina-6/sangre , Masculino , Obesidad/fisiopatología , Sobrepeso , Análisis de Regresión , Factor de Necrosis Tumoral alfa/sangreRESUMEN
INTRODUCTION. Many patients with non-alcoholic fatty liver disease (NAFLD) have impaired glucose regulation or type 2 diabetes mellitus (DM). We investigated characteristics of NAFLD patients associated with hyperglycemia. METHODS. During a 2-hour oral glucose tolerance test (OGTT), serum glucose and insulin were measured in 152 NAFLD patients. RESULTS. 48.7% of NAFLD patients had hyperglycemia. Age (odds ratio (OR) = 1.08, 95% confidence interval (CI): 1.03-1.13), body mass index (BMI) (OR = 1.12, 95% CI: 1.01-1.25), and lower high-density lipoprotein cholesterol (HDL-C) (OR = 0.95, 95% CI: 0.92-0.98) proved to be independent predictors of hyperglycemia. After OGTT, 30 min insulin was lower in hyperglycemic patients (74.2 ± 49.7 versus 94.5 ± 53.9 µIU/mL, P = 0.02), while 90 min insulin (170.1 ± 84.6 versus 122.9 ± 97.7 µU/mL, P = 0.01) and 120 min insulin (164.0 ± 101.2 versus 85.3 ± 61.9 µIU/mL, P < 0.01) were higher. CONCLUSIONS. NAFLD patients with higher BMI, lower HDL-C, or older age were more likely to have impaired glucose metabolism. An OGTT could be of value for early diagnosis of DM among this population.
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Glucemia/metabolismo , Hígado Graso/sangre , Adulto , Factores de Edad , Anciano , Índice de Masa Corporal , HDL-Colesterol/sangre , Estudios de Cohortes , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/patología , Hígado Graso/complicaciones , Hígado Graso/patología , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Hiperglucemia/sangre , Hiperglucemia/complicaciones , Hiperglucemia/patología , Insulina/sangre , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico , Estudios Prospectivos , Factores de RiesgoRESUMEN
Experimental and clinical evidence suggests that a heterogeneous group of bone-marrow-derived circulating progenitor cells, with variations in phenotype and function, provide an endogenous repair mechanism, contributing to vascular healing and remodeling under physiological and pathological conditions, such as cancer, atherosclerosis, myocardial infarction, and end-stage heart failure. Implantation of ventricular assist devices (VADs) for circulatory support is indicated in selected patients with end-stage heart failure as a bridge to heart transplantation, however seldom; improvement of ventricular contractility has been well documented with prolonged cardiac unloading. The current review summarizes recent findings from in vitro and in vivo studies, focusing on the biological features and the possible role of progenitor cells in the transient myocardial recovery, occasionally seen after VAD implantation, and speculates on their clinical utilities for the treatment of the failing human heart.
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Células Endoteliales/patología , Insuficiencia Cardíaca/terapia , Corazón Auxiliar , Miocardio/patología , Células Madre/patología , Animales , Movimiento Celular , Células Endoteliales/inmunología , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Humanos , Contracción Miocárdica , Miocardio/inmunología , Fenotipo , Recuperación de la Función , Regeneración , Células Madre/inmunología , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Bone marrow-derived circulating progenitor cells possess tissue repair potential, improving perfusion, left ventricular remodeling, and contractility in experimental models. We quantified and investigated the kinetics of 4 circulating progenitor cell sub-populations on the basis of CD34, CD133, and vascular endothelial growth factor receptor-2 (VEGFR-2) antigen expression. METHODS: CD34+, CD34+/CD133+/VEGFR-2-, CD34+/CD133+/VEGFR-2+, and CD34+/CD133-/VEGFR-2+ cells were counted in 10 male patients with end-stage congestive heart failure. Five underwent left ventricular/biventricular assist device (LVAD/BiVAD) implantation (VAD group), and 5 were ineligible for VAD implantation (no-VAD group). Peripheral blood was collected at 3 time points for each patient: before, 15, and 60 days after VAD placement in the VAD group and at the same time points in the no-VAD group. Purified CD34+ cells were stained with anti-CD34, anti-CD133, and anti-VEGFR-2 monoclonal antibodies and analyzed by flow cytometry. Serum levels of granulocyte-colony stimulating factor (G-CSF), interleukin-8, vascular endothelial growth factor-alpha (VEGF-alpha), and B-type natriuretic peptide (BNP) were also measured. RESULTS: In the VAD group the number of CD34+ cells/ml of blood tended to increase, from 159.6 +/- 137.0 at baseline to 428.9 +/- 224.3 at 15 days, and decreased to 343.8 +/- 165.7 at 60 days (p = 0.05 vs no-VAD group). In the other 3 cell populations, no significant differences occurred over time or between groups. A significant interaction between BNP levels and VAD status was observed (p = 0.005): BNP levels decreased over time in VAD patients vs no-VAD patients. G-CSF levels tended to decrease over time in both groups, but without a significant difference (p = 0.3). Serum levels of interleukin-8 and VEGF-alpha over time or between VAD and no-VAD patients were not significantly different. CONCLUSIONS: After VAD implantation, a transient increase occurs in the number of circulating CD34+ cells, in parallel to a reduction in BNP levels. Release of these cells from the bone marrow may contribute to the improvement of tissue perfusion and cardiac recovery occasionally seen after VAD placement.
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Antígenos CD34/metabolismo , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/terapia , Corazón Auxiliar , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Antígeno AC133 , Adulto , Anciano , Antígenos CD/metabolismo , Estudios de Casos y Controles , Diferenciación Celular/fisiología , Proliferación Celular , Glicoproteínas/metabolismo , Factor Estimulante de Colonias de Granulocitos/sangre , Insuficiencia Cardíaca/metabolismo , Humanos , Interleucina-8/sangre , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Péptidos/metabolismo , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
OBJECTIVE: Abundant evidence supports the central role of inflammatory cytokines in immune responses mediating the pathogenesis of atherosclerosis, coronary artery disease, and its complications, such as myocardial infarction and unstable angina. METHODS: We investigated the association of genetic polymorphisms of the inflammatory cytokines, IL-10, TGF-beta1, IFN-gamma, IL-6, and TNF-alpha with the clinical presentation of coronary artery disease in 26 patients with stable angina, 45 patients with unstable angina and 58 patients who had experienced nonfatal myocardial infarction. Genotyping was performed by the sequence-specific primer polymerase chain reaction method. RESULTS: A significant difference in the frequencies of -174G/C IL-6 alleles was observed, with the low in-vitro producing -174*C allele predominating in patients with myocardial infarction, compared with stable angina and unstable angina patients, after the analysis of genotypes (P=0.024 and 0.022, respectively), phenotypes [P=0.0099, odds ratio (OR)=0.271, 95% confidence interval (CI)=0.1012-0.7292; P=0.03, OR=0.40, respectively] and haplotypes (P=0.007, OR=3.028, 95% CI=1.347-6.806; P=0.0096, OR=2.368, 95% CI=1.262-4.444; respectively). In addition, a predominance of the -1082ACC/ATA IL-10 genotype in the myocardial infarction group compared with the unstable angina group and the -874 A/A IFN-gamma genotype in the stable angina group compared with the unstable angina and the myocardial infarction group, was found. No significant differences in the distribution of genotypes, phenotypes and haplotypes in the three study groups, for the TNF-alpha-308 A/G and TGF-beta1-codon 25 G/C, codon 10 T/C polymorphisms were detected. CONCLUSION: Our data provide evidence that the IL-6-174G/C polymorphism may be involved in the pathogenesis of coronary artery disease, contributing to genetic susceptibility for myocardial infarction.