TNF-beta Research Articles

Polymorphism in the lymphotoxin-alpha gene, position +252 (rs909253), is not associated with preeclampsia development in Brazilian women.

To investigate the frequencies of polymorphic allele and genotypes for the LT-α gene, position +252 (rs909253), in Brazilian women with preeclampsia. This is a case-control study, in which 30 women with preeclampsia, classified according to the criteria of the National High Blood Pressure Education Program, and 115 women in the control group, with at least two healthy pregnancies, were selected. Peripheral blood was collected, and DNA was extracted, followed by genotyping, using specific primers and restriction analysis. The genotypes obtained were AA, AG and GG. Statistical analysis was performed using the χ2 association test. The Hardy-Weinberg Equilibrium was tested using the Haploview Program. The results showed no association between genotypes and preeclampsia development (χ2=2.0; p=0.4). When the AG and GG genotypes were grouped according to allele G presence or absence (genotype AA), the data showed that the presence of allele G was not significantly different between cases (women with preeclampsia) and controls (χ2=0.0; p=1.0). The LT-α gene polymorphism, position +252 (rs909253), seems not to be an important candidate for the development of preeclampsia. Other inflammatory genes should be researched, and studies involving gene-environment interactions should be performed, in order to reach a better understanding of the etiology of the preeclampsia.

Genetic Variation of BCL2 (rs2279115), NEIL2 (rs804270), LTA (rs909253), PSCA (rs2294008) and PLCE1 (rs3765524, rs10509670) Genes and Their Correlation to Gastric Cancer Risk Based on Universal Tagged Arrays and Fe3O4 Magnetic Nanoparticles.

With the help of Fe3O4 nagnetic nanoparticles as a solid carrier and an excellent tool for separation, six SNP loci (rs2279115 of BCL2 gene, rs804270 of NEIL2 gene, rs909253 of LTA gene, rs2294008 of PSCA gene, rs3765524 and rs10509670 of PLCE1 gene) were selected to evaluate their relation to gastric cancer risk. Using two kinds of functionalized magnetic nanoparticles and universal tagged arrays, the whole operation procedure including genome DNA extraction and SNP genotyping was performed. All genotypes and allele frequencies were calculated in the cases and controls respectively to analyze their association with gastric cancer risk. Totally 200 pathological samples and 134 normal control subjects were collected. The results demonstrated that four SNP loci (rs2279115, rs804270, rs909253 and rs3765524) showed a potential association with gastric cancer risk, and the other two (rs2294008, rs10509670) possessed no difference/association among cases and controls.

EVALUATION OF INTERLEUKIN-6, LYMPHOTOXIN-α AND TNF-α GENE POLYMORPHISMS IN CHRONIC PERIODONTITIS

Background: Periodontitis is a chronic inflammatory disruption of the periodontal supportive tissues. There are the numerous evidences for his bacterial etiology. Though the occurrence of periodontal bacteria is considered to be the main cause of periodontitis, certain characteristics of the individual immune response may also have inuuence on the disease development and progression, and on the treatment outcomes. There are some reports that attempt to identify genetic factors associated with periodontitis including polymorphisms of interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) genes. We were interested from the distribution of several genotypes of the cytokines: interleukin-6 (G-174C) and (G-597A), lymphotoxin-α (A+252G), and tumour necrosis factor-alpha (G-308A) in patients with chronic periodontitis. Aim: To investigate the association of chronic periodontitis with certain gene polymorphisms of interleukin-6 (IL-6), Lymphotoxinα, and tumor necrosis factor-alpha (TNF-α). Material and methods: The study included 30 patients with moderate or severe chronic periodontitis, and 10 persons with healthy periodontium. Total genomic DNA was extracted from the buccal epithelial cells. TNF-A (G-308A), IL-6 (G-174C), IL-6 (G-597A) and LT-A (A+252G) genes polymorphisms were analyzed by Polymerase chain reaction (PCR). Results: Outcomes showed a large variety in genotype’s distribution in the investigated groups. No important difference was observed in the distribution of IL-6, TNF-α and LT-α genotypes between chronic periodontitis patients and controls in this study be reason of the small studied group. However, a signiucant difference in the LT-α was observed – a prevalence of the genotype GG in patients with severe periodontitis. In relation with IL-6 (G-597A) and IL6 (G-174C) genotyping in both of them in patients with severe periodontitis was occurred most frequently the genotype GG. In patients with periodontitis the frequency of genotype GG of TNF-α (G-308A) was significantly increased. Conclusion: The assessment IL-6 (G-597A) and IL6 (G-174C), and TNF-α (G-308A) revealed that genotype GG was moderate associated with chronic periodontitis in Bulgarian individuals. As a result of these findings we may suppose that the G allele may play an important role in the development and progression of periodontal disease in this population. The frequency of LT-A (A252G) was significantly greater in severe periodontitis patients in this study.

Genetic targeting of protease activated receptor 2 reduces inflammatory astrogliosis and improves recovery of function after spinal cord injury

Inflammatory-astrogliosis exacerbates damage in the injured spinal cord and limits repair. Here we identify Protease Activated Receptor 2 (PAR2) as an essential regulator of these events with mice lacking the PAR2 gene showing greater improvements in motor coordination and strength after compression-spinal cord injury (SCI) compared to wild type littermates. Molecular profiling of the injury epicenter, and spinal segments above and below, demonstrated that mice lacking PAR2 had significantly attenuated elevations in key hallmarks of astrogliosis (glial fibrillary acidic protein (GFAP), vimentin and neurocan) and in expression of pro-inflammatory cytokines (interleukin-6 (IL-6), tumor necrosis factor (TNF) and interleukin-1 beta (IL-1β)). SCI in PAR2−/− mice was also accompanied by improved preservation of protein kinase C gamma (PKCγ)-immunopositive corticospinal axons and reductions in GFAP-immunoreactivity, expression of the pro-apoptotic marker BCL2-interacting mediator of cell death (BIM), and in signal transducer and activator of transcription 3 (STAT3). The potential mechanistic link between PAR2, STAT3 and astrogliosis was further investigated in primary astrocytes to reveal that the SCI-related serine protease, neurosin (kallikrein 6) promotes IL-6 secretion in a PAR2 and STAT3-dependent manner. Data point to a signaling circuit in primary astrocytes in which neurosin signaling at PAR2 promotes IL-6 secretion and canonical STAT3 signaling. IL-6 promotes expression of GFAP, vimentin, additional IL-6 and robust increases in both neurosin and PAR2, thereby driving the PAR2-signaling circuit forward. Given the significant reductions in astrogliosis and inflammation as well as superior neuromotor recovery observed in PAR2 knockout mice after SCI, we suggest that this receptor and its agonists represent new drug targets to foster neuromotor recovery.

Signal pathway defects of Toll-like receptors 2-p38 mitogen activated protein kinase signal pathway defects and immune suppression in children with measles

Objective To investigate the expression of Toll-like receptors 2(TLR2)mRNA, p38 mitogen activated protein kinase(p38 MAPK)mRNA and cytokine in peripheral blood of children with measles and to study the effect and possible mechanism for TLR2-p38 MAPK signal pathway defects on immune suppression in the children with measles during acute phase. Methods Thirty children with measles hospitalized in the department of infectious diseases from June 2012 to July 2013 were enrolled into the measles group, and 30 healthy children were chosen as the healthy control group.The mRNA expressions of TLR and p38 MAPK in peripheral blood mononuclear cells (PBMC)were detected by reverse transcription-polymerase chain reaction (RT-PCR). The protein levels of interferon-γ(IFN-γ), tumor necrosis factor-β(TNF-β), interleukin(IL)-12, IL-6 and IL-10 in plasma were measured by using enzyme linked immunosorbent assay (ELISA), and flow cytometry (FCM)was applied to detect the percentage of lymphocyte subpopulation.The serum IgG, IgA and IgM levels were detected by velocity scatter turbidimetry. Results (1)The expressions of TLR2 mRNA and p38 MAPK mRNA in the measles group were both significantly lower than those in the healthy control group (all P 0.05). Conclusions The mRNA expressions of TLR2 and p38 MAPK are low in PBMC in the measles children during acute phase.There are different degrees of suppression of cell immunity, humoral immune and cytokines disorder in children with measles.Defects of TLR2-p38 MAPK signal pathway may cause the formation of measles immune suppression. Key words: Measles; Toll-like receptors 2; p38 mitogen activated protein kinase; Immune suppression; Child

Single nucleotide polymorphisms of the inflamatory cytokine genes: interleukin-1B, tumor necrosis factors-A and tumor necrosis factor-B in adult patients with immune thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by thrombocytopenia due to platelet autoantibodies, causing an accelerated clearance of opsonized platelets by phagocytes. The etiology of ITP remains unclear, both genetic and environmental factors may have a role in the disease development. The aim of our study was to investigate a possible association of three single nucleotide polymorphisms (SNP) in the genes for interleukin beta (IL1B-511C/T), tumor necrosis factor beta (TNF+252G/A) and tumor necrosis factor alpha (TNFA-308G/A) with ITP. We have analyzed 125 adult patients with ITP and 120 healthy matched controls. Genotyping was performed by using PCR- RFLP methods. Our results demonstrated significantly different genotype distributions and allele frequencies for TNFB+252G/A in patients with ITP, p = 0.005 and p = 0.009 with Yates correction. We did not find any significant differences in the genotype distribution or allele frequencies for the other two genes. We have found significantly different genotype distribution and allele frequencies for TNFA-308G/A between patients with unresponsive and responsive ITP patients, p = 0.016 and p = 0.009. There were no significant differences in genotype distribution and allele frequencies for ILB-511C/T and TNFB+252G/A polymorphisms between those two groups of patients. We did not find any significant differences in genotype distribution and allele frequencies for all three polymorphisms between splenectomized and unsplenectomized ITP patients. The obtained data indicate that the A allele of TNFB+252G/A is more frequent in these patients than in the controls and that this polymorphism may play a significant role in disease susceptibility. The A allele of TNFA-308G/A was more frequent in patients with unresponsive ITP, indicating that this gene polymorphisms may contribute to therapy resistance.

ICOS-ICOSL interaction regulates Lymphotoxin alpha expression and maturation of lymphoid-like stromal cells during inflammation

ICOS-ICOSL interaction regulates Lymphotoxin alpha expression and maturation of lymphoid-like stromal cells during inflammation

Intermittent Administration of Parathyroid Hormone Ameliorates Periapical Lesions in Mice

IntroductionIntermittent administration of parathyroid hormone (PTH) promotes oral osseous wound healing and protects against ligature-induced alveolar bone loss. However, its therapeutic value on periapical periodontitis is unknown. The goal of this study was to determine the effect of intermittent PTH administration on the progression of periapical periodontitis. MethodsSeven lymphotoxin alpha–deficient mice received pulp exposures of mandibular first and second molars. Exposed pulp in the right mandible was covered with plaque-contaminated fibrin, whereas exposed pulp in the left mandible was left open. After 4 weeks, the periapical tissues were examined to determine the effect of plaque-contaminated fibrin to induce periapical lesions. Fourteen mice received pulp exposure covered with plaque-contaminated fibrin. PTH (40 μg/kg/d) was administered intermittently to half of the mice for 3 weeks beginning 1 week after pulp exposure. The remaining half received saline injections as the vehicle control. At sacrifice, mandibles and tibiae were harvested and processed for histologic examination. Evaluation of neutrophils and blood vessels was performed after staining with immunofluorescence, and periradicular bone was histomorphometrically analyzed. ResultsThe exposed pulp covered with plaque-contaminated fibrin resulted in significantly larger periapical lesions compared with the control. Intermittent PTH administration reduced the size of periapical lesions significantly. Significantly less neutrophil infiltration around the root apex was found in PTH-treated animals compared with the control. ConclusionsPTH treatment suppressed periapical inflammation by reducing neutrophil infiltration and protected against tissue destruction by periapical periodontitis.

The proprotein convertase subtilisin/kexin furinA regulates zebrafish host response against Mycobacterium marinum.

Tuberculosis is a chronic bacterial disease with a complex pathogenesis. An effective immunity against Mycobacterium tuberculosis requires both the innate and adaptive immune responses, including proper T helper (Th) type 1 cell function. FURIN is a proprotein convertase subtilisin/kexin (PCSK) enzyme, which is highly expressed in Th1 type cells. FURIN expression in T cells is essential for maintaining peripheral immune tolerance, but its role in the innate immunity and infections has remained elusive. Here, we utilized Mycobacterium marinum infection models in zebrafish (Danio rerio) to investigate how furin regulates host responses against mycobacteria. In steady-state furinAtd204e/+ fish reduced furinA mRNA levels associated with low granulocyte counts and elevated Th cell transcription factor expressions. Silencing furin genes reduced the survival of M. marinum-infected zebrafish embryos. A mycobacterial infection upregulated furinA in adult zebrafish, and infected furinAtd204e/+ mutants exhibited a proinflammatory phenotype characterized by elevated tumor necrosis factor a (tnfa), lymphotoxin alpha (lta) and interleukin 17a/f3 (il17a/f3) expression levels. The enhanced innate immune response in the furinAtd204e/+ mutants correlated with a significantly decreased bacterial burden in a chronic M. marinum infection model. Our data show that upregulated furinA expression can serve as a marker for mycobacterial disease, since it inhibits early host responses and consequently promotes bacterial growth in a chronic infection.

TNF-β genetic variant contributes to the risk of non-small cell lung cancer

To investigate the association of TNF-β 252A >G variant with the risk of non-small cell lung cancer (NSCLC). Total 956 patients with NSCLC were recruited between January 2000 and December 2008 at Cancer Hospital, Chinese Academy of Medical Science as the case group, and 994 frequency-matched controls were randomly selected from a pool of cancer-free subjects recruited from a nutritional group. All the participants were unrelated Han Chinese. There were no age, gender restrictions. Smoking status of the subjects was surveyed. Informed consent was obtained and 3 ml peripheral blood was collected from each subject. All samples were genotyped by polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). The OR and 95%CI were estimated by logistic regression to evaluate the relationship between TNF-β 252 A/G variant and the risk of lung cancer. The frequencies of TNF-β 252 AA, AG and GG genotype were 30.9% (307/994) , 47.4% (471/994) and 21.7% (216/994) in lung cancer cases and 35.7% (341/956) , 48.1% (460/956) and 16.2% (155/956) in controls. Logistic regression analysis revealed that TNF-β 252 GG genotype contributed to a decreased risk of developing NSCLC (OR = 0.64, 95%CI: 0.49-0.83) compared with AA genotype. When stratified by smoking status, the individuals with 252 GG genotype had a significant increased risk of NSCLC (OR = 1.54, 95%CI:1.00-2.39) among smokers; which was less than those with AA genotype among smokers (OR = 2.88, 95%CI:1.91-2.24). When further stratified by smoking index, individuals with 252 GG genotype had a significant decreased risk of NSCLC among heavy smokers with OR (95%CI) of 2.24 (1.33-3.74), which was less than those with AA genotype (OR = 4.62, 95%CI:2.88-7.41). TNF-β genetic variant may interact with environment factor to contribute to the susceptibility to NSCLC.

Vasoplegic syndrome in cardiac surgery: role of synergism between polymorphism of tumor necrosis factor beta and plasminogen activator inhibitor type 1

Cardiopulmonary bypass can lead to postoperative hemodynamic disorders. Several genetic polymorphisms have been studied in this setting. We investigated the possible existence of a synergism between polymorphisms of plasminogen activator inhibitor type 1 (PAI-1) and tumoral necrosis factor beta (TNF-B) on hemodynamic response after cardiac surgery

CD4+ T-Cell Profiles and Peripheral Blood Ex-Vivo Responses to T-Cell Directed Stimulation Delineate COPD Phenotypes.

The heterogeneous clinical phenotypes of chronic obstructive pulmonary disease (COPD) challenge successful drug development. To identify COPD subgroups beyond clinical phenotypes, we interrogated blood immune cell profiles and ex-vivo responses of current and former smokers, with or without COPD, in the longitudinal COPD Genetic Epidemiology study (COPDGene) cohort. CD4+ and CD8+ T cells and monocytes were profiled by flow cytometry. Microarray analysis was performed on the RNA from the aforementioned isolated cells. T-cell directed whole blood ex-vivo stimulation was used to assess functional responses. Blood CD4+ T-cell transcript analysis distinguished patients with COPD from control smokers and also enriched for a subset of patients with COPD that had a history of exacerbations of the disease. Analogous analyses of CD8+ T cells and monocytes failed to discriminate patients with COPD from the control population. Patients with COPD had a diminished cytokine response, compared to control smokers, characterized by low levels of granulocyte-monocyte colony stimulation factor (GM-CSF), interferon gamma (IFN-ɣ), interleukin one-alpha (IL-1α), tumor necrosis factor-alpha (TNF-α) and tumor necrosis factor-beta (TNF-β) secreted in response to T-cell directed ex-vivo stimulation. This cytokine response associated with baseline disease severity (forced expiratory volume in 1 second [FEV1]% predicted), rapidly declining lung function, and emphysema. Our observations indicate that COPD phenotypes can be further differentiated based on blood CD4+ T-cell profiles and resultant immune responses, suggesting a role for these cells in COPD pathophysiology.

Association between ANKK1 (rs1800497) and LTA (rs909253) Genetic Variants and Risk of Schizophrenia.

Limited research has assessed associations between schizophrenia and genetic variants of the ankyrin repeat and kinase domain containing 1 (ANKK1) and lymphotoxin-alpha (LTA) genes among individuals of Middle Eastern ancestry. Here we present the first association study investigating the ANKK1 rs1800497 (T>C) and LTA rs909253 (A>G) single-nucleotide polymorphisms in an Egyptian population. Among 120 patients with DSM-IV and PANSS (Positive and Negative Syndrome Scale) assessments of schizophrenia and 100 healthy controls, we determined the genotypes for the polymorphisms using endonuclease digestion of amplified genomic DNA. Results confirmed previous findings from different ethnic populations, in that the rs1800497 and rs909253 polymorphisms were both associated with risk of schizophrenia. Differences between the genotypes of cases and controls were strongly significant (P = 0.0005 for rs1800497 and P = 0.001 for rs909253). The relative risk to schizophrenia was 1.2 (P = 0.01) for the C allele and 0.8 (P = 0.04) for the G allele. The CC, GG, and combined CC/AA genotypes were all more frequent in cases than in controls. These results support an association between ANKK1 and LTA genetic markers and vulnerability to schizophrenia and show the potential influence of just one copy of the mutant C or G allele in the Egyptian population.

CoCr wear particles generated from CoCr alloy metal-on-metal hip replacements, and cobalt ions stimulate apoptosis and expression of general toxicology-related genes in monocyte-like U937 cells

Cobalt-chromium (CoCr) particles in the nanometre size range and their concomitant release of Co and Cr ions into the patients' circulation are produced by wear at the articulating surfaces of metal-on-metal (MoM) implants. This process is associated with inflammation, bone loss and implant loosening and led to the withdrawal from the market of the DePuy ASR™ MoM hip replacements in 2010. Ions released from CoCr particles derived from a resurfacing implant in vitro and their subsequent cellular up-take were measured by ICP-MS. Moreover, the ability of such metal debris and Co ions to induce both apoptosis was evaluated with both FACS and immunoblotting. qRT-PCR was used to assess the effects on the expression of lymphotoxin alpha (LTA), BCL2-associated athanogene (BAG1), nitric oxide synthase 2 inducible (NOS2), FBJ murine osteosarcoma viral oncogene homolog (FOS), growth arrest and DNA-damage-inducible alpha (GADD45A). ICP-MS showed that the wear debris released significant (p<0.05) amounts of Co and Cr ions into the culture medium, and significant (p<0.05) cellular uptake of both ions. There was also an increase (p<0.05) in apoptosis after a 48h exposure to wear debris. Analysis of qRT-PCR results found significant up-regulation (p<0.05) particularly of NOS2 and BAG1 in Co pre-treated cells which were subsequently exposed to Co ions+debris. Metal debris was more effective as an inducer of apoptosis and gene expression when cells had been pre-treated with Co ions. This suggests that if a patient receives sequential bilateral CoCr implants, the second implant may be more likely to produce adverse effects than the first one.

Tumor necrosis factor beta NcoI polymorphism is associated with inflammatory and metabolic markers in multiple sclerosis patients

To evaluate the association between the tumor necrosis factor beta (TNF-β) NcoI polymorphism and inflammatory and metabolic markers in patients with multiple sclerosis (MS) patients and the association of these markers with disease disability, a 782 base-pair fragment of the TNF-β gene was amplified from genomic DNA and digested with the NcoI restriction enzyme. The serum levels of numerous cytokines (IL-1β, IL-12, IL-6, TNF-α, IFN-γ, IL-4, IL-10, and IL-17) serum lipid levels, plasma insulin levels, and the Homeostasis Model Assessment—Insulin Resistance (HOMA-IR) levels were evaluated in 123 female and 43 male patients with MS. Females carrying the TNFB2/B2 genotype presented with decreased IL-4 and IL-10 levels and increased TNF-α, glucose, insulin, and HOMA-IR levels; moreover, there were positive correlations between EDSS and glucose and between EDSS and HOMA-IR in these females. Males carrying the TNFB2/B2 genotype exhibited increased levels of TNF-α, IFN-γ, and IL-17 (p=0.0326) and decreased levels of IL-4, IL-10, insulin, and HOMA-IR; there was a positive correlation between EDSS and TNF-α levels. The TNFB2/B2 genotype of TNF-β NcoI polymorphism was associated with increased inflammatory and metabolic markers and this association was different according to sex of MS patients.

Funcionality characterization of RS2229094 (T&gt;C) polymorphism and LT[Alpha] expression in human retinas

AbstractPurpose To determine the expression and localization of lymphotoxin alpha (LTα) in human retinas, and investigate the functionality of the LTα rs2229094 (T&gt;C) polymorphism, previously associated to proliferative vitreoretinopathy (PVR) development.Methods Phase I: RNA from 3 healthy human retinas and 2 peripheral blood samples was subjected to reverse transcription polymerase chain reaction (RT‐PCR) analysis. In addition, 3 human eyes with chronic retinal detachment (RD) and one healthy control were subjected to immunohistochemistry (IHC) with specific antibody against LTα. Phase II: Functionality of T and C alleles was assessed by using pCEFL‐Flag expression vector, and transient transfection assays. Besides, expression analysis by RT‐PCR, Western‐blot and subcellular localization of both alleles, by immunofluorescence (IF) assay were performed.Results Phase I: Signals of mRNA LTα below significance levels were detected in healthy human retinas. Peripheral blood analysis showed different LTα transcripts with premature stop codons. IHC staining revealed no differences between human healthy and RD retinas. Phase II: No differences in mRNA and protein expression levels and subcellular localization between both alleles were found. Both alelles showed cytoplasmic LTα localization.Conclusion Although results suggest lack of functionality, and it appears to be no differences regarding LTα expression and localization, this polymorphism could remain as a valid biomarker to identify patients at high‐risk for developing PVR after RD, due to the strong association between PVR and LTα rs2229094 polymorphism previously identified by our group.

Tumor necrosis factor beta NcoI polymorphism (rs909253) is associated with inflammatory and metabolic markers in acute ischemic stroke.

Polymorphisms in genes coding for pro-inflammatory molecules represent important factors for the pathogenesis and outcome of stroke. The aim of this study was to evaluate the relationship between the tumor necrosis factor beta (TNF-β) NcoI (rs909253) polymorphism with inflammatory and metabolic markers in acute ischemic stroke. Ninety-three patients and 134 controls were included. The TNF-β polymorphism was determined using PCR-RFLP with NcoI restriction enzyme. Stroke subtypes and neurological deficit score were evaluated. White blood cell counts, erythrocyte sedimentation rate (ESR), plasma levels of IL-6 and TNF-α, serum high sensitivity C-reactive Protein (hsCRP), serum lipid profile, plasma levels of glucose and insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) were determined. Stroke patients presented higher white blood cell counts, hsCRP, ESR, glucose, insulin, and HOMA-IR, and lower HDL cholesterol than controls (p < 0.01). There was no difference in genotypic and allelic frequency of TNF-β NcoI polymorphism among patients and controls (p > 0.05). However, stroke patients carrying the TNFB2/B2 genotype presented higher levels of TNF-α, white blood cell counts, total cholesterol, LDL cholesterol, glucose, insulin, and HOMA-IR than those with other genotypes (p < 0.05). White blood cells, IL-6, hsCRP, and ESR were positively correlated with the neurological deficit of the patients (p < 0.05). Taken together, TNF-β NcoI polymorphism, by itself, was not associated with increased susceptibility for stroke development. However, the homozygous genotype for the allele TNFB2 was associated with higher expression of classical inflammatory and metabolic markers of development and outcome of stroke than other genotypes. The identification of variant alleles might allow both better prediction of susceptibility for stroke as well the identification of novel stroke mechanisms that could be target to new therapeutic approaches. Stroke patients carrying the TNFB2 variant allele could have a beneficial effect with the anti-inflammatory therapies in the early inflammatory phase of stroke.

Acute coronary syndrome and gene polymorphisms influence leukocyte mRNA expression of adhesion molecules and inflammatory proteins

Objectives: Atherosclerosis is a progressive complex disease with early onset. Adhesion molecules, proteinases and inflammatory proteins are involved in the atherosclerotic process that leads to cardiovascular disease such as acute coronary syndrome (ACS). Relationship of VCAM1, ICAM1, LGALS2, MMP9, LIGHT, LTA and NFKB gene polymorphisms with leukocyte mRNA expression and serum levels was evaluated in patients with ACS

Genetic polymorphisms and sepsis in premature neonates.

Identifying single nucleotide polymorphisms (SNPs) in the genes involved in sepsis may help to clarify the pathophysiology of neonatal sepsis. The aim of this study was to evaluate the relationships between sepsis in pre-term neonates and genes potentially involved in the response to invasion by infectious agents. The study involved 101 pre-term neonates born between June 2008 and May 2012 with a diagnosis of microbiologically confirmed sepsis, 98 pre-term neonates with clinical sepsis and 100 randomly selected, otherwise healthy pre-term neonates born during the study period. During the study, 47 SNPs in 18 candidate genes were genotyped on Guthrie cards using an ABI PRISM 7900 HT Fast real-time and MAssARRAY for nucleic acids instruments. Genotypes CT and TT of rs1143643 (the IL1β gene) and genotype GG of rs2664349GG (the MMP-16 gene) were associated with a significantly increased overall risk of developing sepsis (p = 0.03, p = 0.05 and p = 0.03), whereas genotypes AG of rs4358188 (the BPI gene) and CT of rs1799946 (the DEFβ1 gene) were associated with a significantly reduced risk of developing sepsis (p = 0.05 for both). Among the patients with bacteriologically confirmed sepsis, only genotype GG of rs2664349 (the MMP-16 gene) showed a significant association with an increased risk (p = 0.02). Genotypes GG of rs2569190 (the CD14 gene) and AT of rs4073 (the IL8 gene) were associated with a significantly increased risk of developing severe sepsis (p = 0.05 and p = 0.01). Genotype AG of rs1800629 (the LTA gene) and genotypes CC and CT of rs1341023 (the BPI gene) were associated with a significantly increased risk of developing Gram-negative sepsis (p = 0.04, p = 0.04 and p = 0.03). These results show that genetic variability seems to play a role in sepsis in pre-term neonates by influencing susceptibility to and the severity of the disease, as well as the risk of having disease due to specific pathogens.

Tumor necrosis factor beta (TNF-β) NcoI polymorphism is associated with multiple sclerosis in Caucasian patients from Southern Brazil independently from HLA-DRB1

This study evaluated the association of tumor necrosis factor beta (TNF-β) NcoI polymorphism with the presence of multiple sclerosis (MS), disability, and HLA-DRB1 alleles in 208 Brazilian MS patients. As controls, 147 healthy individuals were included. The disability was evaluated at baseline and 5-year follow-up using the Expanded Disability Status Scale (EDSS). The TNF-β genotypes were determined using PCR and restriction fragment length polymorphism and serum TNF-α level was determined using enzyme-linked immunosorbent assay. Among the MS patients, 166 (79.8%) were white, 39 (18.7%) were brown, and three (1.4%) were Asiandescents (those were excluded from the further analysis). Among the 205 MS patients, 149 (72.6%) presented remitting-relapsing MS. The baseline and 5-year follow-up EDSS ranged from 0.0 to 3.0 and from 1.0 to 5.7, respectively. The TNFB2/B2 genotype was associated with the presence of MS among the white patients (p = 0.0443). Brown patients presented higher disability (p = 0.0234) and higher TNF-α levels (p = 0.0463) than white patients. White and brown patients carrying TNFB2/B2 genotype exhibited higher TNF-α levels (p = 0.0354 and p = 0.0309, respectively)than those with other geotypes. Association between TNF-β NcoI genotypes and HLA-DRB1 alleles was not observed among the MS patients (p > 0.05). Taken together, TNFB2 allele was associated with the presence of MS independently of HLA-DRB1 in white patients and the TNFB2/B2 genotype was associated with increased TNF-α levels in white and brown patients, which could be an important genetic factor candidate for the susceptibility and pathogenesis of MS.