Expressions of ASC and caspase-1 but not AIM2 are disrupted in chronic HBV infected patients

ObjectiveTo determine the mRNA levels of absent in melanoma 2 (AIM2), apoptosis-associated speck like protein containing a caspase recruitment domain (ASC) and caspase-1 in the peripheral blood mononuclear cells of chronic hepatitis B virus (CHB) infected patients.MethodsThis study was conducted on 60 CHB patients and 60 healthy controls and the mRNA levels of AIM2, ASC and caspase-1 were examined in parallel with beta-actin (as housekeeping gene) using real-time polymerase chain reaction technique.ResultsOur results indicated that expression of ASC and caspase-1 but not AIM2 were significantly decreased in peripheral blood mononuclear cells isolated from CHB patients compared to healthy controls.ConclusionsAccording to our results, it is likely that CHB patients are unable to firmly express ASC and caspase-1 genes and in turn properly activate IL1β and IL-18 subsequent to hepatitis B virus infection. Thus, these results propose a mechanism which almost partially may describe a reasonable fact that why the infection is sustained in the CHB patients.     

Impaired activities of cyclic adenosine monophosphate-responsive element binding protein, protein kinase A and calcium-independent phospholipase A2 are involved in deteriorated regeneration of cirrhotic liver after partial hepatectomy in rats

Aims: This study is to elucidate whether cyclic adenosine monophosphate (cAMP)-mediated signal is involved in lower regenerative potential of cirrhotic liver. Methods: Hepatic cAMP concentration, activities of protein kinase A (PKA), c-AMP responsive element binding protein (CREB) and Ca(2+) -independent phospholipase A(2) (iPLA2) and regeneration rate were compared between rats with thioacetamide-induced cirrhotic and normal livers after two-third hepatectomy. Results: The liver regeneration estimated by the rates of [(3) H]-thymidine incorporation and staining of proliferating cell nuclear antigen was significantly lower in the cirrhotic group. CREB, PKA and iPLA2 activities, assessed by western blots and electromobility shift assay, were significantly impaired after hepatectomy in the cirrhosis group. PKA and iPLA2 silencing by siRNA transfection significantly inhibited CREB activity and cell growth in transformed hepatocytes in vitro. Conclusions: CREB dysfunction, mediated by PKA and iPLA2 suppression, may be involved in the deteriorated liver regeneration in the cirrhotic rats.     

Impaired protein synthesis induced by acute alcohol intoxication is associated with changes in eIF4E in muscle and eIF2B in liver

BACKGROUND: Acute alcohol intoxication in rats decreases protein synthesis in skeletal muscle and, to a lesser extent, in liver. The purpose of the present study was to examine potential mechanisms for the inhibitory effect of acute ethanol exposure. METHODS: Rats were injected intraperitoneally with either ethanol (75 mmol/kg) or saline, and tissues were examined 2.5 hr later. Rates of protein synthesis in vivo were determined by [3H]phenylalanine incorporation into protein, and various eukaryotic initiation factors (eIFs) were quantitated by Western blot analysis to identify possible mechanisms for regulating translation. RESULTS: Protein synthesis in gastrocnemius and liver was decreased (39% and 21%, respectively) after alcohol administration, compared with saline-injected control animals. Alcohol administration did not alter tissue RNA content but diminished translational efficiency in muscle (43%) and liver (24%). Hepatic eIF2B activity was decreased 24% in alcohol-treated rats, and this was associated with a 95% increase in eIF2alpha phosphorylation. However, alcohol did not alter the amount of 4E-binding protein 1 (4E-BP1) bound to eIF4E, cIF4E bound to eIF4G, or the phosphorylation state of either 4E-BP1 or eIF4E. In contrast to liver, neither eIF2B activity nor the phosphorylation of eIF2alpha was affected in muscle of alcohol-treated rats. However, acute alcohol intoxication increased binding of 4E-BP1 to eIF4E (113%), decreased the amount of cIF4E bound to cIF4G (81%), and decreased the amount of 4E-BP1 in the phosphorylated gamma-form (77%). The plasma concentrations of insulin and insulin-like growth factor-I were unchanged by alcohol, but muscle insulin-like growth factor-I messenger ribonucleic acid abundance was decreased 35%. CONCLUSIONS: These data suggest that acute alcohol intoxication decreases translation initiation and protein synthesis in liver and muscle via different mechanisms. Changes in eIF2B appear to predominate in liver, whereas alterations in eIF4E availability appear more critical in skeletal muscle for controlling translation initiation.     

Specificity of the cyclic GMP-binding activity and of a cyclic GMP-dependent cyclic GMP phosphodiesterase in Dictyostelium discoideum

The nucleotide specificity of the cyclic GMP-binding activity in a homogenate of Dictyostelium discoideum was determined by competition of cyclic GMP derivatives with [8-3H]-cyclic GMP for the binding sites. The results indicate that cyclic GMP is bound to the binding proteins by hydrogen bonds at N2H2, N1-H and/or C6 = O, N7, 2(1)-OH and 3(1)-O and possibly via a charge-charge interaction with the phosphate moiety of cyclic GMP. Cyclic AMP only competes with cyclic GMP for binding at a 20,000-fold higher concentration. The same cyclic GMP derivatives were used to modify the hydrolysis of [8-3H]cyclic GMP by phosphodiesterase. The phosphodiesterase is activated by cyclic GMP. The nucleotide specificity of activation of the enzyme differs from the specificity of the enzyme for hydrolysis. This indicates that activation by cyclic GMP and hydrolysis of cyclic GMP occur at different sites of the enzyme. Cyclic AMP neither activates the cyclic GMP phosphodiesterase nor competes with cyclic GMP for hydrolysis. This indicates that intracellular cyclic AMP does not interfere with the action of intracellular cyclic GMP in D. discoideum.     

Antibodies to E1 and E2/Protein X components of pyruvate dehydrogenase complex in sera of patients with primary biliary cirrhosis

Aims/Methods: Using purified E1 component of pyruvate dehydrogenase complex (PDC) from bovine heart, we measured the levels of anti-E1 anti-bodies in PBC sera using ELISA and determined the degree of inhibition that these antibodies exerted on E1 enzyme activity. We also estimated levels of anti-E2/Protein X (Pro-X) antibodies in PBC sera using purified E2 and Pro-X of PDC which were copurified with E1.Results/Conclusions: Anti-E1 antibodies were detected in 87.5% (35/40) of PBC sera. Some of these sera inhibited E1 enzyme antivity but inhibition did not correlate with levels of anti-E1 antibodies.A high positive correlation (r=0.918) was found between levels of anti-E1 and anti-E2/Pro-X antibodies, suggesting that anti-PDC antibody production was stimulated by PDC itself. Levels of IgG class anti-E2/Pro-X antibodies were significantly higher in sera of symptomatic PBC patients than in those of asymtomatic PBC patients. It was also found that patients who were positive for only IgM class anti-E2/Pro-X antibodies had early-stage PBC.     

Mutation and functional analysis of ABCC2/multidrug resistance protein 2 in a Japanese patient with Dubin–Johnson syndrome

Dubin–Johnson syndrome (DJS) is a recessive inherited disorder characterized by conjugated hyperbilirubinemia. It is caused by dysfunction of adenosine triphosphate‐binding cassette, sub‐family C, member 2 (ABCC2/MRP2) on the canalicular membrane of hepatocytes. We performed mutational analysis of the ABCC2/MRP2 gene in a Japanese female with DJS. Furthermore, we investigated the effects of the two identified DJS‐associated mutations on MRP2 function. We found a compound heterozygous mutation in the patient: W709R (c.2124T>C), a missense mutation in exon 17, and R1310X (c.3928C>T), a nonsense mutation in exon 28. DJS‐associated mutations have been shown to impair the protein maturation and transport activity of ABCC2/MRP2. We established HEK293 cell lines stably expressing one of the two identified DJS‐associated mutations. Expressed W709R MRP2 was mainly core‐glycosylated, predominantly retained in the endoplasmic reticulum, and exhibited no transport activity, suggesting that this mutation causes deficient maturation and impaired protein sorting. No MRP2 protein was expressed from HEK293 cells transfected with an R1310X‐containing construct. This compound heterozygous mutation of the MRP2 gene causes dysfunction of the MRP2 protein and the hyperbilirubinemia seen in DJS.     

视黄醇结合蛋白4、胱抑素 C 与2型糖尿病胫前色素沉着斑的相关性分析

选择165例2型糖尿病患者,其中合并胫前色素沉着斑(PPP)者80例(PPP 组),无 PPP 者85例(NPPP 组),以及50名糖调节正常者为对照组(NGR 组)。记录并比较各组患者的性别、年龄、糖尿病病程、体重指数(BMI)、收缩压、舒张压、空腹血糖(FBG)、餐后2 h 血糖(2hPG)、甘油三酯(TG)、总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、HbA1C、视黄醇结合蛋白4(RBP4)、胱抑素 C 等。结果显示, NPPP 组 BMI、FBG、2hPG、TG、胱抑素 C 高于 NGR 组(P<0.01)。 PPP 组患者 BMI、收缩压、FBG、2hPG、TG、胱抑素 C、RBP4高于 NGR 组(P<0.05或 P<0.01)。 PPP 组患者糖尿病病程、FBG、2hPG、HbA1C、胱抑素 C、RBP4明显高于 NPPP 组(P<0.01)。 Pearson 相关分析显示血清 RBP4与胱抑素 C 呈线性正相关(r =0.77, P<0.01)。受试者工作特征曲线显示 RBP4及胱抑素 C 曲线下面积分别为0.81、0.78(P<0.01)。二元logistic 回归分析结果显示,糖尿病病程、HbA1C、RBP4与 PPP 的发生呈正相关(r =0.37、0.26、0.22,P<0.05或 P<0.01)。     

Combined factor IX and protein C deficiency in a child: Thrombogenic effects of two factor IX concentrates

We have recently described an unusual situation which involved a combination of a factor IX and a protein C deficiency in a young child who presented, according to the bleeding tendency, as a hemophilia B patient in this particular hemophiliac, baseline prothrombin fragment F₁₊₂ levels were unexpectedly elevated and increased after an injection of a very high purity factor IX concentrate. This observation raised a question regarding the substitution schedule in the case of repeated injections of factor IX, since the thrombotic tendency has been a major concern with some factor IX concentrates. We monitored factor IX, prothrombin fragment F₁₊₂ and D-dimer plasma levels before and during the 6 hr following the injection of an immunopurified factor IX concentrate. The results showed an increase in the F₁₊₂ levels after the factor IX injection, but an increase lower than previously observed with an ion-exchange chromatography-purified concentrate. Furthermore the F₁₊₂ level returned to baseline value 6 hr after administration. This factor IX concentrate seems to be best for use in the patient where repeated injections are involved (as employed during surgery). Moreover, the data point out the advantage of a monoclonal antibody-purified factor IX concentrate over less purified concentrates in a specific situation, with regard to the thrombogenic risk.     

Association of common haplotypes of surfactant protein A1 and A2 (SFTPA1 and SFTPA2) genes with severity of lung disease in cystic fibrosis

Most individual cystic fibrosis transmembrane conductance regulator (CFTR) mutations appear not to correlate directly with severity of lung damage in cystic fibrosis (CF). Components of innate immunity, namely, mannose-binding lectin (MBL2), and surfactant protein A1 and A2 genes (SFTPA1 and SFTPA2), were shown to be critical in pulmonary host defenses. A pilot association study was conducted to identify genetic modifiers of lung disease in adult patients with CF. The structural and promoter (-221x/y) variants of MBL2, variants at codons 19, 50, 62, and 219 of SFTPA1, and at codons 9, 91, and 223 for SFTPA2, were studied in 135 adults with CF and compared to their forced expired volume in 1 sec (FEV1), diffusion of CO (DLCO), and other pulmonary scores. Predicted FEV1 was significantly lower in adults with the SFTPA1 6A3 allele and SFTPA2 1A1) allele (P = 0.01 and 0.009, respectively). The extended haplotype 6A3/1A1, which includes SFTPA1 and SFTPA2, was associated with lower pulmonary function, using FEV1 (P = 0.005) and poor pulmonary scores which were determined by American Medical Association, American Thoracic Society, and modified Shwachman-Kulczycki scores. Lower FEV1 and DLCO values were associated with MBL2 coding variants in those who had the DeltaF508 CFTR mutation (P = 0.03 and 0.004, respectively). These results support the current hypothesis that variants in pulmonary host defense molecules are potentially genetic modifiers of pulmonary disease in CF. Further work in larger populations is required to provide important new insights into the pathogenesis of CF.     

Insulin resistance in Type 2 (non-insulin-dependent) diabetic patients and their relatives is not associated with a defect in the expression of the insulin-responsive glucose transporter (GLUT-4) gene in human skeletal muscle

Summary To study whether insulin resistance in Type 2 (non-insulin-dependent) diabetes mellitus is due to a defect in the expression of the insulin-responsive glucose transporter gene (GLUT-4) in human skeletal muscle, we measured the level of GLUT-4 mRNA and (in some of the subjects) its protein in muscle biopsies taken from 14 insulin-resistant patients with Type 2 diabetes, 10 first-degree relatives of the diabetic patients and 12 insulin-sensitive control subjects. Insulin sensitivity was measured with a +45 mU· ·min^–1 euglycaemic insulin clamp in combination with indirect calorimetry and infusion of [3-³H]glucose. GLUT-4 mRNA was measured using a human GLUT-4 cDNA probe and GLUT-4 protein with a polyclonal antibody specific for the 15 amino acid carboxyterminal peptide. Both Type 2 diabetic patients and their relatives showed impaired stimulation of total-body glucose disposal by insulin compared with control subjects (29.5±2.1 and 34.0±4.8 vs 57.9±3.1 mol·kg lean body mass^–1·min^–1; p<0.01). This impairment in glucose disposal was primarily accounted for by a reduction in insulin-stimulated storage of glucose as glycogen (13.0±2.4 and 15.6±3.9 vs 36.9±2.2 mol·kg lean body mass^–1·min^–1; p<0.01). The levels of GLUT-4 mRNA expressed both per g of total RNA and per g DNA, were higher in the diabetic patients compared with the control subjects (116±25 vs 53±10 pg/g RNA and 177±35 vs 112±29 pg/g DNA; p<0.05, p<0.01, respectively). The GLUT-4 mRNA levels in the relatives were not significantly different from that observed in the control subjects (90±16 pg/g RNA and 117±23 pg/g DNA; p = NS). The GLUT-4 protein levels did not significantly differ between control subjects, diabetic patients and relatives (494±85, 567±133 and 323±80 cpm/100 g protein). No correlation was observed between the level of GLUT-4 mRNA andits protein. However, the level of GLUT-4 mRNA and the rate of total-body glucose disposal correlated positively in the control group and in the relatives (both p<0.05) but not in the diabetic subjects. A positive correlation between the level of GLUT-4 protein and total-body glucose disposal was also observed in the control subjects (r = 0.759; p<0.05) and in the relatives (r = 0.794; p<0.01) but not in the diabetic subjects. We conclude that insulin resistance in Type 2 diabetes is not related to a defect in the expression of the GLUT-4 gene in skeletal muscle. Nevertheless, the levels of GLUT-4 mRNA and GLUT-4 protein are related to the rate of total-body glucose disposal in subjects with normal fasting glucose concentrations.     

视黄醇结合蛋白4、胱抑素C与2型糖尿病下肢动脉病变的关系

选取209例2型糖尿病患者,根据踝肱指数(ABI)分为单纯2型糖尿病组、2型糖尿病伴轻中度闭塞组、2型糖尿病伴重度闭塞组,以60名健康体检者作为对照组.检测血清视黄醇结合蛋白4(RBP4)、胱抑素C和生化指标.结果显示,各组间血清RBP4、胱抑素C水平随下肢动脉病变程度逐渐升高,2型糖尿病伴中度和重度闭塞组显著高于对照组(P＜0.05或P＜0.01),伴下肢动脉病变组RBP4、胱抑素C水平显著高于不伴下肢动脉病变组(均P＜0.01).Pearson相关分析结果显示总胆固醇、甘油三酯、低密度脂蛋白胆固醇、体重指数、腰臀比、胱抑素C等与血清RBP4呈正相关,与高密度脂蛋白胆固醇呈负相关(P＜0.05或P＜0.01).Logistic回归分析发现血清RBP4、胱抑素C与2型糖尿病下肢动脉病变显著相关(P＜0.05或P＜0.01).     

Retinol-binding protein 4 is associated with components of the metabolic syndrome, but not with insulin resistance, in men with type 2 diabetes or coronary artery disease

Aims/hypothesis Retinol-binding protein 4 (RBP4) has recently been reported to be associated with insulin resistance and the metabolic syndrome. This study tested the hypothesis that RBP4 is a marker of insulin resistance and the metabolic syndrome in patients with type 2 diabetes or coronary artery disease (CAD) or in non-diabetic control subjects without CAD. Methods Serum RBP4 was measured in 365 men (126 with type 2 diabetes, 143 with CAD and 96 control subjects) and correlated with the homeostasis model assessment of insulin resistance index (HOMA-IR), components of the metabolic syndrome and lipoprotein metabolism. RBP4 was detected by ELISA and validated by quantitative Western blotting. Results RBP4 concentrations detected by ELISA were shown to be strongly associated with the results gained in quantitative Western blots. There were no associations of RBP4 with HOMA-IR or HbA_1c in any of the groups studied. In patients with type 2 diabetes there were significant positive correlations of RBP4 with total cholesterol, LDL-cholesterol, VLDL-cholesterol, plasma triacylglycerol and hepatic lipase activity. In patients with CAD, there were significant associations of RBP4 with VLDL-cholesterol, plasma triacylglycerol and hepatic lipase activity, while non-diabetic control subjects without CAD showed positive correlations of RBP4 with VLDL-cholesterol and plasma triacylglycerol. Conclusions/interpretation RBP4 does not seem to be a valuable marker for identification of the metabolic syndrome or insulin resistance in male patients with type 2 diabetes or CAD. Independent associations of RBP4 with pro-atherogenic lipoproteins and enzymes of lipoprotein metabolism indicate a possible role of RBP4 in lipid metabolism.     

Retinol-binding protein 4 as a plasma biomarker of renal dysfunction and cardiovascular disease in type 2 diabetes

OBJECTIVE: The retinol-binding protein 4 (RBP4) has been linked to the insulin resistance state in obesity and type 2 diabetes in animal studies. Data in humans are controversial and their relationship with organ damage in diabetic patients is lacking. We studied the association of plasma RBP4 with organ complications in type 2 diabetic patients. SETTING: Sant Joan University Hospital, Reus, Spain. SUBJECTS: 165 nonsmoker type 2 diabetic subjects according to American Diabetes Association criteria, aged 36-79 years, without proteinuria or severely decreased glomerular filtration rates (MDRD-GFR <30 mL min(-1) 1.73 m(-2)), were included in the study. MAIN OUTCOME MEASURE: Plasma RBP4 concentrations were the primary outcome variable. Statistics were performed in relation to clinical and subclinical arteriosclerosis, renal function parameters and biochemical data. RESULTS: Plasma RBP4 concentrations were positively correlated with serum creatinine levels (r = 0.322, P < 0.001) and inversely correlated with MDRD-GFR (r = -0.468, P = 0.009). Patients with moderately renal dysfunction (MDRD-GFR <60 mL min(-1) 1.73 m(-2)) had higher plasma RBP4 concentrations than those with normal to mildly decreased GFR (55.3 +/- 24.6 vs. 40.8 +/- 15.4, P <0.001). Patients in the top quartile of RBP4 concentrations had an increased adjusted odds ratio for moderately renal dysfunction compared with lower quartiles (4.68; 95% CI: 1.52-14.36, P = 0.007). The presence of microalbuminuria was not associated with RBP4. Plasma RBP4 concentrations were higher in those subjects with previous clinical arteriosclerosis than in event-free subjects (48.8 +/- 24.2 vs. 40.6 +/- 13.9, P = 0.045). The presence of retinopathy or polyneuropathy did not differ across RBP4 quartiles. CONCLUSIONS: Plasma RBP4 concentration might be a biomarker of nephropathy and cardiovascular disease in type 2 diabetic subjects.     

Inflammatory cytokines and signaling pathways are associated with survival of primary chronic lymphocytic leukemia cells in vitro: a dominant role of CCL2

Background

Chronic lymphocytic leukemia cells show prolonged survival in vivo, but rapidly die by spontaneous apoptosis in vitro, unless they are co-cultured with stromal cells or non-malignant leukocytes. The objective of this study was to characterize the survival-inducing cross-talk of chronic lymphocytic leukemia cells with their microenvironment to identify novel therapeutic targets.

Design and Methods

We analyzed and compared microarray-based expression profiles of chronic lymphocytic leukemia cells before and after three different survival-inducing culture conditions: (i) stromal cell co-culture, (ii) stromal cell conditioned medium and (iii) high cell density cultures of unsorted peripheral blood mononuclear cells. Cytokine antibody arrays were applied to study the composition of soluble factors present in these cultures.

Results

The different survival-supportive culture conditions induced distinct gene expression changes, the majority of which were common to all three conditions. Pathway analyses identified – in addition to known signaling networks in chronic lymphocytic leukemia – novel pathways, of which Toll-like receptor signaling, nuclear respiratory factor-2 (NRF2)-mediated oxidative stress response, and signaling via triggering receptor expressed on myeloid cells-1 (TREM1) were the most relevant. A high proportion of up-regulated genes were inflammatory cytokines, of which chemokine (C-C motif) ligand 2 (CCL2) was shown to be induced in monocytes by the presence of chronic lymphocytic leukemia cells in vitro. In addition, increased serum levels of this chemokine were detected in patients with chronic lymphocytic leukemia.

Conclusions

Our data provide several lines of evidence that an inflammatory microenvironment is induced in survival-supportive cultures of chronic lymphocytic leukemia cells which might be directly or indirectly involved in the prolonged survival of the malignant cells.     

Enhanced efficacy of pegylated interferon alpha‐2a over pegylated interferon and ribavirin in chronic hepatitis C genotype 4A randomized trial and quality of life analysis

Aim: The therapy of chronic hepatitis C genotype 4 (HCV‐4) has not been optimized yet. This randomized, prospective, parallel‐group clinical trial compared the efficacy and safety of pegylated interferon α‐2a (PEG‐IFN α‐2a) plus ribavirin and PEG‐IFN α‐2b plus ribavirin and assessed the health‐related quality of life (HRQOL) in patients with chronic HCV‐4. Methods: Eligible patients with proven chronic HCV‐4 were randomized to receive either a weekly dose of PEG‐IFN α‐2a (180 μg) or PEG‐IFN α‐2b (1.5 μg/kg) and a daily dose of ribavirin (1000–1200 mg) for 48 weeks with 24 weeks post‐treatment follow‐up. The primary end point was sustained virological response (SVR) defined by undetectable HCV RNA 24 weeks after treatment. The Short form‐36 Health Survey version 2 (SF‐36v2) and the Chronic Liver Disease questionnaires (CLDQ) were assessed before, during and after therapy. Results: The overall SVR rate of the entire cohort was 59.9%. The SVR rates were significantly higher in patients treated with PEG‐IFN α‐2a and ribavirin (Group A; n=109) compared with those treated with PEG‐IFN α‐2b and ribavirin (Group B; n=108, 70.6 vs. 54.6%, respectively; P=0.017). The relapse rates were 5.1% for PEG‐IFN α‐2a and 15.7% for PEG‐IFN α‐2b (P=0.0019). The SF‐36v2 and CLDQ were low during therapy and improved significantly after therapy successful therapy. Conclusion: Pegylated interferon α‐2a plus ribavirin was significantly more effective than PEG‐IFN α‐2b and ribavirin therapy in the treatment of chronic HCV‐4 patients. The tolerability and adverse events were comparable between the two regimens. The HRQOL improved significantly after successful PEG‐IFN α‐2a plus ribavirin therapy.     

Polymorphisms of the TLR2 and TLR4 genes are associated with risk of gastric cancer in a Brazilian population

AIM: To investigate toll-like receptor 2 (TLR2) -196 to -174 del, and TLR4 (+896A/G rs4986790 and +1196C/T rs4986791) polymorphisms at risk of chronic gastritis and gastric cancer in a Brazilian population and association of gastric lesions with risk factors such as smoking, alcohol intake and Helicobacter pylori infection.METHODS: In this case-control study, polymorphism at TLR2 -196 to -174 del was investigated by using the allele-specific polymerase chain reaction (PCR) method, while the PCR-restriction fragment length polymorphism technique was carried out to identify the TLR4 (rs4986790 and rs4986791) genotypes in 607 Brazilian individuals (208 with chronic gastritis-CG, 174 with gastric cancer-GC and 225 controls -C).RESULTS: The single nucleotide polymorphisms TLR4+1196C/T was not associated with risk of chronic gastritis or gastric cancer and the homozygous genotypes TLR4+896GG and TLR4+1196TT were absent in the studied population. However, the frequency of TLR2 -196 to -174 ins/del + del/del and TLR4+896AG genotypes was significantly higher (P < 0.01 and P = 0.01, respectively) in the cancer group (33.4% and 11.5%, respectively) than in the control group (16.9% and 4.5%, respectively). It was also observed that the G-C haplotype of the TLR4+896A/G+1196C/T (P = 0.02) and the combination of variant alleles of the TLR2/TLR4+896G (P = 0.02) are associated with susceptibility to gastric cancer. In addition, the multiple logistic regression showed that male gender [odds ratio (OR) = 2.70; 95% CI: 1.66-4.41; P < 0.01], alcohol intake (OR = 2.93; 95% CI: 1.76-4.87; P < 0.01), TLR2 -196 to -174 del (OR = 2.64; 95% CI: 1.56-4.44; P < 0.01) and TLR4+896G (OR = 3.19; 95% CI: 1.34- 7.61; P < 0.01) polymorphisms were associated with a higher susceptibility to developing this neoplasm.CONCLUSION: Our data indicate that TLR2 -196 to -174 del and TLR4+896G may increase the risk of gastric cancer in a Brazilian population.