Interleukin-1β gene polymorphism associated with hepatocellular carcinoma in hepatitis B virus infection

AIM: To examine the effect of interleukin-1-beta (IL-1beta) promoter region C-511T and IL-1 receptor antagonist (IL-1RN) polymorphism among the patients with chronic hepatitis B virus (HBV) infection (HCC and non-HCC). METHODS: Genomic DNA from 136 Thai patients with chronic HBV infection (HCC=46 and non-HCC=90) and 152 healthy individuals was genotyped for IL-1beta gene polymorphism (-511) using polymerase chain reaction with sequence specific primers (PCR-SSP). The variable number of tandem repeats (VNTR) of IL-1RN gene was assessed by a PCR-based assay. The association between these genes and status of the disease was evaluated by chi2 test. RESULTS: IL-1B-511 genotype C/C was found to be significantly different in patients with HCC when compared with healthy individuals (P=0.036, OR=2.29, 95%CI=1.05-4.97) and patients without HCC (P=0.036, OR=2.52, 95%CI=1.05-6.04). Analysis of allele frequencies of IL-1B-511 showed that IL-1B-511 C allele was also significantly increased in patients with HCC, compared to that in healthy control (P=0.033, OR=1.72, 95%CI=1.04-2.84). However, no significant association in IL-1RN gene was found between the two groups. CONCLUSION: IL-1B-511C allele, which may be associated with high IL-1B production in the liver, is a genetic marker for the development of HCC in chronic hepatitis B patients in Thai population.     

Interleukin-1β gene polymorphism associated with hepatocellular carcinoma in hepatitis B virus infection

AIM: To examine the effect of interleukin-1-beta (IL-1β)promoter region C-511T and IL-1 receptor antagonist (IL-1RN) polymorphism among the patients with chronic hepatitis B virus (HBV) infection (HCC and non-HCC).METHODS: Genomic DNA from 136 Thai patients with chronic HBV infection (HCC=46 and non-HCC=90) and 152 healthy individuals was genotyped for IL-1β gene polymorphism (-511) using polymerase chain reaction with sequence specific primers (PCR-SSP). The variable number of tandem repeats (VNTR) of IL-1RN gene was assessed by a PCR-based assay. The association between these genes and status of the disease was evaluated by X2 test.RESULTS: IL-1B-511 genotype C/C was found to be significantly different in patients with HCC when compared with healthy individuals (P = 0.036, OR = 2.29,95%CI = 1.05-4.97) and patients without HCC (P=0.036,OR=2.52, 95%CI=1.05-6.04). Analysis of allele frequencies of IL-1B-511 showed that IL-1B-511 C allele was also significantly increased in patients with HCC, compared to that in healthy control (P=0.033,OR= 1.72, 95%CI=1.04-2.84). However, no significant association in IL-1RN gene was found between the two groups.CONCLUSION: IL-1B-511C allele, which may be associated with high IL-1B production in the liver, is a genetic marker for the development of HCC in chronic hepatitis B patients in Thai population.     

Interleukin-1beta gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection

Hepatitis C virus (HCV) infection is a major risk factor for developing hepatocellular carcinoma (HCC), a life-threatening sequel. However, the factors that affect disease progression to HCC have not been thoroughly elucidated. Genetic polymorphisms in proinflammatory cytokines, the interleukin 1 (IL-1) family (IL-1beta and IL-1ra) and tumor necrosis factor-alpha (TNF-alpha), were studied in 274 Japanese patients with chronic HCV infection and 55 healthy individuals using standard polymerase chain reaction-based genotyping techniques. The association between these polymorphisms and disease status was evaluated while controlling for confounding clinical variables. The proportion of patients with HCC in the IL-1beta-31 T/T (55%, odds ratio to C/C was 2.63, P =.009) genotype was higher than in the T/C (44%, odds ratio to C/C was 1.64, P =.149) and C/C genotypes (35%). The IL-1beta-31 and -511 loci were in near complete linkage disequilibrium, and the IL-1beta-511/-31 haplotype C-T was significantly associated with the presence of HCC (odds ratio of 1.51, P =.02). Polymorphisms in the TNF-alpha gene were not associated with disease. A multivariate analysis revealed that the IL-1beta-31 T/T genotype, alpha-fetoprotein >20 microg/L, presence of cirrhosis, male sex, and age >60 years were associated with the presence of HCC at odds ratios of 3.73 (T/T vs. C/C), 4.12, 4.03, 3.89, and 3.27, respectively. In conclusion, the IL-1beta-31 genotype T/T or the IL-1beta-511/-31 haplotype C-T is associated with the presence of HCC in Japanese patients with chronic HCV infection.     

Influence of inflammatory cytokine polymorphisms on eradication rates of Helicobacter pylori

Pro-inflammatory cytokines and anti-inflammatory cytokines are produced in gastric mucosa from inflammatory cells activated by Helicobacter pylori (H. pylori) infection. Of the inflammatory cytokines, interleukin (IL)-1β and tumor necrosis factor (TNF)-α have a potent inhibitive effect on gastric acid production. Polymorphisms in these genes are associated with individual differences in cytokine messenger RNA levels, which result in different gastric mucosal inflammation, different acid inhibition and different gastroduodenal disease risks in response to H. pylori infection. The sustained higher intragastric pH during an eradication therapy is known to be one of the therapeutic determinants of the H. pylori eradication as well as antibiotics resistance and poor compliance. The IL-1B- 511 polymorphism is related to eradication rate, and, in combined analysis of previous reports, the eradication rate in patients with the IL-1B- 511 C/C genotype (77.4%, 209/270), low IL-1β producer genotype, is lower than that of the IL-1B- 511 C/T and T/T genotypes (87.2%, 631/724) (Odds ratio for eradication failure: 1.98, 95% confidence interval: 1.38–2.84, P  = 0.0002). Moreover, the odds ratio of combined CYP2C19 rapid metabolizer- IL-1B- 511 C/C type for eradication failure is 11.15 (5.23–23.78) times that of the CYP2C19 poor metabolizer- IL-1B- 511 non-C/C type. However, there is no positive data indicating the role of other inflammatory cytokine polymorphisms (e.g. IL-1RN , TNF-A or IL-10 ) in eradication therapy. Nevertheless, the studies show that inflammatory cytokine polymorphisms, especially the IL-1B- 511 T/T genotype, are the determinants of eradication by affecting gastric acid secretion and mucosal inflammation. Therefore, the tailored eradication therapy, considering inflammatory cytokine polymorphisms, may be effective for the higher eradication rates.     

The TNF-α, IL-1B and IL-10 polymorphisms and risk for hepatocellular carcinoma: a meta-analysis

Objective  

TNF-α-308 G/A, TNF-α-238 G/A, IL-1B-31 T/C, IL-1B-511 C/T, and IL-10-1082 G/A polymorphisms have been reported to influence the risk for hepatocellular carcinoma (HCC) in many studies; however, the results still remains controversial and ambiguous. The aim of this study was to determine more precise estimations for the relationship between TNF-α, IL-1B, and IL-10 polymorphisms and the risk for HCC by meta-analysis.     

Interleukin 1beta polymorphisms increase risk of hypochlorhydria and atrophic gastritis and reduce risk of duodenal ulcer recurrence in Japan

BACKGROUND & AIMS: Interleukin-1 beta (IL-1beta) polymorphisms are associated with increased risk of gastric cancer in whites. This study aimed to examine effects of these polymorphisms on gastric acid secretion, atrophic gastritis, and risk of peptic ulcer in Japan. METHODS: We determined IL-1B-511/-31 and IL-1RN genotypes and measured gastric juice pH, serum pepsinogen (PG) I and II levels, and gastritis and atrophy scores in Helicobacter pylori-positive patients with gastritis only, gastric ulcers, or duodenal ulcers (DUs), and H. pylori-negative controls. RESULTS: In the H. pylori-positive group, subjects with the proinflammatory IL-1B-511 T/T genotype had the highest atrophy and gastritis scores, the highest median gastric juice pH, and the lowest median serum PG I/PG II ratios. Although gastric juice pH significantly increased and serum PG I and PG I/PG II ratios significantly decreased in the IL-1B-511 T/T genotype group with age, no such age-dependent changes were observed in the C/C genotype group. Changes in the C/T genotype group were intermediate. In the H. pylori-negative group, the IL-1 loci had no effect on any of the physiologic or morphologic parameters. Carriage of IL-1RN allele 2 significantly protected against DU disease while the IL-1B-511 T/T genotype significantly protected against DU recurrence in patients older than 60 years. CONCLUSIONS: Proinflammatory IL-1beta polymorphisms are associated with hypochlorhydria and atrophic gastritis in Japan. The effects are dependent on H. pylori infection and become more significant with advancing age. This may explain the high incidence of gastric cancer in Japan and also the age-dependent decrease in DU recurrence in infected subjects.     

白细胞介素-1B-511单核苷酸多态性与胃癌关系的流行病学研究

目的研究中国胃癌高、低发区白细胞介素（IL）-1B-511单核苷酸多态性、幽门螺杆菌（Hp）感染与胃癌的芙系。方法胃癌高发区（陕西省）胃癌患者、健康志愿者各102例，胃癌低发区（广东省）胃癌患者、健康志愿者各104例，两组人群在性别比及年龄上均匹配。采用限制性片段长度多态性（PCR—RFLP）分析IL-1B-511单核苷酸多态性，酶联免疫吸附法（ELISA）检测血清抗Hp—IgG抗体。结果在胃癌低发区，胃癌患者IL-1B-511T／T基因型频率明显高于对照人群（26．9％比13．4％，X^2=5．85，P〈0．05；OR=2．37，95％CI为1．16～4．82）。在胃癌高发区，胃癌患者IL-1B-511 T／T基因型频率与对照人群尢明显差异（27．5％比24．5％，X^2=0．41，P〉0．05）；高发区对照人群的IL-1B-511 T／T基因型频牢明显高于低发区相应人群（24．5％比13．4％，X^2=4．1，P〈0．05）。Hp感染轻度增加低发区人群发生胃癌的危险性（OR=3．03，95％CI为1．61～5．71），而IL-1B-511 T／T基因型增加Hp感染后胃癌发生的危险性（OR=8．0，95％CI为1．39～35．7）。结论IL-1B-511 T／T基因型与中国人胃癌发生有关，IL-1B-511 T／T基因型增加HP感染后胃癌发生的危险性。     

Cytokine profile in Egyptian hepatitis C virus genotype-4 in relation to liver disease progression

AIM: To observe the imbalance between T helper cell Th1 and Th2 cytokines in several chronic hepatitis disease at different stages of disease progression. METHODS: We measured the cytokine levels of Thl (IL-2 and IL-2R), Th2 (IL-10) and the pro-inflammatory cytokines (IL-6 and IL-6R and TNF and TNF-RI and Ⅱ) by the ELISA technique in the sera of 33 hepatocellular carcinoma (HCC) patients and 20 chronic liver disease (CLD) patients. In addition, 20 asymptomatic hepatitis C virus carriers and 20 healthy subjects negative for hepatitis C virus(HCV) markers served as controls. RESULTS: Anti-HCV antibodies were found to be positive in 94% of HCC cases and 75% of CLD cases. On the other hand, HCV viremia was detected using RT-PCR in 67% of HCC cases and 65% of CLD cases. HBsAg was positive in 9% of HCC cases and 30% of CLD cases. Also bilharzial-Ab was positive in 55% of HCC cases, 65% of CLD cases and in 70% of asymptomatic carriers (ASC). HCC patients had significantly higher values of IL-2R, TNF-RⅡ (P<0.001), and TNF-RI (P>0.05), but lower TNFα (P<0.001) and IL-6 (P = 0.032) in comparison to ASC. But, in comparison to non-cancer controls, HCC patients had higher values of IL-2R, IL-6R, TNF-RI and TNF-RⅡ, but lower TNF-α (P<0.001). CLD patients had higher IL-2R, TNF-RI, and TNF-RⅡ (P<0.001) than ASC. But, in comparison to non-cancer controls, CLD patients had higher values of IL-2R, TNF-RI and TNF- RⅡ, but lower TNF-α (P<0.001). IL-10 was higher (though not significantly) in HCC and CLD patients than in symptomatic carriers and non-cancer controls. CONCLUSION: Liver disease progression from CLD to HCC due to HCV genotype-4 infection is associated with an imbalance between Thl and Th2 cytokines. IL-2R, TNF-RI, and TNF-RⅡ could be used as potential markers.     

Relationship between HLA-DRB1*0101, DRB1*0301 alleles and interleukin-12 in haemophilic patients and hepatitis C virus positive hepatocellular carcinoma patients

The immune system can effectively eliminate hepatitis C virus (HCV) in 15 % of acute hepatitis cases. It is assumed that certain HLA-DR alleles present HCV epitopes more effectively to CD4 helper T cells than do others resulting in vigorous proliferative response to these epitopes and probably HCV recovery. So, we aimed at investigating the frequency of HLA-DRB1*0101 and DRB1*0301 alleles in child and adult haemophilics and in HCV positive hepatocellular carcinoma (HCC) patients in a trial to predict patients who require early therapeutic intervention. We also evaluated interleukin (IL)-12 levels in these patients since IL-12 induces interferon (IFN)-gamma production. This study was conducted on 50 antiHIV negative male patients subdivided into: 25 HCV negative haemophilics (group I), 10 HCV positive haemophilics (group II) and 15 HCV positive HCC (group III). Fifteen healthy persons of matched age and free of HCV and HIV infections were chosen as controls (group IV). All patients and controls were subjected to thorough history taking and clinical examination, routine and diagnostic investigations, viral markers, DRB1*0101 and DRB1*0301 amplification by polymerase chain reaction and plasma IL-12 quantitation by enzyme linked immunosorbent assay (ELISA). The frequencies of DRB1*0101 and DRB1*0301 were 20% and 30% respectively in HCV positive haemophilics and 13.3% and 40%, respectively in HCC. IL-12 levels were significantly lower in HCC cases than in HCV positive haemophilics. Among the haemophilics, IL-12 levels were non-significantly higher in children than in adults and were associated with the given number of blood product bags. DRB1*0101 and DRB1*0301 may have a role in HCV clearance and persistence in Egyptian patients with haemophilia and HCC. Low IL-12 levels encountered in HCV positive haemophilics suggest its relation to immunopathogenesis and outcome of HCV infection.     

Characteristics and prognosis of patients in Japan with viral marker-negative hepatocellular carcinoma

Background and Aim: The characteristics and prognosis of patients with hepatitis virus marker‐negative hepatocellular carcinoma (HCC) is not fully elucidated in Japan. We investigated the characteristics and prognosis of HCC patients in whom no markers for hepatitis virus infection were detected, in comparison with those of HCC patients with hepatitis virus infection. Methods: Viral markers for hepatitis B and C virus (HBV and HCV) infection were measured in 1152 patients in whom initial HCC was diagnosed between 1991 and 2004. Patient characteristics, characteristics of HCC and survival were compared between patients in whom no marker was positive (viral marker‐negative HCC) and those in whom chronic HBV or HCV infection was confirmed by viral markers (viral HCC). Results: Overall, 119 patients (10.3%) were shown to have viral marker‐negative HCC. Hepatocellular carcinoma was detected under surveillance in a significantly smaller percentage of patients with viral marker‐negative HCC than of patients with viral HCC (P < 0.0001). The tumor was significantly larger (P < 0.0001) and vascular invasion was significantly more prevalent (P = 0.0003) in patients with viral marker‐negative HCC than in those with viral HCC. The survival rate of patients with viral marker‐negative HCC was significantly lower than that of patients with viral HCC (P = 0.0378). Conclusion: The patients with HCC in whom hepatitis viral infection had not been confirmed tended not to be under surveillance, resulting in the detection of HCC at more advanced stage and with a poorer prognosis. Efforts to identify patients without hepatitis virus infection who should be under surveillance for HCC will be necessary in the future.     

Association between interleukin-1 gene polymorphisms and Helicobacter pylori infection in gastric carcinogenesis in a Chinese population

BACKGROUND AND AIM: Helicobacter pylori is a major cause of chronic gastritis and peptic ulcer disease and a definite carcinogen for gastric adenocarcinoma. However, the underlying pathogenic mechanisms are not fully understood. Interleukin-1 (IL-1) is a key cytokine involved in H. pylori-induced gastric inflammation. The present study aimed to determine polymorphisms of IL-1B and IL-1 receptor antagonist (IL-1RN) genes and their association with H. pylori infection and gastroduodenal diseases in Chinese patients. METHODS: Three hundred and ninety-nine patients with gastroduodenal diseases (129 chronic gastritis, 127 duodenal ulcer and 143 non-cardiac gastric cancer) and 264 healthy controls were genotyped for IL-1B-511 and IL-1RN gene polymorphisms by the PCR-RFLP method. H. pylori infection status was determined by a validated serological test. RESULTS: The frequency of IL-1B-511 T allele was significantly higher in H. pylori positive patients with non-cardiac gastric cancer than in both H. pylori negative patients with non-cardiac gastric cancer (60%vs 46%, P = 0.0342, OR = 1.666, 95% confidence interval [CI]: 1.045-2.656) and in healthy controls (60%vs 48%, P = 0.0071, OR = 1.665, 95%CI: 1.149-2.412). However, the polymorphism was not associated with chronic gastritis and duodenal ulcer. Multivariate logistic regression analyses identified that IL-1B-511 T/T carrier status was an independent risk factor for non-cardiac gastric cancer in the presence of H. pylori infection (adjusted OR = 3.01, 95%CI: 1.27-7.11, P = 0.01), and the frequency of IL-1B-511 T allele was an increased risk factor for developing gastric cancer (P = 0.03, adjusted OR = 2.29, 95%CI: 1.08-4.86). There was no association between IL-1RN gene polymorphisms and H. pylori infection and other gastroduodenal diseases. CONCLUSION: IL-1B-511 T allele is associated with H. pylori infection in non-cardiac gastric cancer in a Chinese population. The IL-1B-511 gene polymorphism appears to play an important role in gastric carcinogenesis in Chinese patients with H. pylori infection.     

Polymorphisms of interleukin-1B and interleukin-1 receptor antagonist genes in patients with chronic hepatitis B

AIM:To investigate the relationships between polymorphismsof interleukin-1B(IL-1B)promoter region -511C/T andinterleukin-1 receptor antagonist gene(IL-1RN)andsusceptibility to chronic hepatitis B in Chinese population.METHODS:Genomic DNA was extracted from the peripheralblood of 190 patients with chronic hepatitis B and 249 normalcontrols and then subjected to polymerase chain reaction(PCR)amplification.The PCR products were digested byrestriction endonuclease AvaI.The products of digestion weresubjected to 20 g/L gel electrophoresis and ethidium bromidestaining.RESULTS:The frequencies of IL-1B(-511)genotypes CC,CT and Tr in patients with chronic hepatitis B were 23.7%,49.5% and 26.8%,while 26.1%,47.4% and 26.5%respectively in controls.The results showed that there wasno significant difference in the frequencies of alleles orgenotypes in IL-1B between patients with chronic hepatitisB and controls.The distributions of IL-1B(-511)genotypeCC were significantly different between the two subgroups(HBV-DNA≤1×10~3 copies/mL as subgroup I,HBV-DNA>1×10~3 copies/mL as subgroup Ⅱ)of chronic hepatitis B(P=0.029).Only four of the five kinds of polymorphism(1/1,1/2,2/2 and 1/4)were found in this study.The frequenciesof IL-1RN genotypes 1/1,1/2,2/2 and 1/4 were 88.9%,9.0%,0.5% and 1.6% in patients with chronic hepatitis B respect,while were 81.1%,16.9%,0.4% and 1.6% respectively incontrols.The frequencies of genotypel/2 and IL-1RN allele2 in patients with chronic hepatitis B were lower than thosein controls(P=0.016 and P=0.029,respectively).CONCLUSION:There is an association between polymorphismsof the promoter region -511C/T of IL-1B and IL-1RN intron 2and chronic hepatitis B virus infection.Subjects with IL-1RN2 may be resistant to HBV infection,and IL-1B(-511)genotype CC is closely related with HBV-DNA replication,which gives some new clues to the study of pathogenesis ofchronic hepatitis B.     

Decreased function of peripheral blood dendritic cells in patients with hepatocellular carcinoma with hepatitis B and C virus infection

BACKGROUND: Tumour immunity does not seem to be induced effectively in tumour-bearing hosts, including in patients with hepatocellular carcinoma (HCC). One possible reason is that function of dendritic cells (DC) is decreased in such hosts. METHODS: We evaluated T cell stimulatory activity and interleukin (IL)-12 production of DC and interferon (IFN)-gamma and IL-10 production of T cells of peripheral blood from 12 control individuals and 21 patients with chronic hepatitis C virus (HCV) infection (six with chronic hepatitis (CH), eight with liver cirrhosis (LC) and 13 with HCC). Five hepatitis B virus (HBV)-infected patients with HCC were included as a disease control group. The DC were prepared by the culture of T cell-depleted populations of peripheral blood mononuclear cells in the presence of granulocyte-macrophage colony stimulating factor and IL-4 for a total of 11-12 days. The cytokine levels were assayed by ELISA. To test the stimulatory function of DC in T cell proliferation, mytomycin C-treated DC were cultured with allogeneic T cells from a control. RESULTS: When the T cell-stimulatory activity of DC was expressed as stimulation index value of [3H]-thymidine incorporation of T cells, the values were lower in HCV-infected HCC (2.6 +/- 1.8, P < 0.01) than in controls (5.5 +/- 2.0) and CH (5.0 +/- 1.3). Staphylococcus aureus Cowan 1-induced IL-12 production of DC was decreased in HCV-infected HCC (P < 0.001, P < 0.01 and P < 0.05, respectively) compared with controls, CH and LC, while similar amounts of IL-10 were produced in patients and controls. Interleukin-10 and IFN-gamma production of T cells in response to anti-CD3 antibody or IL-12 were equivalent between patient groups and controls, respectively. Similarly decreased DC function and normal T cell response were observed in HBV-infected HCC patients. CONCLUSIONS: These findings suggest that the depressed function of DC is associated with pathogenesis of HCC with HBV or HCV infection.     

Polymorphisms of interleukin-1B and interleukin-1 receptor antagonist genes in patients with chronic hepatitis B

AIM：To investigate the relationships between polymorphisms of interleukin-lB (IL-1B) promoter region -511CLT and interleukin-1 receptor antagonist gene (IL-1RN) and susceptibility to chronic hepatitis B in Chinese population. METHODS: Genomic DNA was extracted from the peripheral blood of 190 patients with chronic hepatitis B and 249 normal controls and then subjected to polymerase chain reaction (PCR) amplification. The PCR products were digested by restriction endonuclease AvaI. The products of digestion were subjected to 20 g/L gel electrophoresis and ethidium bromide staining. RESULTS: The frequencies of IL-1B (-511) genotypes CC, CT and TT in patients with chronic hepatitis B were 23.7%, 49.5% and 26.8%, while 26.1%, 47.4% and 26.5% respectively in controls. The results showed that there was no significant difference in the frequencies of alleles or genotypes in IL-1B between patients with chronic hepatitis B and controls. The distributions of IL-1B (-511) genotype CC were significantly different between the two subgroups (HBV-DNA ≤1&#215;10^3 copies/mL as subgroup I, HBV-DNA&gt; 1&#215;10^3 copies/mL as subgroup Ⅱ) of chronic hepatitis B (P=0.029). Only four of the five kinds of polymorphism (1/1, 1/2, 2/2 and 1/4) were found in this study. The frequencies of IL-1RN genotypes 1/1, 1/2, 2/2 and 1/4 were 88.9%, 9.0%, 0.5% and 1.6% in patients with chronic hepatitis B respectively, while were 81.1%, 16.9%, 0.4% and 1.6% respectively in controls. The frequencies of genotype1/2 and IL-1RN allele 2 in patients with chronic hepatitis B were lower than those in controls (P=0.016 and P=0.029, respectively). CONCLUSION: There is an association between polyrnorphisms of the promoter region -511C/T of IL-1B and IL-1RN intron 2 and chronic hepatitis B virus infection. SubJects with IL-1RN 2 may be resistant to HBV infection, and IL-1B(-511) geNotype CC is closely related with HBV-DNA replication, which gives some new clues to the study of pathogenesis of chronic hepatitis B.     

Gastric mucosal cytokine levels in relation to host interleukin-1 polymorphisms and Helicobacter pyloricagA genotype

OBJECTIVE: The outcome of a Helicobacter pylori infection is related in part to interrelationships among H. pylori virulence factors and the H. pylori-induced mucosal response. The host inflammatory response is partly governed by polymorphisms in pro-inflammatory genes. MATERIAL AND METHODS: Cytokine levels (interleukin (IL)-1beta, IL-6 and IL-8) were examined in H. pylori-infected and uninfected normal-appearing mucosa from patients with non-ulcer dyspepsia (NUD), margins of gastric ulcers and cancer tissues. Cytokine levels were compared with cagA genotypes and host interleukin (IL)-1 polymorphisms. RESULTS: The study comprised 168 Thai patients. All infected patients possessed anti-CagA antibody. Gastric mucosal IL-8 levels were significantly higher in H.pylori-positive cases than in -negative cases in all three tissue types (e.g. 1115 versus 217 pg/mg protein for NUD) (p<0.001). Normal-appearing but H. pylori-infected antral mucosa of patients with cagA type 1a strains had higher IL-8 levels than those with type 2a strains (2632 versus 1036 pg/mg protein) (p<0.005). IL-1B-511T/T carriers had higher antral mucosal IL-1ss levels versus non-carriers (pg/mg protein) (T/T=221, T/C=178, C/C=70) (p=0.005). IL-1B-511T/T carriers also had higher IL-1beta levels versus non-carriers in H. pylori-negative patients. CONCLUSIONS: It was found that both the host factors (IL-1 polymorphisms) and bacterial factors (cagA type 1a versus type 2a) influenced gastric mucosal cytokine levels. Future studies should concentrate on interactions among host factors (e.g. genetics and tissue responses) and bacterial and environmental factors.     

Occult hepatitis B virus infection as a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C in whom viral eradication fails.

Aim: Recent studies have suggested that an occult hepatitis B virus (HBV) infection negative for HBsAg but positive for HBV-DNA contributes to hepatocellular carcinoma (HCC) development in patients with chronic hepatitis C. Some follow-up studies have suggested the clinical importance of occult HBV infections in HCC development even after interferon (IFN) therapy, but a recent study denies the significance of the impact of occult HBV infection. Focusing on HCC development in patients in whom hepatitis C virus (HCV) eradication by interferon (IFN) therapy had failed, we conducted this study in order to assess the impact of occult HBV infections on HCC development in these patients. Methods: We enrolled 141 patients with chronic hepatitis C (histological stage F2 or F3) who were seropositive for HCV-RNA even after IFN therapy. Serum HBV-DNA was assayed using the real-time polymerase chain reaction. During follow-up, ultrasonography and/or computed tomography (CT) were performed at least every 6 months to monitor HCC development. Results: The cumulative incidence rates of HCC were 8.9%, 25.7% and 53.7% at 5 years, 10 years and 15 years, respectively, after IFN therapy. Multivariate analysis indicated that low platelet counts (<12 x 10(4)/mm(3)), occult HBV infection, high ALT levels (>/=80 IU/L) after IFN therapy and the staging of liver fibrosis were important independent factors affecting the appearance of HCC. Conclusions: Occult HBV was a risk factor for HCC development in patients with chronic hepatitis C in whom HCV eradication had failed. Therefore, patients with chronic hepatitis C with occult HBV should be monitored carefully for HCC after IFN therapy.     

The role of interleukin-1beta gene polymorphism in the gastric carcinogenesis]

BACKGROUND/AIMS: This study was aimed to investigate the polymorphism of interleukin-1beta(IL-1B) and IL-1 receptor antagonist (IL-1RN) gene and the relationship between genotypes and development of gastric adenocarcinoma in Korean, and to investigate the role of Helicobacter pylori (H. pylori) infection. METHODS: The study population comprised of 258 patients with gastric adenocarcinoma. They were classified according to Lauren's classification and the status of H. pylori infection. Genomic DNA was extracted from the gastric tissue. As a control, genomic DNA from peripheral lymphocyte of 100 healthy individuals was used. The amplified products of -511 bp and -31 bp fragments in the IL-1B by PCR were digested by restriction enzyme and separated for RFLP. Variable number tandem repeats were amplified and subjected to RFLP of IL-1RN. RESULTS: There was no significant difference in the genotype of IL-1B-511T and IL-1B-31C between the adenocarcinoma group and the control group. IL-1RN allele 1 homozygote in the intestinal type showed high frequency of 91.7% (p=0.007). In the H. pylori-positive group of the adenocarcinoma, the frequency of IL-1B-31C was significantly higher than that of H. pylori-negative group (p=0.045). CONCLUSIONS: The single nucleotide polymorphism of IL-1B-31C may contribute to the development of the gastric adenocarcinoma in the H. pylori-positive population.     

Polymorphisms of interleukin-1beta in Japanese patients with hepatitis B virus infection

BACKGROUND/AIMS: Hepatitis B virus (HBV) induces liver cirrhosis (LC) and hepatocellular carcinoma (HCC) mainly by causing chronic necro-inflammatory hepatic disease. Our aim was to investigate the relationships between the polymorphisms of the interleukin-1B (IL-1B) promoter region and the interleukin-1 receptor antagonist gene (IL-1RN) and disease progression in an HBV-infected Japanese population. METHODS: Genomic DNA was extracted from the peripheral blood of 237 HBV carriers. Polymorphisms in IL-1B and IL-1RN were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and PCR with confronting two-pair primers (PCR-CTPP) methods. These polymorphic sites include the promoter regions of IL-1B at positions -511 and -31, and IL-1RN variable tandem repeats. RESULTS: The IL-1B -31 and -511 loci were in complete linkage disequilibrium, and the frequency of the IL-1B -31 T carrier (IL-1B -31 T/T or T/C) was significantly higher in HBV carriers with LC compared to those without LC (LC; 86.1% vs non-LC; 72.1%, P=0.009). There was no difference in the genotype distribution of the IL-1RN polymorphism. CONCLUSIONS: This is the first report describing the association between IL-1B polymorphism and HBV-related hepatic fibrosis, and our data suggest that IL-1B polymorphisms may be related to disease progression of HBV-related hepatitis in Japan.     

Virological analysis, genotypes and mutational patterns of the HBV precore/core gene in HBV/HCV-related hepatocellular carcinoma

We investigated the replicative profile of hepatitis B (HBV) and hepatitis C (HCV) viruses and the mutational pattern of the HBV precore/core (pre-C/C) domain in hepatocellular carcinoma (HCC). Thirty-eight consecutive patients with HCC were included in the study - 18 of them with HBV/HCV co-infection and 20 with HBV single infection. Twenty-three additional patients with co-infection, without HCC were recruited as the control group. Replication activity was evaluated by detecting and quantitating both HBV and HCV genomes. The HBV pre-C/C region, encompassing the pregenome encapsidation signal involved in viral replication, was analysed by direct sequencing. HBV viraemia levels were significantly lower (P = 0.04) in patients with co-infection in comparison with single-infected HCC, whereas two different HBV viraemia profiles were detected in co-infection with or without circulating HCV. HBV genotype D was prevalent in the three groups and HCV genotype 1b was found to be the infecting strain in all patients. Lower variability in the pre-C/C region was found in co-infection in comparison with HBV single infection (P = 0.0004). A synonymous T1936C mutation was found in all co-infected HCC cases not related to the presence or absence of circulating HCV, and a hypermutated pre-C strain, characterized by the same mutational pattern, was identified in three HCC cases. The mutational pattern of the pre-C/C region was closely related to HBV replication efficiency, and specific HBV mutations selectively associated with HCV co-infection could be linked with accelerated HBV/HCV-related disease progression.     

No relationship between IL-1B gene polymorphism and gastric acid secretion in younger healthy volunteers

AIM: To investigate the influence of IL-1B-511 gene polymorphism on IL-1B mRNA expression and gastric acid output in individual with or without Helicobacter pylori (H pylori) infection. METHODS: IL-1B mRNA expression and gastric acid secretion in 117 health volunteers were assayed using semi-quantitative RT-PCR and gastric juice assay, respectively. Pepsinogen (PG) Ⅰ and Ⅱ of 255 subjects (including 117 health volunteers) were also examined. RESULTS: T/T genotype individuals with H pylori infection had a more decreased PG Ⅰ/Ⅱ ratio. In gastric antrum mucosa, the individuals with H pylori infection had higher IL-1B expression than those without H pylori infection, but there was no obvious difference among each genotype. In gastric corpus, the individuals with H pylori infection had a significantly higher IL-1B expression than those without H pylori infection. IL-1B-511T/T genotype was markedly higher as compared with the other two genotypes. Both maximal acid output and basic acid output were similar among each genotype in IL-1B-511 gene locus, regardless of H pylori infection. CONCLUSION: IL-1B-511 T allele does not decrease gastric acid output, although it has a stimulated influence on IL-1B expression. Consequently, the pathway, through which IL-1B plays a central role in gastric cancer development, might not depend on low acid, but on the other regulation mechanisms.