IL1B and IL1RN polymorphic genes and Helicobacter pylori cagA strains decrease the risk of reflux esophagitis

BACKGROUND & AIMS: Proinflammatory interleukin (IL)-1 gene polymorphisms associated with high levels of IL-1beta activity increase the risk for hypochlorhydria and distal gastric carcinoma. The aim of this study was to evaluate whether carriers of these polymorphic genes are protected against gastroesophageal reflux disease (GERD). TNFA-308 polymorphisms were also studied. METHODS: We prospectively evaluated 385 patients without gastric cancer and peptic ulcer. Of these patients, 383 (98 with GERD and 285 controls) were successfully genotyped for all cytokines studied. The cagA status of Helicobacter pylori isolates was determined by polymerase chain reaction (PCR). IL1B-511/-31, IL1RN, and TNFA-308 polymorphisms were genotyped by PCR, PCR/restriction fragment length polymorphism, or PCR/confronting 2-pair primers. Histologic gastritis was assessed according to the updated Sydney system. The role of the proinflammatory cytokine genotypes in the genesis of GERD was evaluated before and after stratification by H. pylori status in logistic regression models controlling for confounding factors. RESULTS: IL1B-31 (a near-complete linkage disequilibrium between polymorphism at -31 and -511 was found) and IL1RN*2 allele polymorphisms were associated with GERD. After stratification, in the group of H. pylori-positive patients, cagA-positive status, IL1B-31 polymorphic alleles, IL1RN*2 alleles, and the degree of corpus gastritis were negatively associated with GERD. In the H. pylori-negative group, IL1B-31C/C genotype was inversely associated with GERD even after adjustment for age and sex. CONCLUSIONS: This study provides evidence supporting the independent protective role of cagA-positive H. pylori status and IL1B and ILRN allele polymorphisms against GERD.     

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.     

IL-1 RN 2/2 genotype and simultaneous carriage of genotypes IL-1 RN 2/2 and IL-1beta-511 T/T associated with oesophagitis in Helicobacter pylori-negative patients

BACKGROUND: Interleukin-1 receptor antagonist genotype 2/2 is associated with a prolonged and enhanced inflammatory response. It is suspected of being a risk factor for atrophic gastritis and gastric cancer and for some autoimmune diseases. No specific genetic risk factors for oesophagitis have been identified so far and there are no reports of IL-1 polymorphism in relation to oesophageal disease. METHODS: We studied the IL-1RN, IL-1beta-511 and IL-1beta + 3953 polymorphisms in an unselected series of 142 adult patients scheduled for gastrointestinal endoscopy because of dyspepsia. The control group consisted of university staff and students (n = 179). Helicobacter pylori status was determined by antibody testing and bacterial detection. RESULTS: Endoscopic oesophagitis was noted in 40 patients. The IL-1RN 2/2 genotype was significantly more prevalent in the patients with H. pylori-negative oesophagitis than in the control subjects (27% versus 9%; OR 3.574, CI 1.23-10.35, P = 0.034) or in the dyspeptic patients (27% versus 7%; OR 5.089. CI 1.51-17.11, P = 0.009). IL-1beta-511 T/T genotype tended to be more frequent in the H. pylori-negative patients with oesophagitis than in the control subjects (P = 0.071). The strongest association was between the simultaneous carriage of genotypes IL-1RN 2/2 and IL-1beta -511 T/T and H. pylori-negative oesophagitis. where the combined genotype was more prevalent than in the control subjects (23% versus 6%; OR 4.492, CI 1.40-14.46, P = 0.012) or the dyspeptic patients without oesophagitis (23% versus 3%: OR 9.706. CI 2.12-44.42, P = 0.003). CONCLUSIONS: The results indicate that the IL-1RN 2/2 genotype and the carriage of combined genotypes IL-1RN 2/2 + IL-1beta-511 T/T are associated with H. pylori-negative oesophagitis. This is the first report on the association between IL-1 gene polymorphism and oesophagitis.     

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.     

白细胞介素-1基因多态性与消化性溃疡的关系

背景：大量临床流行病学证据表明消化性溃疡发病率的地域差异与宿主免疫遗传因素密切相关,目前宿主炎症因子基因多态性与消化性溃疡的关系正受到广泛关注。目的：探讨白细胞介素（IL）-1B-511、IL-1RN基因多态性与消化性溃疡的关系。方法：选取2008年9月～2009年5月昆明医学院第一附属医院确诊的57例十二指肠溃疡（DU）、38例胃溃疡（GU）以及40例非萎缩性胃炎（NAG）患者。以快速尿素酶试验和Giemsa染色检测幽门螺杆菌（H.pylori）感染,采用PCR-RFLP检测IL-1B-511、IL-1RN基因多态性。分析IL-1基因多态性、H.pylori感染、年龄与不同疾病之间的关系。结果：NAG、DU和GU组之间H.pylori感染率、IL-1B-511、IL-1RN基因型频率的差异无统计学意义。与NAG和DU相比,年龄≥60岁是GU的危险因素（OR=5.650,95%CI：1.811～17.624;OR=3.159,95%CI：1.254～7.955）。IL-1B-511、IL-1RN基因型和H.pylori感染与消化性溃疡类型无关（P〉0.05）。结论：在昆明市,年龄≥60岁是GU的危险因素,IL-1基因多态性与消化性溃疡无关。     

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.     

Role of host interleukin 1β gene (IL-1B) and interleukin 1 receptor antagonist gene (IL-1RN) polymorphisms in clinical outcomes in Helicobacter pylori-positive Turkish patients with dyspepsia

BACKGROUND: Helicobacter pylori infection leads to different clinical outcomes depending on both host and bacterial factors. In a recent study, we identified H. pylori cagE and babA2 genotypes as independent predictors of duodenal ulcer (DU) and gastric cancer (GC) in dyspepsia patients, but no previous studies have examined the role of host-related genetic factors in Turkey. This time our aim was to evaluate whether polymorphisms of the interleukin 1B (IL-1B) and the interleukin 1 receptor antagonist (IL-1RN) genes are important factors in the differential expression of gastroduodenal diseases in H. pylori-positive dyspepsia patients. METHODS: Ninety-three H. pylori-positive patients, 30 with nonulcer dyspepsia (NUD), 30 with DU, and 33 with GC, were investigated. The IL-1B-511 and IL-1B-31 biallelic polymorphisms, and the IL-1RN intron 2 variable number tandem repeat were genotyped by polymerase chain reaction and single-strand confirmation polymorphism analysis. RESULTS: The IL-1RN-1/1 genotype was significantly more prevalent among patients with NUD than among those with GC (chi(2) = 9.270; P = 0.002), and the IL-1RN-1/2 genotype was significantly more common in patients with GC (chi(2) = 6.01; P = 0.014). Multivariate regression analysis showed that cagE, babA2, and IL-1RN-1/2 genotypes were independent predictors of GC, but when patients with benign disorders were grouped together (NUD + DU) and compared with patients with GC, regression analysis disclosed that babA2 (P = 0.000) and IL-1B-31 gene polymorphisms (CC or CT) (P = 0.01) were the only independent markers of GC. CONCLUSIONS: When analyzed together with host genetic factors, the wellestablished bacterial risk factor babA2 seems to be the most important predictor of malignant disorders, and the presence of the IL-1B-31TT genotype emerges as a protective factor against them.     

Effect of interleukin 1 polymorphisms on gastric mucosal interleukin 1beta production in Helicobacter pylori infection

BACKGROUND & AIMS: Although epidemiological studies suggest that interleukin (IL)-1 genetic polymorphisms are involved in Helicobacter pylori-related gastric carcinogenesis, the data are conflicting regarding the effects of these polymorphisms on IL-1beta production. METHODS: IL-1B-511 polymorphism was genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism, and IL-1RN variable number of tandem repeats was determined by PCR. Mucosal IL-1beta levels were measured by enzyme-linked immunosorbent assay. To determine which factors influence mucosal IL-1beta levels, gastric inflammation, and atrophy, multiple regression analyses were performed. RESULTS: We studied 117 H. pylori-infected Japanese patients. Carriers of the IL-1B-511T/T genotype or IL-1RN*2 allele had higher mucosal IL-1beta levels than noncarriers (partial regression coefficient [PRC] +/- SE), TT versus CC: 37.6 +/- 6 [antrum] and 32.1 +/- 6 [corpus] pg/mg protein (P < 0.001 for each), *1/*2 versus *1/*1: 24 +/- 8 [antrum] (P <0.01) and 36.5 +/- 7 [corpus] (P <0.001). Simultaneous carriers of IL-1B-511T/T genotype and IL-1RN*2 allele had the highest IL-1beta levels (82.9 +/- 12 [antrum] and 87.2 +/- 11 [corpus]) and showed a synergistic effect between 2 loci. The *1/*2 carriers were closely related to atrophy (PRC +/- SE; 0.87 +/- 0.4 [antrum] and 0.93 +/- 0.4 [corpus], P < 0.05), whereas being a carrier of the -511T/T genotype was related to severe gastric inflammation. CONCLUSIONS: IL-1 genetic polymorphisms influenced H. pylori-related gastric mucosal IL-1beta levels and were related to gastric inflammation and atrophy, factors thought to be important in gastric carcinogenesis.     

云南哈尼族彝族幽门螺杆菌感染人群胃癌易感基因研究

胃癌的发生是生物、环境、宿主等因素共同作用的结果．宿主遗传因素与幽门螺杆菌（H．pylori）感染后的不同临床结局有关。目的：筛选云南红河州哈尼族彝族Hpylori感染人群的胃癌易感基因,探讨不同基因型和等位基因与H．pylori感染宿主胃癌发病风险的相关性。方法：通过PubMed、CNKI和HapMap数据筛选出12个中国人群胃癌易感相关单核苷酸多态性（SNP）位点,以芯片技术对哈尼族彝族H．pylori感染慢性胃炎和胃癌患者的这些SNP位点进行分型。结果：IL-1β-3IC／T和IL-1β-511C/T位点存在完全连锁不平衡．其基因型（P=0．014）和等位基因频率（P=0．049）在胃癌和胃炎组中有显著差异,-511CT／-31CT（OR=2．256,95％CI：1．048～4．855）和-511TT/-31CC（OR=3．312,95％CI：1．462～7．502）基因型胃癌发病风险显著高于-511CC／-31TT基因型。COX-2．899C／G位点基因型频率在胃癌和胃炎组中有显著差异（P=0．033）,GG基因型胃癌发病风险显著高于CG基因型（OR=2．796,95％CI：1．053～7．423）。TNF—α-238A／G位点基因型频率在胃癌和胃炎组中有显著差异（P=0．037）．AA、AG基因型胃癌发病风险显著高于GG基因型（OR=2．600．95％CI：1．130～5．985）。结论：IL-1β-31C、IL-1β-511T等位基因和COX-2—899GG基因型可增高云南红河州哈尼族彝族Hpylori感染人群的胃癌发病风险,TNF-α-238GG基因型对上述人群的胃癌发生具有保护作用。     

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.     

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.     

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。     

Impact of interleukin-1beta genetic polymorphisms on the development of hepatitis C virus-related hepatocellular carcinoma in Japan

To examine the effects of polymorphisms in the gene encoding proinflammatory interleukin (IL)-1beta in patients infected with hepatitis C virus (HCV) in Japan, we studied 364 patients with chronic HCV infection (146 of whom had hepatocellular carcinoma [HCC] and 218 of whom did not) and 230 healthy control subjects. IL-1B-511 and IL-1RN genotypes were ascertained, and IL-1B-511 genotype T/T was found to be significant risk factors for the development of HCC, indicating that polymorphism in the IL-1B-511 genetic locus is one of the possible determinants of progression of hepatitis C to HCC.     

Interleukin 1B and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma

BACKGROUND & AIMS: Interleukin (IL)-1 gene cluster proinflammatory polymorphisms have been associated with development of gastric atrophy and with increased risk of gastric carcinoma. We aimed to determine the association between IL-1 loci polymorphisms and increased risk of gastric carcinoma in samples from a Portuguese population, and to find whether there was any relationship with the histologic types of gastric carcinoma. METHODS: In a case-control study including 220 controls and 152 patients with gastric carcinoma (intestinal, 76; diffuse, 37; and atypical, 39), both the IL-1B-511 biallelic polymorphism and the IL-1RN penta-allelic variable number of tandem repeats were genotyped. RESULTS: We found a significant association between the IL-1 polymorphisms and increased risk for tumor development in patients with intestinal-type gastric carcinoma. A trend towards an increased risk of tumor development was also observed in patients with diffuse-type gastric carcinoma. No significant relationship was observed in patients with atypical carcinoma. Carriers of IL-1B-511T and IL-1RN*2 homozygotes had increased risk for developing intestinal-type gastric carcinoma with odds ratios of 2.7 (95% confidence interval [CI], 1.5-4.9) and 3.1 (95% CI, 1.5-6.5), respectively. Statistical analysis showed an interaction between the 2 loci with the risk conferred by the IL-1B-511T allele substantially increased (odds ratio, 9.0; 95% CI, 3.5-23.0) in individuals homozygous for the IL-1RN*2 allele. CONCLUSIONS: Our results provide further support to the association between IL-1 gene cluster proinflammatory polymorphisms and increased risk of gastric carcinoma. Furthermore, we found evidence pointing to the existence of a synergistic interaction between the IL-1B and IL-1RN polymorphisms.     

Helicobacter pylori-induced enlarged-fold gastritis is associated with increased mutagenicity of gastric juice, increased oxidative DNA damage, and an increased risk of gastric carcinoma

BACKGROUND AND AIM: The severe inflammation, increased cell proliferation and marked acid inhibition observed in subjects with Helicobacter pylori-associated enlarged-fold gastritis suggest that enlarged-fold gastritis may be a risk factor for gastric carcinoma. The purpose of the present study was to determine whether a relationship exists between enlarged-fold gastritis and gastric carcinoma. METHODS: One hundred and thirty-five H. pylori-positive patients with early gastric carcinoma and 141 age- and sex-matched H. pylori-positive controls without gastric carcinoma were involved in the study. The widths of gastric body folds were measured by double-contrast radiographs. The mutagenicity of gastric juice was assayed using the Ames test and Salmonella typhimurium TA-98 or TA-100 with S9-mix. Levels of 8-hydroxydeoxyguanosine (8-OHdG) in gastric mucosa were examined using high-performance liquid chromatographic-electrochemical detection. RESULTS: An upward shift in the distribution of gastric fold widths in H. pylori-positive patients with early gastric carcinoma was found. Enlarged-fold gastritis (fold width >/=5 mm) was observed in 81% of the patients with gastric carcinoma, compared with 46% of H. pylori-positive controls. The odds ratio for gastric carcinoma increased with increasing fold width to a maximum of 35.5 in persons with fold width >/=7 mm. The prevalence of diffuse-type early gastric carcinoma in the body region increased with increasing fold width. The mutagenicity of gastric juice from the patients with enlarged-fold gastritis was significantly higher than that in H. pylori-negative controls and H. pylori-positive patients without enlarged folds. Mucosal 8-OHdG levels in the body region of patients with enlarged-fold gastritis were significantly higher than in H. pylori-negative controls and H. pylori-positive patients without enlarged-fold gastritis. Eradication of H. pylori significantly decreased the mutagenicity of gastric juice and 8-OHdG levels in the gastric mucosa from patients with enlarged-fold gastritis. CONCLUSION: A significant association is suggested between enlarged-fold gastritis and gastric carcinoma.     

Cytokine gene polymorphisms influence mucosal cytokine expression, gastric inflammation, and host specific colonisation during Helicobacter pylori infection

BACKGROUND AND AIMS: Recent studies linked cytokine gene polymorphisms to H pylori related gastric cancer development. The current study evaluated the role of cytokine gene polymorphisms for mucosal cytokine expression, the gastric inflammatory response, and bacterial colonisation during H pylori infection. PATIENTS AND METHODS: In 207 H pylori infected patients with chronic gastritis, polymorphisms at different loci of the interleukin (IL)-10, IL-1B, IL-1 receptor antagonist (IL-1RN), tumour necrosis factor (TNF)-A, and interferon (IFN)-G genes were genotyped by polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) analysis, and allelic discriminating TaqMan PCR. Mucosal cytokine mRNA copy numbers were determined by real time quantitative PCR. Presence of bacterial virulence factors was investigated by cagA, vacAs1/2, and babA2 PCR. Biopsies were assessed with regard to the degrees of granulocytic/lymphocytic infiltration and the presence of intestinal metaplasia (IM) and atrophic gastritis (AG). RESULTS: Proinflammatory IL-1 polymorphisms (IL-1RN*2(+)/IL-1B-511T/-31C(+)) were associated with increased IL-1beta expression, more severe degrees of inflammation, and an increased prevalence of IM and AG. Carriers of the IL-10-1082G/-819C/-592C alleles (GCC haplotype) had higher mucosal IL-10 mRNA levels than ATA haplotype carriers and were associated with colonisation by more virulent cagA(+), vacAs1(+), and babA2(+) H pylori strains. The TNF-A-307(G/A) and IFN-G+874(A/T) polymorphisms did not influence mucosal cytokine expression or the inflammatory response to H pylori. CONCLUSIONS: Cytokine gene polymorphisms influence mucosal cytokine expression, gastric inflammation, and the long term development of precancerous lesions in H pylori infection. Host polymorphisms are associated with certain bacterial strain types, suggesting host specific colonisation or adaptation. These findings contribute to the understanding of the complex interplay between host and bacterial factors involved in the development of gastric pathology.     

Synergistic effect of Helicobacter pylori virulence factors and interleukin-1 polymorphisms for the development of severe histological changes in the gastric mucosa

Polymorphisms of the IL-1B and IL-1RN genes (which encode interleukin [IL]-1beta and IL-1 receptor antagonist, respectively) have been associated with hypochlorhydria and gastric cancer. We investigated the influence of bacterial virulence factors and host IL-1 polymorphisms on the development of histologic abnormalities in 210 Helicobacter pylori-infected patients with chronic gastritis. cagA(+)/vacAs1(+) H. pylori strains were associated with intestinal metaplasia (IM), atrophic gastritis (AG), and severe inflammation. Carriers of the proinflammatory IL-1B -511T/-31C and IL-1RN*2 alleles had an increased risk for the development of AG, IM, and severe inflammation, with odds ratios (ORs) of 1.7 (95% confidence interval [CI], 0.8-3.4) to 4.4 (95% CI, 1.5-12.9). The highest prevalence of severe gastric abnormalities was found in patients with both host and bacterial high-risk genotypes (cagA(+)/vacAs1(+)/IL-1B -511T/IL-1RN*2), with ORs of 24.8 (95% CI, 5.2-117.3) for severe lymphocytic infiltration, 9.5 (95% CI, 2.8-32.1) for severe granulocytic infiltration, 6.0 (95% CI, 2.4-15.5) for IM, and 2.4 (95% CI, 0.93-6.2) for AG. Combined bacterial/host genotyping thus may provide a clinical tool to identify patients at high risk of developing cancer.     

Relationship between Helicobacter pylori status and serum pepsinogens as serologic markers in atrophic gastritis.

BACKGROUND/AIMS: Serum pepsinogen levels are considered as a non-endoscopic blood test in the diagnosis of atrophic gastritis. The objective of the present study was to investigate whether there is any difference between pepsinogen levels in Helicobacter pylori-positive and -negative patients with atrophic gastritis, and to analyze the relationship between histopathology and pepsinogen levels after treatment in H. pylori-positive patients with atrophic gastritis. METHODS: The study enrolled a total of 30 cases with atrophic gastritis (18 H. pylori-positive and 12 H. pylori-negative). The H. pylori-positive cases received a one-week eradication treatment. Initially for all and after the treatment for H. pylori-positive cases, serum pepsinogen I and II levels, anti-H. pylori IgG titration and histopathologic analysis were carried out. RESULTS: In the H. pylori-positive patients with atrophic gastritis, the levels of pepsinogen I and pepsinogen I/II ratio were lower while the levels of pepsinogen II were higher compared to the H. pylori-negative patients (p<0.05 for all). The post-treatment serum pepsinogen I levels and pepsinogen I/II ratios did not change in the H. pylori-positive group, while the levels of pepsinogen II, H. pylori antibody titration and gastric atrophy degree remarkably decreased (p<0.05 for all). CONCLUSIONS: In atrophic gastritis, the levels of serum pepsinogen and pepsinogen I/II ratio show a difference in H. pylori-negative versus -positive cases. Additionally, the usage of pepsinogen II as a serum marker in predicting the eradication of H. pylori with atrophic gastritis could be more reliable than pepsinogen I or the I/II ratio.     

Association of polymorphisms of interleukin-1 beta gene and Helicobacter pylori infection with the risk of gastric ulcer

BACKGROUND/AIMS: Interleukin-1 beta (IL-1 beta) plays an important role in gastric inflammation and physiology. Functional polymorphisms of IL-1 beta gene have been related to different risks of gastric cancer and duodenal ulcer but their role in gastric ulcer remains unknown. In this study, we investigate a plausible association between gastric ulcer and the polymorphisms in the IL-1 beta and IL-1 receptor antagonist (IL-1RN) genes. The relationships among the cytokine genotyping, other environmental risks such as Helicobacter pylori infection and smoking, and clinical characteristics of gastric ulcer were also determined. METHODOLOGY: Peripheral blood DNAs from 120 unrelated Taiwan Chinese patients with gastric ulcer and 238 ethnically matched healthy controls were genotyped for the promoter (position -31 and -511) and Taq I polymorphism (position +3954) in the IL-1 beta gene and the variable number of tandem repeats polymorphisms in intron 2 of the IL-1RN gene. The status of Helicobacter pylori infection was determined by serology. RESULTS: The seropositive rate of Helicobacter pylori (95/120 vs. 134/238, OR: 2.95, 95%CI 1.77-4.91), habitual smoking (67/120 vs. 82/238, OR: 2.40, 95%CI 1.54-3.77) and blood group O (63/120 vs. 98/238, OR: 1.55, 95%CI 1.0-2.41) were significantly higher in patients with gastric ulcer than controls. The distributions of allele frequencies of IL-1 beta (-31 C/T or -511 C/T or +3954) and IL-1RN were similar between patients with gastric ulcer and controls. No significant differences were observed, including those analyzed after stratification of the infected population and by the ulcer subgroup. CONCLUSIONS: Our data suggested that Helicobacter pylori infection, cigarette smoking, and blood group O are risk factors of gastric ulcer and IL-1 beta or IL-1RN polymorphisms do not influence susceptibility to gastric ulcer in a Taiwanese population.     

Association of interleukin 1B gene polymorphism and gastric cancers in high and low prevalence regions in China

AIM: Our aim was to study the relationship between interleukin 1B (IL-1B) polymorphism, Helicobacter pylori infection, and gastric cancer in high prevalent (Shanxi) and low prevalent (Guangdong) regions in China. METHOD: Genomic DNA was extracted from peripheral blood of 192 healthy volunteers, 84 gastric cancer patients from Guangdong and 169 healthy volunteers, and 86 gastric cancer patients from Shanxi. Polymorphisms in IL-1B that encodes IL-1beta and IL-1RN that encodes IL-1 receptor antagonist were analysed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). These polymorphic sites include promoter regions of IL-1B at positions +3954, -511 (C-T transition), and -31 (T-C transition), and IL-1RN variable tandem repeats. RESULTS: In the low prevalence region, the frequencies of the IL-1B +3954 T/T and IL-1RN *2/*2 genotypes were similar. IL-1B -511T/T genotype frequency was significantly higher among patients with gastric cancer (25.0%) than control subjects (12.5%) (chi2=6.7, p=0.01). In the high prevalence region, the frequencies of the IL-1B +3954T/T and -511T/T genotypes and the IL-1RN *2/*2 genotype in the cancer and control groups were similar. IL-1B -31C/C genotype frequency was significantly higher among patients with gastric cancer (90.0%) than controls (78.0%) (chi2=5.0, p=0.025). Compared with the low prevalence region, control subjects from the high prevalence region had a higher frequency of the IL-1B -511T/T genotype (23.0% v 12.5%; chi2=7.0, p<0.008). While H pylori infection alone had only a modest effect on the risk of gastric cancer development (odds ratio (OR) 5.0 (95% confidence interval (CI) 1.5-16.3)), combined with the IL-1B -511T/T genotype the risk was markedly elevated (OR 17.1, 95% CI 3.8-76.4). CONCLUSION: IL-1B -511T/T genotypes are associated with gastric cancer in China. The effect of IL-1B polymorphism is less obvious in areas of high prevalence for gastric cancer.