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The aim of this study was to investigate the effect of consuming small amounts of beer or a nonalcoholic beer taste beverage (non-beer) on gastric emptying and the polymorphisms in alcohol metabolism-related enzyme-encoding genes. Twenty male healthy volunteers were questioned regarding their alcohol consumption status, and body measurement was performed. The genetic polymorphisms in ADH1B (rs1229984, Arg47His) and ALDH2 (rs671 Glu487Lys) were analyzed. The subjects consumed 150 mL of beer or non-beer once per week, followed by the ingestion of 200 kcal of the test nutrient containing 13 C-acetate 15 min later, after which the subjects' exhalations were collected up to 120 min. The concentration peak of 13 C was measured as Tmax. Diamine oxidase (DAO) activity for the marker of small intestinal function activity was also measured the day after the test. Gastric emptying was significantly slower in the group that consumed a small amount of beer, and in daily beer consumption group, and also in the ADH1B *2/*2, ALDH2 *1/*2 genotypes compared to non-beer drinking group. DAO values were not significantly changed between beer and non-beer group. The consumption of even a small amount of beer and the polymorphisms in ADH1B / ALDH2 affects gastric motility.

Background: Aberrant methylation patterns in CpG island are known to be influential in gene silencing. Histamine plays important physiological roles in the upper gastrointestinal tract and acts via the H2 receptor. We report an investigation into the effect of HRH2 promoter polymorphism (rs2607474 G > A) on the methylation of DAPK and CDH1., Methods: Non cancerous gastric mucosa samples were obtained from 115 subjects with gastric cancer (GC) and 412 non-cancer subjects (non-GC). Methylation status of genes was determined by MSP. The genotyping of rs2607474 was performed by PCR-SSCP., Results: Methylation of DAPK and CDH1 was observed in 296 and 246 subjects, respectively. The frequency of CDH1 methylation in the subjects with GC was significantly lower in cancer lesion than in non cancerous mucosa, whereas that of DAPK methylation was not different. The allelic distribution of rs2607474 was 401GG, 119GA and 7AA. The GG homozygote was associated with a significantly increased risk for methylation of both DAPK and CDH1 (p < 0.0001 and p = 0.0009, respectively). In the non-GC subjects or more than 60 years of age, GG homozygote was more closely associated with both DAPK and CDH1 methylation. However, this genotype did not show an increased risk for the development of methylation of both genes in patients with GC. In H. pylori negative subjects, GG homozygote showed an increased risk for the methylation of both DAPK and CDH1 (p = 0.0074 and p = 0.0016, respectively), whereas this genotype was associated with an increased risk for the development of DAPK methylation in H. pylori positive subjects (p = 0.0018). In addition, in subjects older than 60 years of age, atrophy and metaplasia scores were significantly higher in the GG homozygote (p = 0.011 and p = 0.039, respectively) and a significant correlation was observed between age and atrophy or metaplasia., Conclusions: Our results suggest that rs2607474 GG homozygote confers a significantly increased risk for age- and inflammation-related DAPK and CDH1 methylation.

Aim: To clarify the association between a polymorphism -449 C>G (rs72696119) in 5'-UTR of NFKB1 with ulcerative colitis (UC)., Methods: The studied population comprised 639 subjects, including patients with UC (UC cases, n = 174) and subjects without UC (controls, n = 465). We employed polymerase chain reaction-single strand conformation polymorphism to detect the gene polymorphism., Results: The rs72696119 G allele frequencies in controls and UC cases were 33.4% and 38.5%, respectively (P = 0.10). Genotype frequency of the GG homozygote in UC cases was significantly higher than that in controls (P = 0.017), and the GG homozygote was significantly associated with susceptibility to UC [odds ratio (OR), 1.88; 95%CI, 1.13-3.14]. In male subjects, the GG homozygote was associated with an increased risk for UC (OR, 3.10; 95%CI, 1.47-6.54; P = 0.0053), whereas this association was not found in female subjects. In addition, the GG homozygote was significantly associated with the risk of non-continuous disease (OR, 2.06; 95%CI, 1.12-3.79; P = 0.029), not having total colitis (OR, 2.40; 95%CI, 1.09-3.80, P = 0.040), disease which developed before 20 years of age (OR, 2.80; 95%CI, 1.07-7.32, P = 0.041), no hospitalization (OR, 2.28; 95%CI, 1.29-4.05; P = 0.0090) and with a maximum of 8 or less on the UCDAI score (OR, 2.45; 95%CI, 1.23-4.93; P = 0.022)., Conclusion: Our results provide evidence that NFKB1 polymorphism rs72696119 was significantly associated with the development of UC. This polymorphism influences the susceptibility to and pathophysiological features of UC.

Background/aims: We investigated the effect of IL-1β and TNF-α polymorphisms, and its synergistic effect with age, gender and H. pylori status on the gastric pre-malignant condition., Methodology: IL-1β-31(T>C) and -511(C>T) and TNF-α-857 (C>T) polymorphisms were genotyped in 123 cancer free subjects. Degree of histological gastritis in both antrum and corpus, and extension of endoscopic gastric atrophy were also evaluated., Results: Significant associations were found between degrees of mononuclear cell infiltration (p=0.007) and atrophy (p=0.01) in the antrum with IL-1β-31(T>C) polymorphism, and degree of endoscopic gastric atrophy with both IL-1β-31(T>C), -511(C>T) polymorphisms (p=0.03, 0.04, respectively). When subjects were divided into the 3 groups according to the histological severity of gastric mucosal atrophy: the non-atrophic gastritis (NA) group (atrophy score=0 and metaplasia score=0), the severe atrophic gastritis (SA) group (atrophy score>=2 or metaplasia score>=2), and the mild atrophic gastritis (MA) group (all others), synergistic effect was found between numbers of IL-1β-31C, IL-1β-511T variant alleles with co-factors on the development of gastric atrophy in the antrum (gender + H. pylori + number of IL-1β-31C allele: p=0.001, age + gender + H. pylori + number of IL-1β-31C allele: p=0.0008, gender + H. pylori + number of IL-1β-511T allele: p=0.016, age + gender + H. pylori + number of IL-1β-511T allele: p=0.013), while such association was found for TNF-α-857 T allele in the antrum and all genotypes in the corpus., Conclusions: IL-1β-31C, IL-1β-511T variant alleles may accelerate gastric mucosal inflammation and atrophy, not only by themselves, but also through the interaction with co-factors.

Background: CpG island aberrant methylation is shown to be an important mechanism in gene silencing. The important role of IL-17 in inflammatory response to H. pylori colonization has been indicated. We investigated the influence of IL17A polymorphisms, -197 G > A (rs2275913) and *1249 C > T (rs3748067), on the methylation of DAPK and CDH1., Methods: Gastric mucosal samples were obtained from 401 subjects without malignancies. Methylation status of gene was determined by MSP. The genotyping of IL17A was performed by PCR-SSCP., Results: Methylations of DAPK and CDH1 were seen in 196 and 149 of all 401 subjects, respectively. Overall, *1249 T carrier was associated with a decreased risk for DAPK methylation, whereas -197 G > A was not. In the subjects older than 60 years old, *1249 T carrier was more strongly associated with gene methylation and -197 A carrier tended to be associated with an increased risk for CDH1 methylation. When evaluating by inflammation promoting haplotype (-197 mutant carrier with *1249 homozygote), this haplotype had a more strongly increased risk for both DAPK and CDH1 methylations in comparatively older subjects. Both atrophy and metaplasia scores were significantly increased with age in -197 A carrier or *1249 CC homozygote, whereas were not in -197 GG homozygote or *1249 T carrier. PG I/II ratio was more significantly decreased in -197 A carrier than in GG homozygote under influence of H. pylori infection., Conclusions: In -197 A allele carrier with *1249 CC homozygote, the methylations of both DAPK and CDH1 may be increased gradually, but more rapidly than the other genotypes, with age and altered gastric mucosal structure induced by H. pylori infection.

Background and Aim: Histamine plays important physiological roles in upper gastrointestinal tract and acts via the H2 receptor. A polymorphism -1018 G>A (rs2067474) was identified in an enhancer element of the HRH2 promoter. We attempted to clarify the associations of this polymorphism with the progression of gastric mucosal atrophy., Methods: Gastric mucosa samples were obtained from 398 subjects with no malignancies. The rs2067474 genotype was determined by PCR-SSCP method. The degree of gastritis was assessed in 366 subjects and serum pepsinogen (PG) I/II levels were measured in 108 subjects. The subjects with atrophy score higher or equal to 2 and metaplasia score higher or equal to1 were classified into the severe atrophic gastritis group (SA group)., Results: The -1018G>A minor allele frequencies in SA and non-SA groups were 8.02% and 13.3%, respectively (p=0.057). The -1018 GG homozygote had a significantly high risk for gastric mucosal atrophy (OR: 2.03, 95%CI: 1.03-4.01, p=0.042). In H. pylori positive subjects, GG homozygote was a more significant risk factor for gastric mucosal atrophy (OR: 2.32, 95%CI: 1.12-4.81, p=0.023). In addition, in the subjects older than 60 years, GG homozygote had also a significant risk for gastric mucosal atrophy (OR: 2.63, 95%CI: 1.15-6.00, p=0.022). In -1018 GG homozygote, PG I/II ratio was significantly lower in H. pylori positive than negative subjects and was significantly decreased with age (p=0.0032 by ANOVA), whereas it was not in the A carrier., Conclusions: Our results suggest that HRH2 -1018 GG homozygote is a risk factor for the severity of gastric mucosal atrophy under the influence of H. pylori infection, especially in older subjects.

Background/aims: There have been reports showing the protective role of inducible heat-shock protein (HSP) 70 in gastric epithelial cells. An A to G transition at the 1267 position HSP70-2 gene has been shown to be associated with a different level of HSP70 mRNA expression. We aimed to clarify the effect of HSP70-2 polymorphism on the risk of peptic ulcer diseases in a Japanese population., Methodology: A total of 519 subjects participated in this study. All subjects underwent upper gastroscopy. Restriction fragment length polymorphism analysis was performed for polymorphisms at 1267 of HSP70-2 gene in all the subjects., Results: After gastroscopy, 109, 53 and 357 subjects were diagnosed as gastric ulcer, duodenal ulcer and non-ulcer subjects, respectively. Although, there were no significant differences of HSP70-2 genotype distributions among nonulcer subjects, overall ulcer, gastric and duodenal ulcers when the subjects were divided into two groups according to age distribution, logistic regression analysis showed that the BB genotype increased the risk of duodenal ulcer in subjects 60 years and older. (Gender, status of H. pylori infection and NSAID use adjusted OR=3.12, 95%CI=1.33-7.35, p=0.009)., Conclusions: It appears that polymorphism of HSP70-2 gene is not directly associated with the susceptibility to peptic ulcer diseases but BB genotype is associated with an increased risk of duodenal ulcer in older subjects in the Japanese population.

Background: Genetic factors related to DNA repair or xenobiotic pathways might confer different degrees of susceptibility to Helicobacter pylori (H. pylori)-related gastric carcinogenesis. The association between XRCC1 Arg399Gln, and Arg194Trp, GSTP1 Ile104Val, and GSTT1, GSTM1 null polymorphisms with gastric intestinal metaplasia, severity of histological gastritis, and peptic ulcer diseases were evaluated in a Japanese population., Patients and Methods: XRCC1 Arg399Gln and Arg194Trp, GSTP1 Ile104Val and GSTT1, GSTM1 null polymorphisms were genotyped in 280 cancer-free individuals, including 52 gastric and 31 duodenal ulcer patients., Results: Among the five polymorphisms, a significant association between the GSTT1 and GSTM1 null genotypes and increased risk of intestinal metaplasia was found (GSTT1 null: OR=2.42, 95% CI=1.28-4.60, p=0.007, GSTM1 null: OR=2.18, 95% CI=1.15-4.13, p=0.019). When the severity of gastric atrophy was classified into the following three groups: non-atrophy (NA) (atrophy score=0 and metaplasia score=0); severe atrophy (SA) (atrophy score≥2 or metaplasia score≥2) and mild atrophy (MA) (all others), both the GSTT1 and GSTM1 null genotypes held significantly higher risk for developing more severe gastric atrophy (GSTT1 null, SA vs. others: OR=1.95, 95% CI=1.07-3.52, p=0.028, GSTM1 null, NA vs. others: OR=2.57, 95% CI=1.16-5.67, p=0.019, SA vs. others: OR=1.90, 95% CI=1.06-3.42, p=0.032). A significant association was also found between GSTM1 null genotype and increased risk of ulcer diseases (all ulcers: OR=2.42, 95% CI=1.37-4.26, p=0.002, gastric ulcer: OR=2.18, 95% CI=1.11-4.29, p=0.025, duodenal ulcer: OR=2.62, 95% CI=1.15-6.00, p=0.023)., Conclusion: Both the GSTT1 and GSTM1 null genotypes are associated with gastric pre-malignant conditions.

Background: Genetic factors, related to DNA repair or xenobiotic pathways might confer different degrees of susceptibility to gastric carcinogenesis. CpG island hyper methylation (CIHM) is a major event in gastric carcinogenesis. We evaluated the association between XRCC1, GSTP1, GSTT1 and GSTM1 polymorphisms with CIHM status in non-neoplastic gastric mucosa., Methods: XRCC1 Arg399Gln, and Arg194Trp, GSTP1 Ile104Val, and GSTT1, GSTM1 null polymorphisms were genotyped in 415 cancer free subjects, in relation to four candidate CpG (p14, p16, DAP-kinase and CDH1) loci, assessed by Methylation-Specific-Polymerase Chain Reaction (MSP). CIHM high was defined as two or more CpG islands methylated., Results:  Significant association between XRCC1 codon 399 Gln/Gln genotype and reduced susceptibility to CIHM of DAP-kinase (adjusted OR = 0.30, 95%CI = 0.13-0.71, p = .0055) and CIHM high (OR = 0.42, 95%CI = 0.19-0.97, p = .04). XRCC1 codon 399 Gin/Gln genotype also presented lower number of CIHM when compared with both Arg/Gln, and Arg/Arg + Arg/Gln genotypes (p = .02, .046, respectively) When subjects were divided according to age (>50 and <50), an association was found between GSTM1 null genotype and increased susceptibility to CIHM high in the 50 years and older generations (OR = 1.63, 95%CI = 1.01-2.62, p = .045)., Conclusion: XRCC1 codon 399 Gln/Gln genotype is associated with reduced susceptibility to CIHM especially DAP-kinase. GSTM1 null genotype may increase the susceptibility to CIHM especially in older patients. Genetic factors, related to DNA repair or xenobiotic pathways may have a role in CIHM-related gastric carcinogenesis., (© 2011 Blackwell Publishing Ltd.)

Background: There is evidence that changes in MDR1 function and/or expression contribute to the pathogenesis of inflammatory disorders of the gastrointestinal tract., Aims: We aimed to investigate the effect of C3435T polymorphism of the MDR1 gene on histological chronic gastritis, and on the risk of peptic ulcer diseases., Methods: Restriction fragment length polymorphism analysis was performed for polymorphisms at C3435T in the MDR1 gene in 556 cancer-free subjects including 116 gastric and 60 duodenal ulcers, and 380 non-ulcer subjects. Gastritis scores in the antrum were assessed according to the updated Sydney system in 384 subjects., Results: We did not find a significant association between MDR1 genotype and gastritis scores in any of the 384 subjects. However, the 3435T carrier was significantly associated with a higher degree of neutrophil infiltration in H. pylori-positive subjects (CC vs. T carrier: p=0.0495). When the H. pylori positive subjects were divided according to generation, the 3435T carrier was significantly associated with a higher degree of neutrophil infiltration in subjects more than 65 years of age (CC vs. T carrier: p=0.03). Also, the MDR1 3435 TT genotype was significantly associated with a higher degree of atrophy and intestinal metaplasia in the same generation (atrophy, TT vs. C carrier: p=0.038, intestinal metaplasia, TT vs. C carrier: p=0.016). No association was found between MDR1 genotypes and risk of peptic ulcer diseases., Conclusions: It appears that the C3435T polymorphism of MDR1 influences H. pylori-related inflammatory conditions in the stomach, especially in older subjects.

Background: CpG island hypermethylation of tumor suppressor genes is highly involved in gastric carcinogenesis, and enhanced cell proliferation could accelerate this process. Cyclin D1 regulates cell cycle function and may play a role in methylation-related carcinogenesis., Aims: We investigated the association between Cyclin D1 gene G870A polymorphism and the methylation status of tumor suppressor genes in gastric cancer., Methods: Polymorphisms at G870A in the Cyclin D1 gene were genotyped, and methylation status of the p14, p16, DAP-kinase, and CDH1 genes were determined by methylation-specific-polymerase chain reaction in 139 gastric cancer tissues. CIHM high was defined as three or more methylated CpG islands., Results: Although no association was found between methylation status and different stages and Lauren's subtypes, patients with CIHM of DAP-kinase showed significantly worse survival than those without (p = 0.017). In addition, the number of methylated sites was also associated with survival curves (p = 0.0397). The 870G carrier a significantly lower prevalence of CIHM high compared to the AA genotype in advanced-stage gastric cancer (adjusted OR = 0.32, p = 0.047). A weak correlation between the same genotypes and CIHM of p14 were found in the same subtype (adjusted OR = 0.32, p = 0.052). The mean methylation number was significantly lower in G carriers than in AA genotypes in advanced-stage gastric cancer (p = 0.017)., Conclusions: Genetic polymorphism of CCND1 is associated with CIHM status in gastric cancer, especially in the advanced stage, but is independent of clinico-pathological features.

Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator, which plays a pivotal role in inflammatory and immune diseases. We attempted to clarify the association of functional polymorphisms of MIF gene promoter with the development of gastro-duodenal ulcer. The study was performed in 471 stocked DNAs obtained from the subjects, including 93 healthy volunteers, with no evidence of gastric malignancy. We employed the PCR-SSCP method to detect gene polymorphisms. In all 471 DNAs, 92 and 43 were obtained from gastric and duodenal ulcer patients, respectively. By an unadjusted analysis, infection with Helicobacter pylori (H. pylori), male gender and non-steroidal anti-inflammatory drug (NSAID/aspirin) use were significantly associated with a risk for developing a gastric ulcer, whereas MIF promoter polymorphisms were not. On the other hand, infection with H. pylori, male gender and 7-CATT repeat at position -794 were significantly associated with the development of a duodenal ulcer, whereas NSAID/ aspirin use was not. By the analysis after adjustment for age, gender, NSAID/aspirin use and H. pylori infection status, 7/7-CATT homozygote had a significantly increased risk for the development of duodenal ulcers (OR, 6.31; 95% CI, 1.50-26.6; p=0.012). No factors were significantly associated with the development of peptic ulcers in NSAID/aspirin users. Our results suggested that tetranucleotide repeat polymorphism of MIF gene promoter might be associated with the development of duodenal ulcers.

CpG island hyper-methylation (CIHM) is one of the major events in the gastric carcinogenesis. IL-17A, -17F and MIF have a crucial role in the gastric inflammation and carcinogenesis. Recently, we showed that the genetic polymorphisms of MIF-794-CATT repeat are associated with CIHM status in the non-neoplastic gastric mucosa. Consequently, the CIHM status in the gastric cancer tissue, in relation to IL-17A (-197G>A), -17F (7488T>C), and MIF (-173G>C and -794 tetranucleotide repeats) polymorphisms was investigated. Gastric cancer tissues were obtained from 102 patients. CIHM of p14, p16, DAP-kinase and CDH1 genes were determined by methylation-specific polymerase chain reaction (MSP). CIHM high was defined as three or all CpG islands methylated. We employed the PCR-SSCP (multiplex PCR for IL-17A and -17F) method to detect the gene polymorphisms. We did not find significant association between CIHM status and IL-17F (7488T>C) and MIF (-173G>C) polymorphisms. However, concerning the IL-17A (-197G>A) polymorphism, we found that IL-17A G carrier (GG+GA) held a significantly higher risk of CIHM of p16 (OR=11.22, 95% CI=1.38-91.17, p=0.024) and CIHM high (OR=3.51, 95% CI=1.15-10.68, p=0.027). An association was also found between the 7-CATT repeat carrier (5/7 + 6/7 + 7/7) of the MIF polymorphism (-794-CATT) and reduced risk of CIHM of CDH1 (OR=0.36, 95% CI=0.14-0.92, p=0.032). No association was found between CHIM status and homozygote genotypes of each repeat (-794-CATT 5/5, 6/6, and 7/7). The present results provided evidence that the genetic polymorphisms of IL-17A, and MIF-794-CATT repeat are associated with CIHM status in the gastric cancer. Genetic polymorphisms of IL-17A, and MIF-794-CATT repeat may be involved in methylation-related carcinogenesis in the stomach.

A complex interaction of host genetic and environmental factors may be relevant in the development of Helicocobacter pylori-related gastric carcinogenesis. We investigated the effect of vascular endothelial growth factor (VEGF) gene polymorphisms on the risk of gastric cancer (GC) and peptic ulcer diseases in a Japanese population. The G1612A(rs10434) and C936T(rs3025039) polymorphisms in the 3' untranslated region (3'-UTR) of VEGF gene were genotyped in a total of 844 subjects including 385 GC, 143 ulcer including 98 gastric ulcer (GU), 45 duodenal ulcer (DU), and 316 nonulcer subjects. The 1612A carrier held a significantly higher risk of GC when compared to both noncancer and nonulcer (overall noncancer vs. GC; OR = 1.61, 95% CI = 1.17-2.21, P = 0.0038, nonulcer vs. GC; OR = 1.54, 95% CI = 1.07-2.22, P = 0.0197). The 1612A carrier was more closely associated with an increased risk of noncardiac cancer (OR = 1.64, 95% CI = 0.17-2.21, P = 0.0038), lower third cancer (OR = 1.97, 95% CI = 1.30-3.00, P = 0.002), and Lauren's diffuse-type cancer (OR = 1.75, 95% CI = 1.24-2.46, P = 0.001), while the same genotype was not associated with the progression of GC. The C936T genotype was not associated with a risk of GC and its progression. Both the G1612A and C936T genotypes were not associated with the risk of peptic ulcer diseases. Our data suggest that the G1612A, but not C936T polymorphisms in the 3'-UTR of VEGF gene is associated with the susceptibility to GC in the Japanese population.

CpG island hyper-methylation (CIHM) is one of the major events in the gastric carcinogenesis and also occurs in non-neoplastic gastric mucosa. IL-17A, -17F and MIF have a crucial role in the gastric inflammation and carcinogenesis. The CIHM status in the non-cancerous gastric mucosa, in relation to IL-17A (-197G>A, rs2275913), -17F (7488T>C, rs763780) and MIF (-173G>C and -794 tetranucleotide repeats) polymorphisms was investigated. Gastric mucosa samples were obtained from 121 cancer free subjects. CIHM of p14, p16, DAP-kinase and CDH1 genes were determined by methylation-specific polymerase chain reaction (MSP). CIHM high was defined as three or all CpG islands methylated. We employed the PCR-SSCP (multiplex PCR for IL-17A and -17F) method to detect the gene polymorphisms. No association were found between CIHM status and L-17A (-197G>A), IL-17F (7488T>C) and MIF (-173G>C) polymorphisms. MIF 5-CATT repeat carrier (5/5+5/6+5/7) held a significantly higher risk of CIHM of DAP-kinase (OR=2.33, 95% CI=1.07-5.09, p=0.03) and CIHM high (OR=3.63, 95% CI=1.31-10.08, p=0.01). Weak association was also found between the same genotype and increased risk of CIHM of p16 (OR=2.45, 95% CI=0.90-6.68, p=0.08) and CDH1 (OR=2.23, 95% CI=0.94-5.32, p=0.07). 6-CATT repeat carrier (5/6+6/6+6/7) was significantly associated with reduced risk of CIHM of p16 (OR=0.31, 95% CI=0.11-0.90, p=0.03), CDH1 (OR=0.40, 95% CI=0.17-0.98, p=0.045), DAP-kinase (OR=0.37, 95% CI=0.17-0.83, p=0.02) and CIHM high (OR=0.25, 95% CI=0.09-0.74, p=0.01). -7-CATT repeat carrier (6/7+7/7) was weakly associated with reduced risk of CIHM of p16 (OR=0.34, 95% CI=0.10-1.13, p=0.08), DAP-kinase (OR=0.43, 95% CI=0.17-1.06, p=0.07) and CIHM high (OR=0.38, 95%CI=0.12-1.20, p=0.098). The present results provided the first evidence that the genetic polymorphisms MIF polymorphism is associated with CIHM status in the human gastric mucosa. Genetic polymorphisms of MIF-794-CATT repeat may be involved in methylation related carcinogenesis in the stomach.

Background: Heat-shock protein (HSP) 70 plays essential roles in cellular response to a variety of environmental stresses or unfavorable conditions. A to G transition at the 1267 position of the HSP70-2 gene confers different levels of HSP70 mRNA expression. We aimed to clarify the effect of HSP70-2 polymorphism on the risk of premalignant condition, on the degree of acute or chronic inflammation in the stomach., Patients and Methods: A total of 378 individuals participated in this study. Restriction fragment length polymorphism analysis was performed for polymorphisms at 1267 of HSP70-2 gene. Prevalence of intestinal metaplasia was investigated histologically and the degree of histological gastritis in the antrum was classified according to the updated Sydney System., Results: Although a direct association was not observed between HSP70-2 polymorphism and prevalence of intestinal metaplasia, a significant association was found between the BB genotype and lower metaplasia score in individuals who were Helicobacter pylori (H. pylori) positive and aged 60 years or older (BB vs. A carriers; 0.84+/-0.95 vs. 1.23+/-1.01, p=0.0197). When individuals were divided into 3 groups according to the severity of gastric mucosal atrophy: non-atrophic gastritis (NA) group (atrophy score=0 and metaplasia score=0), severe atrophic gastritis (SA) group (atrophy score > or =2 or metaplasia score > or =2), and mild atrophic gastritis (MA) group (all others), the BB genotype was associated with a lower risk of severe atrophy in the SA sub-group (adjusted odds ratio=0.37, 95% confidence interval =0.16-0.84, p=0.0172)., Conclusion: The BB genotype of HSP70-2 gene is associated with a reduced risk of gastric pre-malignant condition in H. pylori-infected older individuals.

Unlabelled: DNA methylation is one of the major events in the early process of gastric carcinogenesis and also occurs in non-neoplastic gastric mucosa. Catechol-O-methyltransferase (COMT) catalyzes the methylation of various endobiotic and xenobiotic substances, and protects DNA from oxidative damage. The association between a common functional polymorphism of COMT Val158Met and DNA methylation status in the stomach was investigated., Patients and Methods: One hundred and sixty-nine gastric mucosa samples from non-cancer patients were obtained by endoscopy. The promoter methylation status of p14 and p16 was determined by methylation-specific PCR (MSP). The COMT Val158Met polymorphism was detected by PCR-restriction fragment length polymorphism (RFLP)., Results: CpG island methylation was observed in 32.5% of the p14, and 37.9% of the p16. The methylation status of both p14 and p16 was not associated with gender or age, while p16 methylation was strongly associated with Helicobacter pylori infection (OR=4.71, 95% CI=2.35-9.46, p<0.0001). The Val/Val genotype held a significantly higher risk of p16 methylation (OR=3.27, 95% CI=1.05-10.25, p=0.0418)., Conclusion: The COMT polymorphism may influence the susceptibility to gene methylation in the gastric mucosa. The promoter CpG island of p16 gene, but not of p14 may be one of the specific regions whose methylation is closely influenced by the COMT polymorphism.

Background/aims: A complex interaction of genetic and environmental factors is relevant in gastric carcinogenesis. Cyclin D1 (CCND1) is known to regulate function in G1 arrest and therefore, may play an important role in carcinogenesis. The present study aimed to clarify the effect of G870A polymorphism of the CCND1 gene on the risk of gastric cancer (GC) in a Japanese population., Methodology: Restriction fragment length polymorphism analysis was performed for polymorphisms at 870GA in the CCND1 gene in 392 GC and 359 cancer-free subjects including 203 H. pylori positive gastritis and 156 H. pylori negative healthy stomach, Results: Non significant association was found between CCND1 G870A genotypes and risk of GC when compared to that of all non-cancer subjects (AA vs. GG+GA: OR = 1.13, 95% CI = 0.81-1.58, A carrier vs. GG: OR = 1.13, 95% CI = 0.81-1.56), healthy stomach(AA vs. GG+GA: OR = 1.27, 95% CI = 0.81-2.00, A carrier vs. GG: OR = 1.13, 95% CI = 0.8-1.84) and gastritis. (AA vs. GG+GA: OR = 1.03, 95% CI = 0.7-1.53, p = 0.92, A carrier vs. GG: 1.06, 95% CI = 0.72-1.56, p = 0.77) No association was found between CCND1 genotypes and any of clinico-pathological features of GC., Conclusion: It appears that the G870 polymorphism of CCND1 is not associated with the risk of GC in the Japanese population.

Host genetic factors may play a key role in determining the long-term outcome of the Helicobacter pylori infection. Toll-like receptor 4 (TLR4) and CD14-mediated recognition of lipo-polysaccharide (LPS) is required for efficient recognition of gram-negative bacterial infections. We investigated the effects of common polymorphisms of TLR4 Asp299Gly, Thr399Ile, and CD14 promoter-C159T on the risk of gastric cancer including its subtypes and clinicopathologic features. We also investigated the effects of these polymorphisms on histologic degree of H. pylori-induced gastritis. The study was performed in 149 gastric cancer (GC) cases [mean age 64.0 +/- 12.4, M:F = 109:40] and 94 patients without evidence of GC (mean age 64.1 +/- 12.3, M:F = 65:25, Peptic ulcer diseases = 43.6%, gastritis = 56.4%) as the control group. TLR4 Asp299Gly, Thr399Ile, and CD14 promoter-C159T were determined by PCR-RFLP in all the patients. Gastritis scores of non-cancerous gastric mucosa were assessed according to the updated Sydney system in H. pylori-positive subjects (n = 179). The frequencies of CD14-260 TT and T carrier were significantly lower in patents with intestinal-type gastric cancer than in controls (OR = 0.31; 95%CI = 0.12-0.78, OR = 0.38; 95%CI = 0.18-0.81, respectively). Compared to patients older than 61 years, the atrophy score in antrum was significantly lower in TT and CT patients. TLR4 Asp299Gly and Thr399Ile were not detected in all the patients. Our data suggests that CD14 promoter-159TT and T carrier were associated with a lower risk of developing gastric mucosal atrophy in H. pylori-infected patients of more than 61 years of age, and these genotypes may reduce the risk of intestinal-type gastric cancer.

Background: Inflammation is a key factor in the process of carcinogenesis from chronic gastritis induced by Helicobacter pylori. Selenoprotein S (SEPS1) is involved in the control of the inflammatory response in the endoplasmic reticulum (ER). Recently the -105G>A polymorphism in the promoter of SEPS1 was shown to increase pro-inflammatory cytokine expression. We examined the association between this polymorphism and the risk of gastric cancer., Methods: We took stomach biopsies during endoscopies of 268 Japanese gastric cancer patients (193 males and 75 females, average age 65.3), and 306 control patients (184 males and 122 females, average age 62.7) and extracted the DNA from the biopsy specimens. All subjects provided written informed consent. For the genotyping of the SEPS1 promoter polymorphism at position -105G>A, PCR-RFLP methods were used and the PCR products were digested with PspGI. Logistic-regression analysis was used to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusting for age, sex, and H. pylori infection status., Results: Among cases, the distribution of genotypes was as follows: 88.4% were GG, 11.2% were GA, and 0.4% were AA. Among controls, the distribution was as follows: 92.5% were GG, 7.2% were GA, and 0.3% were AA. Among males, carrying the A allele was associated with an increased odds of gastric cancer, compared with the GG genotype (OR: 2.0, 95% CI 1.0-4.1, p = 0.07). Compared with the GG genotype, carrying the A allele was significantly associated with increased risks of intestinal type gastric cancer (OR: 2.0, 95%CI 1.0-3.9, p < 0.05) as well as of gastric cancer located in the middle third of the stomach (OR: 2.0, 95%CI 1.0-3.9, p < 0.05)., Conclusion: The -105G>A promoter polymorphism of SEPS1 was associated with the intestinal type of gastric cancer. This polymorphism may influence the inflammatory conditions of gastric mucosa. Larger population-based studies are needed for clarifying the relation between inflammatory responses and SEPS1 polymorphism.

Objective: Superoxide has been implicated in the pathogenesis of Helicobacter pylori-related diseases through inflammation. NADPH oxidase, a major source of superoxide generation, plays a critical role in H. pylori-related gastric inflammation. The aim of this study was to clarify the effect of the p22PHOX C242T polymorphism, an essential component of NADPH oxidase in the risk of gastroduodenal diseases, on the severity of H. pylori-induced gastritis in a Japanese population., Material and Methods: The study comprised 436 patients attending the Endoscopy Center of Fujita Health University Hospital. The p22PHOX C242T polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Gastritis scores of antral gastric mucosa were assessed according to the updated Sydney system., Results: The 436 patients represented 106 gastric ulcers (24.3%), 48 duodenal ulcers (11.0%), and 282 non-ulcer subjects (64.7%). No association was found between p22PHOX polymorphism and the risk of ulcer diseases compared to non-ulcer subjects. However, among H. pylori-positive subjects, the degree of intestinal metaplasia tended to be lower in 242T carriers aged more than 60 years (p=0.0488). The same allele also decreased the risk of developing a more severe intestinal metaplasia in H. pylori-positive female subjects (p=0.0441)., Conclusions: Our data suggest that the p22PHOX 242T allele is associated with a reduced risk of developing a more severe intestinal metaplasia in subjects older than 60 years of age and in female subjects with H. pylori infection.

Background: Heat shock protein 70-2 (HSP70-2) has a cytoprotective role in various conditions and also protects the gastric mucosa. Recently, polymorphism of HSP70-2 at position 1267 was suggested to be associated with carcinogenesis. We investigated the association of this polymorphism with the risk of gastric cancer in the present study., Methods: We examined 223 patients (159 men and 64 women, mean age 64.8 years) with gastric cancer who underwent gastrointestinal endoscopy at our department. The controls were 200 age-matched patients (140 men and 60 women) without gastric cancer diagnosed by gastrointestinal endoscopy. Genotyping was done by PCR-based restriction fragment length polymorphism analysis, and the PCR products were digested with PstI. The two allelic forms, corresponding to the presence or absence of the PstI site, were designated as the P1 allele and P2 allele, respectively. Logistic regression analysis was performed to calculate an odds ratios (ORs) for differences of HSP70-2 polymorphism between the two groups., Results: Among the 223 patients with gastric cancer, 46 (20.6%) had P1/P1, 177 (79.4%) were P1 carriers, and 6 (2.7%) were P2/P2. In the control group, 33 (16.5%) patients had P1/P1 polymorphism, 167 (83.5%) were P1 carriers, and 12 (6.0%) were P2/P2. The OR for gastric cancer of subjects with P2/P2 polymorphism relative to P1 carriers was 0.43 (95% CI = 0.16-1.17) (P = 0.097). Among females, the OR for gastric cancer of subjects with P2/P2 polymorphism relative to P1 carriers was 0.10 (95% CI = 0.012-0.838) (P = 0.014). This polymorphism was also associated with a lower risk of middle third cancer (OR = 0.13; 95% CI = 0.02-1.00)., Conclusions: P2/P2 polymorphism of HSP70-2 at position 1267 was associated with a lower risk of gastric cancer in females.

Background/aims: The role of genetics in the susceptibility to functional dyspepsia (FD) is unclear. Serotonin (5-HT) is expressed in gastro-intestinal tract and modulates the sensory-motor functions in the digestive tract. Genetic association has been reported between C102T polymorphism in the gene encoding 5-HT 2A receptor (5HTR2A) and various diseases. We aimed to clarify the association between 5HTR2A C102T polymorphism and dyspeptic symptom in a Japanese population., Methodology: 91 dyspeptics and 93 non-dyspeptic subjects enrolled in this study. Dyspeptic symptoms were divided into 9 categories. 5HTR2A gene T102C polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism., Results: In the non-dyspeptics, the 5HTR2A geno type distribution was 21TT (22.6%), 50TC (53.8%), and 22CC (23.6%). Meanwhile, the 5HTR2A genotype distribution in dyspeptics was 30 TT (33.0%), 40 TC (43.9%), and 21 CC (23.1%). There was no significant difference between the two groups in the genotype distribution. We did not find any association between 5HTR2A genotypes and dyspeptic patients in different gender and H. pylori infection status. Also, no correlation was found between 5HTR2A polymorphism and any of the 9 different dyspeptic symptoms., Conclusions: Our results suggest that 5HTR2A polymorphism is unlikely to be associated with susceptibility of dyspeptic symptoms. The role of genetics to the development of dyspepsia needs further evaluation.

Background/aims: Reactive oxygen species has been implicated in the development of ulcerative colitis (UC). NADPH oxidase, a major source of superoxide generation play a critical role in H. pylori related gastric inflammation. We aimed to clarify the effect of C242T polymorphism of p22PHOX, an essential component of NADPH oxidase on the risk of UC in a Japanese population., Methodology: 123 UC patients and 459 healthy control (HC) subjects participated in this study. The p22PHOX C242T polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism., Results: In the HC group, the p22 PHOX genotype distribution was 379C/C (82.6%), 79C/T (17.2%), and 5T/T (1.2%). Meanwhile, the p22 PHOX geno type distribution in UC group was 96C/C (78.0%), 26C/T (21.1%), and 1T/T (0.9%). No significant difference of the p22 PHOX genotype distribution was observed between HC and UC groups. (C/C vs. T/T; OR=0.80, 95% CI=0.09-6.84, C/C vs. C/T; OR=1.37, 95% CI=0.83-2.25, C/C vs. T carriers; OR=1.33, 95% CI=0.82-2.18, T/T vs. others; OR=0.74, 95% CI =0.09-6.43). No association was also found between p22PHOX gene polymorphism and different clinicopathological features of UC such as gender, age, age of onset, clinical type, extension of colitis and response to treatment., Conclusions: It appears that the C242T polymorphism of p22 PHOX is not associated with the incidence of gastric cancer in the Japanese population.

Background/aims: The role of genetics in the susceptibility to functional dyspepsia (FD) is unclear. Catechol-O-methyltransferase (COMT) has been an important enzyme in brain gut axis and pain sensitivity. Polymorphism in codon 158 of the COMT gene influences its activity. This study aimed to clarify the association between COMT polymorphism and dyspepsia in a Japanese population., Methodology: 91 dyspeptics and 94 non-dyspeptic subjects enrolled in this study. Dyspeptic symptoms were divided into 9 categories. COMT gene val158met polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism., Results: The frequency of Met carriers was lower in over all dyspeptics than healthy control but the difference was not significant (OR=0.79, 95%CI=0.44-1.41) However, when the interaction between age, gender, H. pylori infection status and the number of COMT 158Met alleles was assessed using ANOVA, a slight interaction with gender + age + COMT polymorphism was found in relation to overall dyspeptics (p=0.0476) No correlation was found between COMT polymorphism and any of 9 symptoms., Conclusions: The data suggest that the COMT genotype seems to influence the susceptibility of dyspepsia when it interacts with gender and age. The role of genetics in the development of dyspepsia needs to further evaluation.

Background/aims: Non-steroidal anti-inflammatory drugs (NSAIDs) aggravate or ameliorate clinical disease activity in patients with ulcerative colitis (UC). UC is associated with increased local production of prostanoids. This study attempted to clarify the relationship between cyclooxygenase-1 (COX1) gene polymorphisms (T-1676C and A-842G/C50T) and ulcerative colitis in a Japanese population., Methodology: The study was performed on 108 patients with UC (mean age: 39.1 years, M:F=56:52) and 293 healthy controls (mean age: 49.0 years, M:F=161:132). The PCR-SSCP method was employed to detect COX1 polymorphisms using DNA extracted from peripheral blood cells., Results: No A-842G/C50T polymorphism was detected in all 401 Japanese subjects. The frequency of -1676C allele of COX1 gene in HC group and UC group was 48.8% and 48.1%, respectively. T-1676C genotypes of COX1 did not show significant association with UC risk. In addition, these genotypes were not also associated with the clinicopathological parameters of UC., Conclusions: This research suggests that COX1 promoter polymorphisms (T-1676C and A-842G/ C50T) may not be associated with the risk of developing ulcerative colitis in a Japanese population.

Toll-like receptors (TLRs) play important roles in the signaling of many pathogen-related molecules and endogenous proteins associated with immune activation. -196 to -174del polymorphism affects the TLR2 gene and alters its promoter activity. We investigated the influence of TLR2 -196 to -174del polymorphism on the risk of gastro-duodenal diseases, on the severity of Helicobacter pylori-induced gastritis in a Japanese population. The study was performed on 309 patients with abdominal discomfort and 146 healthy controls. -196 to -174del polymorphism of TLR2 was investigated by allele-specific polymerase chain reaction method in all of the subjects. Gastritis scores of antral gastric mucosa were assessed according to the updated Sydney system in H. pylori-positive subjects (n = 156). Patients with abdominal discomfort was consisted of 80 gastric ulcers (25.9%), 38 duodenal ulcers (12.3%), five gastric + duodenal ulcers (1.6%), 105 patients with gastritis (34.0%) and 81 normal healthy stomachs (26.2%). We did not find any association between TLR2 polymorphism and risk of gastric ulcer, duodenal ulcer, gastric and duodenal ulcer and gastritis compared to healthy controls. However, the TLR2-196 to -174ins allele was associated with severity of intestinal metaplasia in more than 60 years of ages (P = 0.02). The same allele also increased the risks of developing more severe gastric mucosal atrophy and intestinal metaplasia in female subjects (P < 0.05, P = 0.07 respectively). No association was observed between TLR2 polymorphism and severity of neutrophil and mononuclear cell infiltration. Our data suggest that the TLR2-196 to -174ins allele was associated with more severe intestinal metaplasia in patients older than was correlated with severity of gastric mucosal atrophy and intestinal metaplasia in female subjects.

Background/aims: Three gene polymorphisms of Nrf2, which regulate the expression of detoxifying and antioxidant genes, have been identified. We attempted to clarify the relationship of these polymorphisms with the carcinogenesis in the stomach., Methodology: The study was performed in 209 patients with gastric cancer and 198 patients with no evidence of gastric malignancies on upper gastroduodenal endoscopy. We employed PCR-SSCP method to detect gene polymorphisms., Results: Overall, both polymorphisms at position of -686/-684 and -650 were not significant risk factors of carcinogenesis in the stomach. However, the -686/-684 A/G allele carrier had a significantly reduced risk for gastric carcinogenesis (p = 0.022), especially of diffuse type (p = 0.020), in H. pylori-negative cases. The activity and inflammation scores in Nrf2 -686/-684 A/G carriers were significantly lower than those in the non-A/G carriers (p = 0.038 and p = 0.019, respectively)., Conclusions: The -686/-684 haplotype of Nrf2 gene may be associated with the development of gastric inflammation and with gastric carcinogenesis without the influence of H. pylori infection, although overall association with gastric carcinogenesis seems to be none.

Background/aims: Transcription factor Nrf2 regulates the expression of detoxifying and antioxidant genes. Three promoter polymorphisms of this gene have been identified. This study attempted to clarify the relationship between Nrf2 gene polymorphism and ulcerative colitis in a Japanese population., Methodology: The study was performed in 89 patients with ulcerative colitis (mean age: 40.2 years, M:F = 47:42) and 141 healthy volunteers (mean age: 38.7 years, M:F = 75:66). The PCR-SSCP method was employed to detect Nrf2 polymorphisms using DNA extracted from peripheral blood cells., Results: Comparison of genotype frequency, -686*-684 A* G/A*G genotype was significantly lower in the UC group than those in the HC group (OR = 0.45, 95% CI:0.22-0.93, p = 0.029) and G*G carrier was higher in the UC group, especially in female subjects. Furthermore, -686*-684 G*G carrier was more closely associated with chronic continuous phenotype (OR = 2.57, 95% CI:1.01-6.60, p = 0.043). On the other hand, no association between -650 genotype and ulcerative colitis was found., Conclusions: The -686*-684 genotype of Nrf2 gene may be associated with the development of ulcerative colitis.

We investigated the association between ulcerative colitis (UC) and polymorphisms of IL-17A (rs2275913, G-197A) and IL-17F (rs763780, 7488T/C) genes. We employed the multiplex PCR-SSCP method to detect gene polymorphisms. Both the numbers of -197A (IL-17A) and 7488T (IL-17F) alleles were significantly correlated to the development of UC. The frequencies of -197A/A and 7488T/T genotypes in the UC group were significantly higher than those in the non-UC group. An adjusted analysis revealed that -197A and 7488T alleles were independent risk factors for the developing UC. In addition, both polymorphisms were significantly associated with the pancolitis phenotype. Furthermore, -197A allele was significantly correlated to the chronic relapsing phenotype and -197A/A homozygote was more frequent in steroid-dependent cases, whereas 7488T allele was correlated with the chronic continuous phenotype. Our results provided the first evidence that -197A (IL-17A) and 7488T (IL-17F) alleles may influence the susceptibility to and pathophysiological features of UC independently.

Background: Cyclin D1 (CCND1) is known to regulate function in G1 arrest and therefore may play an important role in carcinogenesis. The aim of this study was to investigate the effect of G870A polymorphism of the CCND1 gene on gastric precancerous condition, on histological chronic gastritis, and on the risk of peptic ulcer diseases., Methods: Restriction fragment length polymorphism analysis was performed for polymorphisms at 870GA in the CCND1 gene in 524 cancer-free subjects, including 111 gastric and 54 duodenal ulcers, and 359 non-ulcer subjects. Gastritis scores of antral gastric mucosa were assessed according to the updated Sydney system in 384 subjects., Results: CCND1 genotype was significantly associated with the severity of intestinal metaplasia by the Kruskal-Wallis test, and this tendency was especially stronger among older subjects of 61 years or older (overall subjects: p=0.035, 61 years approximately : p=0.007). We also found that the 870AA genotype held a significant high risk of intestinal metaplasia [Helicobacter pylori infection adjusted odds ratio (OR)=1.8, 95% confidence interval (CI)=1.03-3.15, p=0.04]. The same genotype was more closely associated with the risk of intestinal metaplasia in older subjects of 61 years or older (H. pylori infection adjusted OR=3.45, 95% CI=1.48-8.08, p=0.004). A non-significant association was found between CCND1 G870A genotypes and the risk of peptic ulcer diseases as well as histological severity of acute or chronic inflammation., Conclusions: It appears that the G870A polymorphism of CCND1 is associated with gastric premalignant condition especially in older subjects.

Transcription factor Nrf2 regulates the expression of detoxifying and antioxidant genes. Three promoter polymorphisms of this gene have been identified. We attempted to clarify the association of these polymorphisms with the development of peptic ulcer diseases. The study was performed with 384 stocked DNAs obtained from subjects with no evidence of gastric malignancy. In all 384 DNAs, 77 and 48 were obtained from gastric and duodenal ulcer patients, respectively. By an unadjusted analysis, infection with Helicobacter pylori (H. pylori), male gender and the -686/-684 G/G carrier (OR, 2.52; 95% CI, 1.19-5.45; p=0.016) were associated with a significantly increased risk for developing gastric ulcer, whereas the -686/-684 A/G homozygote was linked to a significantly reduced risk for developing gastric ulcer (OR, 0.26; 95% CI, 0.099-0.67; p=0.0055). On the other hand, infection with H. pylori and male gender were significantly associated with the development of duodenal ulcer, whereas Nrf2 promoter polymorphisms were not. By the analysis, after adjustment for age, gender, non-steroidal anti-inflammatory drug/aspirin use and H. pylori infection status, the -686/-684 A/G homozygote was associated with a significantly reduced risk for gastric ulcer (OR, 0.25; 95% CI, 0.088-0.73; p=0.011). Our results suggest that promoter polymorphisms of the Nrf2 gene are associated with the susceptibility to gastric ulcer.

Inflammatory changes in the gastric mucosa are commonly observed in Japanese patients with functional dyspepsia (FD). However, detailed data regarding the relationship between the genetic regulatory factors of inflammation and FD are not available. We investigated the associations between FD and genetic polymorphisms of molecules associated with inflammation or immune response (IL-17A, -17F and MIF). The study was performed with 278 subjects (188 with no upper abdominal symptoms and 90 with FD according to the Roma III criteria). We employed the PCR-SSCP (multiplex PCR for IL-17A and -17F) method to detect the gene polymorphisms. Overall, the polymorphisms of the IL-17A, -17F and MIF genes were not correlated with the susceptibility to FD. However, the MIF -173C allele carrier had a significantly increased risk for the development of epigastric pain syndrome (EPS) of FD (OR, 2.12; 95% CI, 1.00-4.49; p=0.0497). In Helicobacter pylori (H. pylori)-infected cases, the number of IL-17F 7488T alleles was positively correlated with the development of EPS (OR, 11.3; 95% CI, 1.23-103.2; p=0.032), while the IL-17F T/T homozygote and the MIF -173C carrier had an increased risk for EPS (OR, 10.4; 95% CI, 1.17-92.3; p=0.036 and OR, 3.66; 95% CI, 1.19-11.3; p=0.024, respectively). In addition, a significant interaction between the IL-17F 7488 polymorphism and H. pylori infection was shown to increase the activity and inflammation scores (p=0.043 and 0.042, respectively). There were no significant associations between the IL-17A polymorphism and FD. Our results provide the first evidence that the IL-17F and MIF gene polymorphisms are significantly associated with the development of FD, particularly EPS, a subgroup of FD, in H. pylori-infected subjects. The genetic polymorphisms of inflammation or immune response-related molecules are involved in the development of one of the FD subgroups via H. pylori-induced gastric inflammation.

Background and Aims: Host genetic factors play a key role in gastric carcinogenesis, but the mechanism has not been clarified. The multi-drug resistance 1 (MDR1) gene mediates the expression of P-glycoprotein, which has a role in active transport of various substrates, including xenobiotics, and thus has a protective function in various tissues and organs like gastrointestinal epithelial cells. C3435T polymorphism in exon 26 of the MDR1 gene influences P-glycoprotein expression and activity in the gastrointestinal tract. We investigated the influences of MDR1 gene polymorphism on the risk of gastric cancer., Method: The study was performed on 157 patients with gastric cancer (GC) and 104 patients without GC as the control group. C3435T polymorphism of MDR1 was investigated by PCR-RFLP in all of the patients., Results: The MDR1 3435 TT genotype showed a significantly higher frequency in controls than in GC patients (OR = 0.43; 95% CI = 0.23-0.79). There were no significant differences of the CT and CC genotype frequencies between GC patients and controls. We also found that the 3435TT genotype of MDR1 was associated with a lower risk of non-cardiac cancer (OR = 0.42; 95% CI = 0.23-0.79), middle-third cancer (OR = 0.36; 95% CI = 0.17-0.77), advanced cancer (OR = 0.31; 95% CI = 0.13-0.73), venous invasion (OR = 0.30; 95% CI = 0.10-0.91), and lymph node metastasis (OR = 0.28; 95% CI = 0.13-0.65)., Conclusion: Our data suggest that 3435T/T polymorphism of MDR1 is associated with a reduced risk of gastric cancer in the Japanese population.

Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator, which plays a pivotal role in inflammatory and immune diseases. We attempted to clarify associations of the functional polymorphisms of the MIF gene promoter with the development of chronic gastritis. The study was performed with 290 stocked DNAs from subjects with no evidence of gastric malignancy. We employed the PCR-SSCP method to detect gene polymorphisms. The severity of histological chronic gastritis in antral biopsy specimens was classified according to the updated Sydney system. Both the 7/7-CATT repeat at position -794 and the -173 C/C genotypes were significantly associated with a risk of developing severe gastric mucosal atrophy (OR, 9.69; 95% CI, 1.29-72.5; and OR, 4.60; 95% CI, 1.05-20.2, respectively). In subjects younger than 60 years old, the number of 7-CATT alleles was significantly correlated with both the activity and inflammation scores (p=0.0079 and 0.0080, respectively). Our results suggested that functional promoter polymorphisms of the MIF gene might be associated with the severity of gastric mucosal inflammation in younger subjects and with the subsequent development of mucosal atrophy.

Cyclooxygenase-1 (COX-1) has been regarded as a constitutively expressed enzyme that generates prostaglandins for gastrointestinal integrity. We attempted to clarify the association between potentially functional polymorphisms (T-1676C and A-842G/C50T) in the COX-1 gene promoter and gastroduodenal disorders in a Japanese population. The study was performed with 480 stocked DNAs from subjects (gastric ulcers in 93 subjects and duodenal ulcers in 44) with no evidence of gastric malignancy. We employed the PCR-SSCP method to detect gene polymorphisms. The severity of histological chronic gastritis in antral biopsy specimens was classified according to the updated Sydney system. The T-1676C polymorphism was not associated with either gastric mucosal atrophy or infiltration of inflammatory cells into gastric mucosa. In non-NSAID (non-steroidal anti-inflammatory drug) users, male gender and Helicobacter pylori (HP) infection were significantly associated with both gastric and duodenal ulcers, whereas the -1676T allele carrier was significantly associated with only gastric ulcers (OR, 2.86; 95% CI, 1.29-6.34). In NSAID users, the number of -1676T alleles was significantly associated with developing gastroduodenal ulcers (OR, 5.80; 95% CI, 1.59-21.1), whereas male gender and HP infection were not. The -842T/ C50T polymorphism was not detected in any of the 480 Japanese subjects. In conclusion, a carrier of the -1676T allele in the COX-1 gene promoter, as well as HP infection and male gender, seem to be significant risk factors for developing gastric ulcers, and the number of -1676T alleles was also a significant risk factor for the NSAID-induced ulcer, whereas the frequency of the A-842G polymorphism was thought to be very rare in the Japanese population.

Background and Aim: Ulcerative colitis (UC) is a multifactorial disease resulting from a complex interaction of genetic and environmental factors. Identifying genetic variants that alter the innate immune response is highly relevant to understanding the pathogenesis of UC. The aim of this study was to investigate the association between CD14 and Toll-like receptor-2 (TLR2) genetic polymorphisms and chronic UC in Japanese patients., Methods: The study population consisted of 102 chronic UC patients and 146 healthy control subjects. Polymorphisms in the promoter at C-260T of CD14 gene were investigated by PCR restriction fragment length polymorphism, and -196 to -174 del of TLR2 was investigated by allele-specific PCR., Results: The frequencies of CD14 TT and T carrier were significantly higher in UC patients than in controls (TT: OR = 3.98, 95% CI 1.82-8.71, P = 0.0005; T carrier: OR = 2.98, 95% CI 1.47-6.01, P = 0.002). In addition, TT and T carrier were more closely associated with distal colitis phenotype (TT: OR = 7.78, 95% CI 2.14-28.28, P = 0.0007; T carrier: OR = 6.30, 95% CI 2.71-14.58, P = 0.005), onset after 20 years of age (TT: OR = 5.28, 95% CI 2.18-12.79; T carrier: OR = 3.79, 95% CI 1.67-8.59), chronic continuous type (TT: OR = 4.26, 95% CI 1.56-11.64; T carrier: OR = 3.09, 95% CI 1.33-7.82), and fewer than two hospitalizations (TT: OR = 4.44, 95% CI 1.81-10.89; T carrier: OR = 3.26, 95% CI 1.43-7.27). There was no significant difference in TLR2 -196 to -174 del/del and del/ins carrier frequencies between UC patients and healthy controls. However, these frequencies were significantly higher in steroid-dependant patients than in controls (del/del: OR = 6.08, 95% CI 1.41-26.21; del carrier: OR = 3.00, 95% CI 1.13-7.98)., Conclusion: The results suggest that existence of a mutation in the CD14 gene is associated with an increased susceptibility to developing UC, especially chronic continuous distal colitis phenotypes that develop after 20 years of age. Furthermore, polymorphism of TLR2 may be related to an increased risk of intensive types such as steroid-dependent patients.

The transcription factor Nrf2 regulates the expression of detoxifying and antioxidant genes. Three polymorphisms of the Nrf2 gene have been reported. We attempted to clarify the relationship between Nrf2 gene polymorphism and chronic gastritis in a Japanese population. The study was performed in 159 patients with no evidence of gastric malignancy on upper gastrointestinal endoscopy (mean age, 62.03 years; male:female ratio, 102:57; peptic ulcer diseases in 69 patients, and Helicobacter pylori (H. pylori) positivity in 73.0%). We employed the PCR-SSCP method to detect gene polymorphisms using DNA extracted from peripheral blood cells or from antral biopsy specimens obtained by endoscopy. The severity of the histological chronic gastritis in antral biopsy specimens was classified according to the updated Sydney system. Although the frequencies of the SNP(-686) and SNP(-650) A alleles were decreased in subjects with peptic ulcers or severe mucosal atrophy, no significant differences were seen. However, the number of -686 G alleles was correlated with both neutrophil activity and mononuclear cell infiltration (p=0.036 and p=0.010, respectively), while the -650 C/C genotype was an independent risk factor for mononuclear cell infiltration (p=0.021 by ANOVA). In addition, both the number of -686 G alleles and the -650 C/C genotype showed an interaction with H. pylori infection to promote the infiltration of mononuclear cells (p=0.037 by ANCOVA and p=0.041 by ANOVA, respectively). Nrf2 promoter polymorphisms are significantly associated with the development of gastric mucosal inflammation, either independently or by interacting with H. pylori infection.