Association between serum pepsinogens and polymorphismof PTPN11 encoding SHP-2 among Helicobacter pylori seropositive Japanese

Helicobacter pylori (H. pylori) plays a crucial role in the development of gastric atrophy and cancer, and cagA-positive strains, which are universal in Japan, increase the risk of these outcomes substantially. The CagA protein is injected from attached H. pylori into gastric epithelial cells and undergoes Src-dependent tyrosine phosphorylation and activation of the eukaryotic phosphatase SHP-2. The CagA/SHP-2 interactions elicit cellular changes that increase the risk of carcinogenesis. We investigated the association of a frequent single nucleotide polymorphism (SNP; JST057927; G-to-A) in the PTPN11 gene that encodes SHP-2 with gastric atrophy and gastric cancer in Japan. Gastric atrophy was assessed by measuring serum pepsinogen I and II levels. The subjects comprised 454 healthy controls (126 males; mean age, 58.4) and 202 gastric cancer cases (134 males and 68 females; mean age, 66.7). All gastric cancer cases and 250 (55%) controls were H. pylori seropositive; 179 (89%) of the gastric cancer cases had gastric atrophy compared to 137 (55%) of the H. pylori seropositive controls (p < 0.001). Among HP seropositive controls compared to the common PTPN11 G/G genotype, the odds ratio of atrophy was nonsignificantly reduced with the G/A genotype (0.70; 95% CI = 0.39-1.25) and significantly reduced with the A/A genotype (0.09; 95% CI = 0.01-0.72). Lower risk for gastric atrophy had a gene-dose association with the A allele (p = 0.01, trend test). There was a clear deficiency of the A/A genotype in those with atrophy compared to those without (1 subject in the gastric atrophy group vs. 8 in the group without). Cancer cases differed from controls in frequencies of PTPN11 G/A genotype only because of a higher prevalence of atrophy among the cancer cases. The G/A SNP in the PTPN11 gene appears to be a risk factor for gastric atrophy in subjects infected with cagA-positive H. pylori. This may explain why only a proportion of CagA-positive individuals develop gastric atrophy and gastric cancer, even though infection with cagA strains is universal in Asian countries such as Japan. The functional consequences of the G/A polymorphism remain to be elucidated.     

Influences of chymase and angiotensin I-converting enzyme gene polymorphisms on gastric cancer risks in Japan.

BACKGROUNDS AND AIMS: The renin-angiotensin system plays an important role in homeostasis. Angiotensin II, which is generated by chymase and angiotensin I-converting enzyme (ACE), controls blood pressure as well as angiogenesis and cell proliferation. The aim of this study was to clarify the association of the chymase gene (CMA/B) and ACE polymorphisms with susceptibility to gastric cancer and peptic ulcer. METHODS: We assessed CMA/B A/G and ACE insertion/deletion (I/D) polymorphisms in H. pylori-positive gastric cancers (n = 119), gastric ulcers (n = 127), and duodenal ulcers (n = 105), and controls (n = 294) consisting of H. pylori-positive gastritis alone (n = 162) and H. pylori-negative subjects (n = 132) by PCR methods. RESULTS: In CMA/B polymorphism, the age- and sex-adjusted odds ratios (OR) of A/A and A/G genotypes relative to the G/G genotype for gastric cancer risk were 7.115 (95% confidence interval, 1.818-27.845) and 1.956 (95% confidence interval, 1.137-3.366), respectively. There was an increased risk for gastric ulcer in the A/A genotype (OR, 3.450; 1.086-10.960). However, there was no association between ACE polymorphism and susceptibility to gastric cancer and peptic ulcer. In allele combination analysis of CMA/B and ACE polymorphisms, the A/I allele combinations (CMA/B G/A or A/A and ACE I/I genotype) significantly increased the risk of gastric cancer development (OR, 4.749, 2.050-11.001) compared with the G/I allele combinations (CMA/B G/G and ACE I/I genotype). CONCLUSIONS: The CMA/B polymorphism was associated with an increased risk for gastric cancer and gastric ulcer development. The genotyping test of the renin-angiotensin system could be useful for the screening of individuals with higher risks of gastric cancer and gastric ulcer.     

Gastric Cancer: the Roles of Diet,Alcohol Drinking,Smoking and Helicobacter pylori in Northeastern Thailand

The incidence of gastric cancer in the countries of South East Asia is variable, ranging from age-standardized ‍rates of 20.9/105 (men) and 10.4/105 (women) in Hanoi, Vietnam to 4.1/105 (men) and 2.1/105 (women) in Khon Kaen, ‍Thailand. The reasons for these differences are unknown. Possible explanations are differences in dietary habits, ‍alcohol drinking, smoking and/or the prevalence of infection with Helicobacter pylori (H. pylori). A case-control ‍study was conducted in Khon Kaen, Thailand, to study the role of these factors in gastric cancer carcinogenesis. 131 ‍gastric cancer cases and 262 matched controls were recruited for the study. Information on dietary habits, alcohol ‍drinking and smoking were collected by a structured questionnaire. Blood samples were available from 111 cases ‍and 232 controls for H. pylori assay. Using an unconditional logistic regression model controlling for age and sex, we ‍assessed the effects of dietary habits, alcohol drinking, smoking and H. pylori infection on the risk of gastric cancer. ‍A high intake of salt (OR=1.8; 95%CI 1.1-3.0) and fermented foods (OR=1.9; 95%CI 1.1-3.3) was found to be ‍associated with an increased risk. Preference for spicy food was not associated with gastric cancer risk in this ‍population. Although there were negative associations between gastric cancer and vegetable and fruit intake, they ‍were rather weak (OR 0.8 for both) and non significant. There were also weak (non-significant) associations with ‍smoking and alcohol consumption, and no association with H. pylori infection (OR=0.6; 95%CI 0.4-1.0). Infection of ‍H. pylori was associated with various indicators of crowding. ‍     

Helicobacter Pylori Eradication as a Preventive Tool Against Gastric Cancer

Helicobacter pylori (H. pylori), which increases the risk of gastric diseases, including digestive ulcers and gastric ‍cancer, is highly prevalent in Asian countries. There is no doubt that eradication of the bacterium is effective as a ‍treatment of digestive ulcer, but eradication aiming to reduce the gastric cancer risk is still controversial. Observational ‍studies in Japan demonstrated that the eradication decreased the gastric cancer risk among 132 stomach cancer ‍patients undergoing endoscopical resection (65 treated with omeprazol and antibiotics and 67 untreated). In Columbia, ‍976 participants were randomized into eight groups in a three-treatment factorial design including H. pylori ‍eradication, resulting in significant regression in the H. pylori eradication group. A recent randomized study in ‍China also showed a significant reduction of gastric cancer risk among those without any gastric atrophy, intestinal ‍metaplasia, and dysplasia. Efficacy of eradication may vary in extent among countries with different incidence rates ‍of gastric cancer. Since the lifetime cumulative risk (0 to 84 years old) of gastric cancer in Japan is reported to be ‍12.7% for males and 4.8% for females (Inoue and Tominaga, 2003), the corresponding values for H. pylori infected ‍Japanese can be estimated at 21.2% in males and 8.0% in females under the assumptions that the relative risk for ‍infected relative to uninfected is 5 and the proportion of those infected is 0.5. Both the fact that not all individuals are ‍infected among those exposed and the knowledge that only a small percentage of individuals infected with the ‍bacterium develop gastric cancer, indicate the importance of gene-environment interactions. Studies on such ‍interactions should provide useful information for anti-H. pylori preventive strategies.     

No Association of an SDHC Gene Polymorphism with Gastric Cancer

It is widely reported that reactive oxygen species (ROS) cause apotosis and carcinogenesis. Marked infiltration ofactivated leukocyte and enhanced production of ROS appear to occur in the gastric mucosa infected with Helicobacterpylori (H. pylori). The previous studies reported that the mutation of the succinate dehydrogenase subunit C (SDHC)gene caused the increase in superoxide anion (O2-) and oxidative stress. To extend these findings, we epidemiologicallyinvestigated the association of a SDHC polymorphism at 3’-untranslated region of exon 6 (JST173800) with H. pyloriinfection, gastric atrophy and gastric cancer risk in Japan. The subjects consisted of 454 health checkup examineeswithout a history of cancer and 202 gastric cancer patients. The SDHC polymorphism was not associated with H.pylori infection seropositivity, gastric atrophy, and cancer risk in this study. Although the polymorphism at the 3’-untranslated region could be hypothesized to be functional, this study did not demonstrate any significant associationof the SDHC gene polymorphism with gastric atrophy and cancer.     

DNMT3a rs1550117 Polymorphism Association with Increased Risk of Helicobacter pylori Infection

Background: DNA methyltransferase-3a (DNMT3a) plays significant roles in embryogenesis and the generationof aberrant methylation in carcinogenesis. This study aimed to investigate associations between single nucleotidepolymorphisms (SNPs) of the DNMT3a gene and risk of Helicobacter pylori infection, gastric atrophy and gastriccancer. Methods: The subjects comprised 447 patients with gastric cancer; 111 individuals with gastric atrophyand 961 healthy controls. Two SNPs (rs1550117 and rs13420827) of the DNMT3a gene were genotyped by Taqmanassay. DNMT3a expression was analyzed in cancer tissues from 89 patients by tissue microarray technique. Oddsratio (ORs) and 95% confidence intervals were calculated by multivariate logistic regression. Results: Amonghealthy controls, risk of H.pylori infection was significantly higher in subjects with the rs1550117 AA genotype,compared to those with GG/AG genotypes of DNMT3a [OR=2.08, (95%CI: 1.02-4.32)]. However, no significantcorrelation was found between the two SNPs and risk of developing gastric atrophy or gastric cancer. In addition,no increase in DNMT3a expression was observed in the gastric cancer with H.pylori infection. Conclusions:This study revealed that DNMT3a rs1550117 polymorphism is significantly associated with an increased risk ofH. pylori infection, but did not support any evidence for contributions of DNMT3a rs1550117 and rs13420827to either gastric atrophy or gastric cancer. The biological roles of DNMT3a polymorphisms require furtherinvestigation.     

No Association between the CDX2 G543C Polymorphism and Risk of Gastric Atrophy and Cancer

Ectopic expression of CDX2 in the stomach is closely associated with chronic Helicobacter pylori (H. pylori)infection and intestinal metaplasia. Whether CDX2 has tumor suppression or tumorigenesis potential remainsto be elucidated. In this study, we investigated the association between the CDX2 G543C polymorphism (silentmutation) and the risk for H. pylori-induced gastric atrophy and cancer as well as H. pylori infection, using 454Japanese subjects undergoing a health checkup and 202 gastric cancer patients. The frequency of the minor allelewas the same as previously reported in China, but different from that reported in England. CDX2 G543C wasnot associated with risk of H. pylori infection, gastric atrophy, or gastric cancer, although the point estimate fornon-cardiac differentiated gastric cancer as compared to controls with gastric atrophy was 2.22 (95%CI=0.17-29.4). In conclusion, our results indicate that the CDX2 G543C polymorphism is unlikely to affect the H. pyloriinfection-gastric atrophy-gastric cancer sequence.     

A C to T polymorphism of Urokinase Plasminogen Activator (P141L) is Associated with Helicobacter pylori Infection

Urokinase plasminogen activator (uPA) plays an important role in tumor invasion and certain inflammatorydiseases. However, few studies have paid attention to how the uPA is associated with Helicobacter pylori infectionand gastric atrophy. This study investigated associations of a C-to-T polymorphism of uPA (P141L, rs2227564) inexon 6 in 454 Japanese health checkup examinees (126 males and 328 females) aged 35 to 85 without a history ofcancer. The uPA was genotyped by polymerase chain reaction with two-pair primers. The genotype distributionwas in Hardy-Weinberg equilibrium (p=0.52) and the frequency of the T allele was 0.239. The risk of H. pylorisero-positivity was significantly reduced with the T/T genotype; the odds ratio (OR) relative to the C/C genotypewas 0.34 (95% confidence interval [CI]: 0.14 to 0.86). Of the sero-negative subjects, 21 with atrophy were infectedwith H. pylori but lost their sero-positivity. After reclassifying them together with the sero-positive subjects, thecorresponding OR was 0.40 (95% CI: 0.16 to 1.00), confirming that the T/T genotype decreased the risk of H.pylori infection. This gene polymorphism was not associated with the risk of gastric atrophy. In conclusion, thisstudy indicated a possibility that the uPA minor homozygous genotype was associated with a reduction of H.pylori infection risk. Further studies are required to confirm these findings.     

Angiotensin I-converting enzyme gene polymorphism modifies the smoking-cancer association: the Hisayama Study.

We examined the long-term contribution of smoking and angiotensin I-converting enzyme (ACE) gene I/D polymorphism to total cancer deaths in a prospective study of a general Japanese population. A total of 937 subjects aged 40 years or older were selected from an original cohort of 1621 subjects and were followed up for 32 years. During the follow-up period, 176 subjects died of cancer. Cancer mortality increased significantly with increasing current smoking levels. Although no clear relationship was observed between ACE genotypes and fatal cancer, the interaction term between current smoking and ACE genotype DD was found to be significant. In stratified analysis by ACE genotype after controlling for age, sex, alcohol intake, body mass index, glucose intolerance, serum total cholesterol and systolic blood pressure, the risk of fatal cancer in currently smoking subjects with genotype DD was twofold greater than that in subjects with genotypes II and ID. Among current smokers, subjects with genotype DD also showed a significantly greater risk of death due to cancer compared with those with genotypes II and ID combined (hazard ratio 1.77; 95% confidence interval 1.04-3.00; P=0.03). In conclusion, our findings suggest that ACE genotype DD enhances the association between smoking and cancer death in the general population.     

Insertion/deletion (I/D) in the Angiotensin-converting Enzyme Gene and Breast Cancer Risk: Lack of Association in a Metaanalysis

Purpose: Breast cancer is an important cause of cancer-related death in women. Numerous studies haveevaluated the association between the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme(ACE) gene and breast cancer risk. However, the specific association is still controversial rather than conclusive.Therefore, we performed a meta-analysis of related studies to address this controversy. Methods: PubMed,EMBASE, Google Scholar and the Chinese National Knowledge Infrastructure databases were systematicallysearched to identify relevant studies. A meta-analysis was performed to examine the association between theI/D polymorphism in the ACE gene and susceptibility to breast cancer. Odds ratios (ORs) and 95% confidenceintervals (95% CIs) were calculated. Results: 10 separate studies of 7 included articles with 10,888 subjects onthe relation between the I/D polymorphism in the ACE gene and breast cancer were analyzed by meta-analysis,and our results showed no association between the I/D polymorphism in the ACE gene and breast cancer in totalpopulation and different populations. No publication bias was found in the present study. Conclusions: The ACEI/D polymorphism may not be associated with breast cancer risk. Further large and well-designed studies areneeded to confirm this conclusion.     

Helicobacter pylori infection, interleukin-1 gene polymorphisms and the risk of colorectal cancer: evidence from a case-control study in Germany

Helicobacter pylori infection is a strong risk factor for gastric cancer. A positive association with colorectal cancer has also been suggested, but available evidence remains inconclusive. In this population-based case-control study we investigated the association between H. pylori seroprevalence and colorectal adenocarcinoma under consideration of pro-inflammatory gene polymorphisms (384 incident cancer patients, 467 matched control subjects). Overall, the H. pylori seroprevalence was higher among cases (51%) than among controls (44%), and a positive association between H. pylori seroprevalence and colorectal adenocarcinoma risk was found, that persisted after adjustment for known potential confounders, including measures of socioeconomic status (odds ratio (OR)=1.41; 95% confidence intervals (CI), 1.06-1.87). Presence of specific H. pylori cytotoxin-associated gene A (CagA) antibodies did not significantly affect the observed risk. Additionally, a pro-inflammatory genotype did not increase the colorectal cancer risk associated with H. pylori infection. H. pylori positive subjects carrying the pro-inflammatory genotypes even had a lower risk.     

Genetic variation in angiotensin I-converting enzyme (ACE) and breast cancer risk: the multiethnic cohort

The A-240T and I/D polymorphisms in the angiotensin I-converting enzyme (ACE) gene are markers of circulating ACE levels and have been associated with numerous cardiovascular disease outcomes. More recently, the low-activity A and I alleles at these polymorphic sites have been inversely related with breast cancer risk. We assessed the relationship between the A-240T and I/D ACE variants and breast cancer risk in a case-control analysis (n = 1263 cases with invasive breast cancer and 2269 controls) among African-American, Japanese, Latina, and white women in the Multiethnic Cohort Study. Odds ratios and 95% confidence intervals are presented adjusted for established breast cancer risk factors. Among all women combined, we observed no significant association between the A-240T polymorphism and breast cancer risk. For the I/D polymorphism, contrary to expectation, women with the I/I genotype had a marginally significant increase in breast cancer risk (versus DD genotype: odds ratio, 1.30; 95% confidence interval, 1.05-1.61), although associations were not entirely consistent across ethnic groups. These data do not support the hypothesis that women with lower ACE levels, as predicted by the low-activity A and I ACE alleles, are at reduced risk of breast cancer. Overall, these results suggest that the A-240T and I/D ACE polymorphisms are not likely to be strong predictors of breast cancer risk.     

Gastric cancer risk in a Mexican population: role of Helicobacter pylori CagA positive infection and polymorphisms in interleukin-1 and -10 genes

Several polymorphisms of the IL1B and IL10 gene promoters have been reported to be associated with gastric cancer risk in Caucasians. However, studies in other populations have shown differing results. We aimed to test for associations between polymorphisms in IL1B (-31 and +3954), IL10-592 and IL1RN variable number of tandem repeats (VNTR) and risk of gastric cancer in a Mexican population. DNA was extracted from sera of 183 gastric adenocarcinoma patients and 377 controls. The IL1B-31, IL1B+3954 and IL10-592 biallelic polymorphisms were discriminated using 5' Nuclease (TaqMan) assays and Pyrosequencing. The IL1RN penta-allelic VNTR polymorphism was genotyped using PCR followed by GeneScan analysis. A significant interaction was found between IL1B-31 and CagA status for the risk of intestinal-type gastric cancer (p = 0.023). Among CagA positive subjects, those with IL1B-31CC genotype had an increased risk of intestinal-type gastric cancer (OR 3.19, 95%CI = 1.05-9.68), compared to carriers of IL1B-31TT genotype. In contrast, among CagA negative subjects, no significant association of IL1B-31CC genotype with gastric cancer was observed. The IL10-592CC genotype was associated with more than doubling of the risk of the intestinal-type gastric cancer (OR, 2.20, 95%CI = 1.04-4.65). A nonsignificantly increased risk for intestinal-type gastric cancer was found in IL1RN*2 carriers (OR 1.49, 95%CI = 0.89-2.50). None of these polymorphisms was significantly related to the risk of diffuse-type gastric cancer. No significant association was found between risk of gastric cancer and the IL1B+3954 polymorphism. Individuals carrying 2 or more of the risk-associated alleles (IL1B-31C, IL1RN *2 and IL10-592C) were at increased risk for intestinal-type gastric cancer, compared to those with 0 or 1 risk-associated allele. The risk from multiple risk-associated alleles was especially high in subjects infected with CagA positive H. pylori. Our results support the identification of the IL1B-31 promoter polymorphism as a useful marker for risk of intestinal type gastric cancer in persons with CagA positive H. pylori infections.     

hOGG1 Ser326Cys polymorphism, interaction with environmental exposures, and gastric cancer risk in Japanese populations

Oxidative DNA damage caused by reactive oxygen species (ROS) generated by Helicobacter pylori (H. pylori ) infection or smoking may be a cause of gastric cancer development. 8-Hydroxydeoxyguanine (8-OHdG) formation is one of the most common types of oxidative DNA damage, while human oxoguanine glycosylase 1 (hOGG1) is responsible for repairing 8-OHdG lesions. Among several hOGG1 gene polymorphisms, the Ser-->Cys polymorphism at position 326 is related to biological function. To investigate the association between Ser326Cys hOGG1 polymorphism and gastric cancer in relation to the potential risk factors of gastric cancer and antioxidant dietary or nutrient intakes, we conducted a case-control study with 142 histologically-confirmed gastric cancer cases and 271 age, sex-matched healthy controls in Japanese populations. Overall, neither the hOGG1 Ser/Cys nor the Cys/Cys genotype was associated with risk of gastric cancer, compared with the Ser/Ser genotype. A significant interaction was observed between hOGG1 Ser/Cys or Cys/Cys genotype and atrophic gastritis (P for interaction=0.03). No significant interaction was found between hOGG1 genotype and antioxidant dietary or nutrient intakes. The results of the present study suggest that patients with atrophic gastritis in conjunction with the hOGG1 Cys allele might have a higher susceptibility to gastric cancer.     

Associations between a PTPN11 Polymorphism and Gastric Atrophy - Opposite in Uzbekistan to that in Japan

Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2) of gastric epithelial cells interacts with cagA from Helicobacter pylori (H. pylori). Our previous studies found the AA genotype of a G/A single nucleotide polymorphism at intron 3 (rs2301756) of PTPN11 gene, which encodes SHP-2, to be associated with a lower risk of gastric atrophy. The present study aimed to examine the association with gastric atrophy among the subjects of a case-control study of peptic ulcer disease (PUD) conducted in the Uzbek Republic. Cases were 95 patients (61 males and 34 females) with PUD aged 16 to 85 years. Controls were 102 hospital volunteers (42 males and 60 females) including 42 patients with miscellaneous diseases, aged 15 to 75 years. Gastric atrophy was evaluated with serum pepsinogens (PG1<70ng/ml and PG1/PG2<3). Polymorphisms of PTPN11 at intron 3 (rs2301756) and intron10 (rs12229892) were genotyped with PCR with confronting two-pair primers (PCR-CTPP). Anti-cagA IgG antibody was detected in 93.7% of cases and 77.5% in controls. Gastric atrophy was observed in 24.2% of the PUD patients and 33.3% in the controls. The A allele at intron 3 was completely linked to the G allele at intron 10. The age, sex, and group (cases and controls) adjusted odds ratio of gastric atrophy was 0.18 (95% confidence interval, 0.04-0.86) for intron 3 GG genotype relative to AA genotype. Since the finding was opposite to that among Japanese, the H. pylori strains and/or lifestyle in Uzbekistan might modify the association.     

Long-term Effect of Helicobacter pylori Infection on Serum Pepsinogens

Serum pepsinogen values are markers of gastric mucosal status and of gastric cancer risk. The effect of Helicobacter pylori infection and sibship size on change of serum pepsinogen values over a seven-year span was investigated. Data from 2584 subjects with phlebotomy were analyzed both in 1989 and in 1996. The subjects were classified by H. pylori serology and sibship size (1–3 vs. 4 and more). Pepsinogen I (PG I) to II (PG II) ratio in'96 minus that in'89 was defined as ΔPG I/II and compared among the groups. ΔPG I/II was lower and decrease of PG I/II was more frequent among H. pylori -positive subjects than among negative subjects. The difference was owing to a decrease of PG I in all subjects and owing to an increase of PG II in those not younger than 30 years in'89. In H. pylori -positive subjects, those with a larger sibship size showed lower ΔPG I/II and higher frequency of PG I/II decline. H. pylori infection exerts a reducing effect on PG I/II during the seven-year span. The effect of H. pylori is stronger among those with a larger sibship size, who are expected to have been infected with H. pylori in childhood. Inducing atrophy of gastric mucosa, which is reflected by a decline of PG I/II, may be one of the mechanisms through which H. pylori elevates the risk of gastric cancer.     

白介素10-1082G/A位点单核苷酸多态性与中国北方人群胃癌发病风险的病例对照研究

背景与目的:个体遗传易感性对胃癌的发生发展具有重要作用,其中免疫抑制因子白细胞介素10(interleukin-10,IL-10)基因-1082G/A位点单核苷酸多态性(single anucleotide polymorphism,SNP)引起研究者重视。本研究分析IL-10-1082G/A SNP在中国北方胃癌高发区和低发区人群中的分布,探讨IL-10-1082G/A SNP与胃癌发病风险的关系。方法:1516例研究对象来自胃癌高发区辽宁庄河(983例)及低发区沈阳(533例),采用聚合酶链反应-限制性片段长度多态(polymerase chain reaction-restriction fragment lengthpolymorphism,PCR-RFLP)方法检测该人群中IL-10-1082G/A位点单核苷酸多态性;采用酶联免疫吸附实验(enzyme-linked immunosorbent assay,ELISA)检测血清幽门螺杆菌(Helicobacter pylori,H.pylori)IgG。采用病理组织学诊断进行疾病分组,按性别和年龄配对,选取基本正常、浅表性胃炎、胃糜烂溃疡、萎缩性胃炎和胃癌组织各111例,用于IL-10-1082G/A SNP与胃癌发病风险的分析。结果:中国北方人群IL-10-1082G/A基因位点AA、AG、GG三种基因型分布频率分别为88.5%、10.9%、0.6%。IL-10-1082AG GG基因型在胃癌组、非胃癌组及正常对照组分布频率分别为19.8%、9.7%和6.3%,IL-10-1082AG GG基因型在胃癌高、低发区人群中的分布的地区及性别差异无统计学意义(P>0.05),而胃癌组高于非胃癌组(P=0.003)及正常对照组(P=0.003),其差异均有统计学意义。以IL-10-1082AA基因型并H.pylori IgG阴性的正常组为对照,IL-10-1082AG GG基因型并H.pylori IgG抗体阴性个体、IL-10-1082AA基因型或AG GG基因型并H.pylori IgG抗体阳性个体胃癌患病风险均提高,OR(95%CI)分别为3.3(1.3～8.6)、4.3(2.0～9.5)、2.5(2.1～3.1),但三组两两进行比较其差异均无统计学意义(P>0.05)。结论:携带IL-10-1082AG GG基因型个体胃癌的发病风险提高,IL-10-1082G/A SNP和H.pylori感染在胃癌发生发展过程中无交互作用。     

Smoking Behavior and Risk of Helicobacter Pylori Infection,Gastric Atrophy and Gastric Cancer in Japanese

Although many studies have shown that smoking is an established risk factor for gastric cancer, relatively few studies have investigated on which step smoking has effects in Helicobacter pylori (H. pylori) related gastric carcinogenesis. In this study we investigated the association of smoking with risk of three steps leading to gastric cancer: H. pylori infection, gastric atrophy, and gastric cancer. Among the participants who visited Aichi Cancer Center Hospital from year 2001 to 2005, 583 cases diagnosed as gastric cancer and age-and sex-frequency-matched 1,742 cancer free controls were sampled, from whom those without serum samples or without information about smoking habit were excluded, leaving 576 cases and 1,599 controls eligible for the analyses. Anti- H. pylori IgG antibody and serum pepsinogens (PG) were measured to detect H. pylori infection and gastric atrophy. Smoking status was asked by a self-administered questionnaire. The odds ratio (OR) of H. pylori infection, as well as the OR of gastric atrophy among the H. pylori seropositive controls was not significant for smokers. The age- and sex-adjusted OR of gastric cancer was significantly elevated relative to the subjects with gastric atrophy: OR=1.62 (95% confidence interval (CI), 1.19-2.22; P=0.002) for ever smokers and 2.52 (1.75-3.64; P<0.001) for current smokers, relative to never smokers. This study revealed that smoking behavior contributed to the increased risk of gastric carcinogenesis from gastric atrophy, but had little influence on H. pylori infection or gastric atrophy development.     

Long-term effect of Helicobacter pylori infection on serum pepsinogens.

Serum pepsinogen values are markers of gastric mucosal status and of gastric cancer risk. The effect of Helicobacter pylori infection and sibship size on change of serum pepsinogen values over a seven-year span was investigated. Data from 2584 subjects with phlebotomy were analyzed both in 1989 and in 1996. The subjects were classified by H. pylori serology and sibship size (1 - 3 vs. 4 and more). Pepsinogen I (PG I) to II (PG II) ratio in '96 minus that in '89 was defined as DeltaPG I / II and compared among the groups. DeltaPG I / II was lower and decrease of PG I / II was more frequent among H. pylori-positive subjects than among negative subjects. The difference was owing to a decrease of PG I in all subjects and owing to an increase of PG II in those not younger than 30 years in '89. In H. pylori-positive subjects, those with a larger sibship size showed lower DeltaPG I / II and higher frequency of PG I / II decline. H. pylori infection exerts a reducing effect on PG I / II during the seven-year span. The effect of H. pylori is stronger among those with a larger sibship size, who are expected to have been infected with H. pylori in childhood. Inducing atrophy of gastric mucosa, which is reflected by a decline of PG I / II, may be one of the mechanisms through which H. pylori elevates the risk of gastric cancer.     

Smoking Behavior and Risk of Helicobacter Pylori Infection,Gastric Atrophy and Gastric Cancer in Japanese

Although many studies have shown that smoking is an established risk factor for gastric cancer, relativelyfew studies have investigated on which step smoking has effects in Helicobacter pylori (H. pylori) related gastriccarcinogenesis. In this study we investigated the association of smoking with risk of three steps leading to gastriccancer: H. pylori infection, gastric atrophy, and gastric cancer. Among the participants who visited Aichi CancerCenter Hospital from year 2001 to 2005, 583 cases diagnosed as gastric cancer and age-and sex-frequency-matched1,742 cancer free controls were sampled, from whom those without serum samples or without information aboutsmoking habit were excluded, leaving 576 cases and 1,599 controls eligible for the analyses. Anti- H. pylori IgGantibody and serum pepsinogens (PG) were measured to detect H. pylori infection and gastric atrophy. Smokingstatus was asked by a self-administered questionnaire. The odds ratio (OR) of H. pylori infection, as well as theOR of gastric atrophy among the H. pylori seropositive controls was not significant for smokers. The age- andsex-adjusted OR of gastric cancer was significantly elevated relative to the subjects with gastric atrophy: OR=1.62(95% confidence interval (CI), 1.19-2.22; P=0.002) for ever smokers and 2.52 (1.75-3.64; P<0.001) for currentsmokers, relative to never smokers. This study revealed that smoking behavior contributed to the increased riskof gastric carcinogenesis from gastric atrophy, and had little influence on H. pylori infection or gastric atrophydevelopment.