Gastric parietal cell antibodies, Helicobacter pylori infection, and chronic atrophic gastritis: evidence from a large population-based study in Germany.

BACKGROUND: Striking similarities between autoimmune gastritis and Helicobacter Pylori (H. pylori)-associated gastritis have suggested a potential link between these two pathologic conditions in the progression of chronic atrophic gastritis (CAG); however, evidence has remained conflicting. METHODS: Serum pepsinogen I and II, and antibodies against H. pylori in general, the cytotoxin-associated gene A protein (CagA) and parietal cells were measured by ELISA in 9,684 subjects aged 50 to 74 years. Antigastric parietal cell antibody (APCA) prevalence was examined in the overall population and according to sex, age, and H. pylori serostatus. The association between APCA prevalence and CAG was assessed by logistic regression, overall and according to H. pylori status, controlling for potential confounding factors. RESULTS: Overall APCA prevalence was 19.5%. APCA prevalence was strongly associated with CAG, and the association was increasing with increasing severity of CAG. Furthermore, the association between APCA and CAG was even stronger among H. pylori-negative subjects [odds ratio (OR) = 11.3; 95% confidence interval (CI): 7.5-17.1)] than among H. pylori-positive subjects (OR = 2.6; 95% CI: 2.1-3.3). CONCLUSIONS: APCA may play a role on the development of gastric atrophy, irrespective of H. pylori infection. IMPACT: Assessment of APCA might be a useful complement to established markers (such as pepsinogens and H. pylori antibodies) in screening for CAG.

Helicobacter pylori infection and colorectal cancer risk: evidence from a large population-based case-control study in Germany.

Evidence concerning the role of Helicobacter pylori infection in the development of colorectal cancer remains controversial. The authors assessed the association of H. pylori seroprevalence with risk of colorectal cancer in a large population-based case-control study from Germany in 2003-2007. Serum antibodies to H. pylori in general and the cytotoxin-associated gene A protein (CagA) were measured in 1,712 incident colorectal cancer cases and 1,669 controls. The association between H. pylori seroprevalence and colorectal cancer risk was estimated by logistic regression, with adjustment for potential confounders and stratification by age group, sex, anatomic subsites, and cancer stage. Overall, H. pylori seroprevalence was higher in cases (46.1%) than in controls (40.1%), resulting in an age- and sex-adjusted odds ratio of 1.30 (95% confidence interval (CI): 1.14, 1.50). Adjustment for established colorectal cancer risk factors decreased the odds ratio to 1.26 (95% CI: 1.09, 1.47), with a further reduction to 1.18 (95% CI: 1.01, 1.38) after additional adjustment for previous colorectal endoscopy. Stratified analyses showed risk elevation to be essentially confined to left-sided colorectal cancer, with an odds ratio of 1.22 (95% CI: 1.02, 1.45), suggesting that H. pylori infection may be associated with a small yet relevant risk increase in the left colorectum.

Helicobacter pylori infection is strongly associated with gastric and duodenal ulcers in a large prospective study.

BACKGROUND & AIMS: Infection with Helicobacter pylori (H pylori) is a risk factor for peptic ulcer disease (PUD), but there are limited longitudinal data on the associations between infection and incident gastric or duodenal ulcers. METHODS: Information on potential risk factors, lifetime history of PUD, and serologic measurements of H pylori infection were obtained from a German cohort of 9953 adults, 50 to 74 years old at baseline (2000-2002). The incidence of ulcers was determined by questionnaires sent to study participants and general practitioners 2 and 5 years later, and was validated by medical records. RESULTS: A lifetime history of PUD was reported by 1030 participants, and during the follow-up period 48 had a first gastric and 22 had a first duodenal ulcer. Infection with H pylori strains that express cytotoxin-associated gene A (cagA) was significantly associated with a lifetime history of PUD (odds ratio, 1.75; 95% confidence interval [CI], 1.50-2.04). Based on longitudinal analyses with physician-validated end points, the adjusted hazard ratios for incident gastric and duodenal ulcer disease were 2.9 (95% CI, 1.5-5.5) and 18.4 (95% CI, 4.2-79.9), respectively, among patients infected with cagA-positive strains of H pylori. CONCLUSIONS: In cross-sectional analysis, infection with cagA-positive strains of H pylori was associated with a 1.75-fold increased risk of peptic ulcer disease. Longitudinal analyses revealed an 18.4- and 2.9-fold increased risk for duodenal ulcer and gastric ulcer, respectively. The proportion of PUD that is attributable to H pylori infection might be larger than previously believed.

Helicobacter pylori infection, chronic atrophic gastritis and major cardiovascular events: a population-based cohort study.

OBJECTIVE: There is debate whether infection with Helicobacter (H.) pylori, the main inducer of chronic atrophic gastritis (CAG), is a risk factor for cardiovascular disease and premature mortality. METHODS: Serological measurements of H. pylori infection and pepsinogen (PG) I and II were obtained in a population-based German cohort of 9953 older adults (50-74 years). Cox regression was employed to estimate hazard ratios (HR) and 95% confidence intervals (CI) for myocardial infarction, stroke, cardiovascular and all-cause mortality during five-year follow-up. RESULTS: According to serology, 4977 participants (51.9%) were infected with H. pylori (2604 with cytotoxin-associated gene A (cagA) strains) and 541 (5.7%) had CAG (PGI<70 ng/mL and PGI/PGII<3). During follow-up, 540 participants died (163 from cardiovascular causes), 170 experienced a primary myocardial infarction and 241 had a stroke. Neither cytotoxin-associated gene A (cagA) negative nor cagA positive H. pylori infections were associated with an increased risk for myocardial infarction, stroke or all-cause mortality. Intriguingly, infection with cagA positive H. pylori strains was inversely associated with cardiovascular mortality (HR, 0.62; CI: 0.41-0.94). No statistically significant associations were observed for the small group of participants with CAG, but point estimates of adjusted HRs for myocardial infarction, stroke and cardiovascular mortality were all below 1 (0.71, 0.59 and 0.65, respectively). CONCLUSIONS: Our results do not support the hypothesis that H. pylori infection or CAG are risk factors for cardiovascular disease or mortality and instead suggest an inverse relationship of cagA positive H. pylori infection with fatal cardiovascular events.

Apparent incidence of Helicobacter pylori in adulthood: to what extent do new infections reflect misclassification?

BACKGROUND: Helicobacter pylori infection is a key risk factor for a variety of gastrointestinal diseases. About half of the world population is infected. Most infections are acquired early in childhood, but the occurrence of new infections among adults has also been suggested. METHODS: We review epidemiological studies providing estimates of incidence of H. pylori infection among adults and evaluate to what extent incidence estimates might have been affected by measurement error of infection status. RESULTS: Thirty-two studies could be included in the review. Annual incidence was lower than 1.0 % in 17 studies; no correlation between length of follow-up and cumulative incidence was observed. Apparent cumulative incidences of the magnitudes observed in most studies would be expected, because of less than perfect sensitivity and specificity of the diagnostic tests, even in the absence of any true new infections. CONCLUSION/IMPACT: Apparent incidence rates of H. pylori infection among adults in Western populations should be interpreted with utmost caution.

Genetic variation in the prostate stem cell antigen gene and upper gastrointestinal cancer in white individuals.

BACKGROUND & AIMS: An association between gastric cancer and the rs2294008 (C>T) polymorphism in the prostate stem cell antigen (PSCA) gene has been reported for several Asian populations. We set out to determine whether such an association exists in white individuals. METHODS: We genotyped 166 relatives of gastric cancer patients, including 43 Helicobacter pylori-infected subjects with hypochlorhydria and gastric atrophy, 65 infected subjects without these abnormalities, 58 H pylori-negative relatives, and 100 population controls. Additionally, a population-based study of chronic atrophic gastritis provided 533 cases and 1054 controls. We then genotyped 2 population-based, case-control studies of upper gastrointestinal cancer: the first included 312 gastric cancer cases and 383 controls; the second included 309 gastric cancer cases, 159 esophageal cancer cases, and 211 controls. Odds ratios were computed from logistic models and adjusted for confounding variables. RESULTS: Carriage of the risk allele (T) of rs2294008 in PSCA was associated with chronic atrophic gastritis (adjusted odds ratio [OR], 1.5; 95% confidence interval [CI]: 1.1-1.9) and noncardia gastric cancer (OR, 1.9; 95% CI: 1.3-2.8). The association was strongest for the diffuse histologic type (OR, 3.2; 95% CI: 1.2-10.7). An inverse association was observed between carriage of the risk allele and gastric cardia cancer (OR, 0.5; 95% CI: 0.3-0.9), esophageal adenocarcinoma (OR, 0.5; 95% CI: 0.3-0.9), and esophageal squamous cell carcinoma (OR, 0.4; 95% CI: 0.2-0.9). CONCLUSIONS: The rs2294008 polymorphism in PSCA increases the risk of noncardia gastric cancer and its precursors in white individuals but protects against proximal cancers.

Grb2-associated binder 1 (Gab1) genetic polymorphism, Helicobacter pylori infection, and chronic atrophic gastritis among older adults from Germany.

Grb2-associated binder 1 (Gab1) plays an important role in the regulation of cell growth and transformation. A single nucleotide polymorphism (SNP) (rs3805246) in the Gab1 gene has been suggested to be related to the risk of Helicobacter pylori infection and chronic atrophic gastritis (CAG) in a study from Japan. We aimed to assess the associations in a population-based study from Germany. In the baseline examination of ESTHER, a population-based study conducted in Saarland, serum pepsinogen I and II and H. pylori serostatus were measured by ELISA. The Gab1 SNP (rs3805246) was genotyped in 351 serologically defined CAG cases and 351 age- and sex-matched non-CAG controls. A nonsignificant association was observed between the Gab1 SNP and CAG, with an adjusted odds ratio of 1.15 (0.85-1.55) for AA/AG carriers compared to GG carriers. The magnitude of the association did not change when the analysis was restricted to H. pylori seropositive subjects. Furthermore, no significant relation was found between the SNP and H. pylori seropositivity among non-CAG controls. We could not confirm a major association between Gab1 SNP (rs3805246) and the predisposition to H. pylori infection and CAG in this study population from Germany. Further studies with larger sample size are needed to clarify a potential modest effect of Gab1 genetic polymorphisms.

Alcohol consumption, serum gamma-glutamyltransferase, and helicobacter pylori infection in a population-based study among 9733 older adults.

PURPOSE: Moderate alcohol consumption has been suggested to facilitate the elimination of Helicobacter pylori infection as the result of its antibacterial effect. We aimed to assess the associations of current and lifetime alcohol consumption as well as serum gamma-glutamyltransferase (GGT), an established biomarker of alcohol consumption, with H. pylori infection in a large population-based study. METHODS: In the baseline examination of the ESTHER study, serological measurements of antibodies against H. pylori and GGT measurements were taken in 9733 subjects ages 50 to 74 years. Information on lifestyle factors and medical history were obtained by self-administered standardized questionnaire. RESULTS: A significant inverse association, in dose-response manner, was observed between both current and lifetime alcohol consumption and H. pylori seropositivity. The estimates based on lifetime consumption were more pronounced than the results for current consumption, and such inverse associations were found both for men and women. Stronger relations were observed for those who only drank wine or mixed drinkers compare with those who only drank beer. Furthermore, there was a significant inverse dose-response relationship between serum GGT levels and H. pylori seropositivity, which was selectively observed among alcohol drinkers. CONCLUSIONS: In conclusion, our results support the hypothesis that moderate alcohol consumption may facilitate elimination of H. pylori.

Sibship size, Helicobacter pylori infection and chronic atrophic gastritis: a population-based study among 9444 older adults from Germany.

BACKGROUND: Early-life social environment has been suggested to play an important role during the development of Helicobacter pylori-related gastric diseases. We aimed to assess the association of sibship size with H. pylori infection and chronic atrophic gastritis (CAG) in a population-based study from Germany. METHODS: In the baseline examination of ESTHER, a study conducted in Saarland, serological measurements of pepsinogen I and II and H. pylori antibodies were taken in 9444 participants aged 50-74 years. Information on potential risk factors and medical history were obtained by self-administered standardized questionnaire. RESULTS: A strong dose-response relationship between sibship size and H. pylori seroprevalence was observed (P < 0.01). Adjusted odds ratios (ORs) 95% confidence interval (CI) for H. pylori seropositivity for subjects with 4, 5, 6 and 7 or more siblings compared with subjects without siblings were 1.45 (1.20-1.77), 1.83 (1.50-2.22) and 1.84 (1.47-2.31), respectively. A large sibship size was also associated with an increased risk of CAG with an adjusted OR of 1.42 (1.01-2.01) for 7 or more compared with less than or equal to 2 siblings. This association was attenuated but not entirely eliminated after additional adjustment for H. pylori infection. Notably, a significant association between large sibship size and CAG was also found among H. pylori-negative subjects. CONCLUSIONS: Our results suggest that large sibship size is associated with increased H. pylori prevalence and CAG risk. The association with CAG risk may be mediated at least in part by H. pylori infection. However, mechanisms other than H. pylori infection may contribute to the 'sibling effect' as well.

Helicobacter pylori infection and gastric cancer risk: evaluation of 15 H. pylori proteins determined by novel multiplex serology.

Infection with Helicobacter pylori is a major cause of gastric cancer (GC). The association likely has been underestimated in the past due to disease-related clearance of the infection. On the other hand, only a minority of the infected individuals develop GC, and better risk stratification is therefore highly desirable. We aimed to assess the association of GC with antibodies to 15 individual H. pylori proteins, determined by novel multiplex serology, to identify potentially relevant risk markers. This analysis was based on 123 GC cases aged 50 to 74 years and 492 age-matched and sex-matched controls from Saarland, Germany. Eight of the antibodies were significantly associated with noncardia GC and seven of them were significantly related to GC at any site. More pronounced associations were observed for noncardia GC; adjusted odds ratios (95% confidence intervals) ranged from 1.60 (1.01-2.54) for HyuA to 5.63 (3.20-9.91) for cytotoxin-associated antigen A (CagA). A dose-response relationship was found between the number of seropositivities and GC (P < 0.001). The seropositivities of CagA and GroEL were found to be independent predictors of GC, which were strongly related to GC risk in a dose-response manner (P < 0.001). In conclusion, GroEL was identified as a new independent risk marker that may contribute to enhanced quantification of H. pylori-related GC risk.

Alcohol consumption and chronic atrophic gastritis: population-based study among 9,444 older adults from Germany.

Moderate alcohol consumption has been suggested to facilitate elimination of Helicobacter pylori infection which is a key risk factor for chronic atrophic gastritis (CAG) and gastric cancer. The aim of our study was to assess the association of alcohol consumption with CAG among older adults from Germany. In the baseline examination of ESTHER, a population-based study conducted in Saarland, serological measurements of pepsinogen I and II (for CAG definition) and H. pylori antibodies were taken in 9,444 subjects aged 50-74 years. Moderate current (<60 g/week) and lifetime (

Inverse association between a pro-inflammatory genetic profile and Helicobacter pylori seropositivity among patients with chronic atrophic gastritis: enhanced elimination of the infection during disease progression?

BACKGROUND: Helicobacter pylori infection is a key risk factor for chronic atrophic gastritis (CAG), an established precursor of gastric cancer. There is increasing evidence of frequent clearance of the infection during progression of CAG. We aimed to assess the association between host inflammatory polymorphisms and H. pylori seropositivity among CAG patients from Germany. METHODS: In the baseline examination of ESTHER, a population-based study conducted in Saarland, serum pepsinogens I and II and H. pylori serostatus were measured by ELISA, and selected genetic polymorphisms (IL1A C-889T, IL1B C-511T, IL1RN A9589T, IL8 T-251A, IL10 T-819C, IL10 A-1082G, LTA C+80A and TNFA G-308A) were assessed by Pyrosequencing for 534 serologically defined CAG cases. RESULTS: H. pylori seropositivity strongly decreased with disease severity, which is defined by quintiles of serum pepsinogen I, from higher than 90% in the least severe cases to hardly over 50% in the most severe cases. The pro-inflammatory genotypes IL10 -819CC and IL1RN 9589TT were significantly associated with decreased H. pylori seroprevalences with odds ratios of 0.45 (95% confidence interval (CI): 0.23-0.88) and 0.41 (95% CI: 0.18-0.92), respectively, after controlling for age, sex and disease severity. H. pylori seropositivity decreased with the number of pro-inflammatory genotypes (p<0.01). CONCLUSIONS: Our results disclose a clear inverse association between a pro-inflammatory genetic profile and H. pylori seropositivity among cases with CAG, supporting suggestions of enhanced elimination of H. pylori during the development of the disease.

Helicobacter pylori infection and chronic atrophic gastritis: associations according to severity of disease.

BACKGROUND: Helicobacter pylori infection is an established risk factor for chronic atrophic gastritis. However, estimates of the strength of this association have varied widely, possibly due to clearance of the infection in severe stages of chronic atrophic gastritis, which may lead to underestimation of the association. We assessed the association of H. pylori infection with chronic atrophic gastritis according to severity of disease. METHODS: We measured serum pepsinogen I and II (as surrogates for chronic atrophic gastritis) and antibodies against H. pylori by ELISA in 9444 men and women aged 50-74 years in a population-based study in Saarland, a state of Germany. The association between H. pylori and chronic atrophic gastritis (defined as pepsinogen I <70 ng/mL and pepsinogen I/II-ratio <3) was analyzed after stratification of chronic atrophic gastritis cases by quintiles of pepsinogen I as proxy marker for severity of chronic atrophic gastritis. RESULTS: When all cases were included, the odds ratio for the association with Chronic atrophic gastritis for H. pylori infection alone was 2.9 (95% confidence interval 2.3-3.6); it was 4.1 (3.2-5.2), for H. pylori infection that was positive for the presence of Ig G antibodies specific to the cytotoxin-associated gene A (CagA) protein-a well-established virulence factor of H. pylori. These ORs ranged from 11 (5.2-22) and 16 (7.7-34) for the quintile of cases with highest pepsinogen I (least severe cases) to 1.0 (0.7-1.6) and 0.9 (0.5-1.5) for the quintile of cases with lowest pepsinogen I (most severe cases). Five of 7 cases with CagA-seropositivity but negative H. pylori serostatus (a pattern indicative of past infection) were in the group of most severe cases. CONCLUSIONS: Our results support the hypothesis of major underestimation of the association of H. pylori and chronic atrophic gastritis, due to clearance of the infection in advanced stages of the disease. These results suggest that the association is much stronger than estimated by most epidemiologic studies to date.

Association between chronic atrophic gastritis and serum antibodies to 15 Helicobacter pylori proteins measured by multiplex serology.

Infection with Helicobacter pylori is a major risk factor for chronic atrophic gastritis (CAG), a precursor lesion of intestinal gastric cancer. The pathogenicity of the bacterium is thought to play an important role in determining the extent and severity of clinical outcome. We aimed to assess the associations between CAG and the serostatus of antibodies to 15 H. pylori proteins. The analyses were based on 534 cases with serologically defined CAG and 1,068 age-matched and sex-matched controls participating in a population-based study conducted in Saarland, Germany among 9,953 men and women ages 50 to 74 years. A newly developed H. pylori multiplex serology method was used to detect antibodies specific to 15 H. pylori antigens. Significant associations were observed between seropositivity for all 15 specific antibodies and the presence of CAG. Exclusion of severe cases, who might have lost the infection in the course of CAG progression, substantially increased the observed associations. In H. pylori-seropositive subjects, cytotoxin-associated gene A (CagA), vacuolating toxin (VacA), helicobacter cysteine-rich protein C (HcpC), and the chaperonin GroEL were identified as independent virulence factors for CAG with adjusted odds ratios (95% confidence interval) of 3.52 (2.01-6.10), 3.19 (1.44-7.05), 4.03 (1.53-10.65), and 2.65 (1.06-6.62), respectively; the simultaneous presence of all four independent virulence factors was associated with an 18-fold risk of CAG. In conclusion, HcpC and GroEL were identified as new independent virulence factors, and in combination with the established virulence factors, CagA and VacA, were strongly associated with CAG.

Association between a pro-inflammatory genetic profile and the risk of chronic atrophic gastritis among older adults from Germany.

BACKGROUND: Pro-inflammatory polymorphisms have been suggested to explain part of the individual diversity in susceptibility to gastric carcinogenesis. We aimed to assess their impact on the risk of chronic atrophic gastritis (CAG) in a population-based study. METHODS: Among 9953 older adults from Saarland/Germany, eight single nucleotide polymorphisms (SNPs) were assessed for 534 cases with serologically defined CAG and 534 age- and sex-matched controls at baseline examination. RESULTS: Of the 8 SNPs, only IL10 T-819C showed a borderline significant association with CAG risk (odds ratio for CC versus TT: 1.67 (95% confidence interval: 1.01-2.76)). No significant differences were observed for the distribution of inferred haplotypes between cases and controls. However, joint evaluation of several cytokine variants suggested an increased risk of CAG among individuals carrying several pro-inflammatory genotypes. CONCLUSIONS: Our findings suggest that a pro-inflammatory genetic profile may contribute to inter-individual variation in gastric cancer risk by increasing the susceptibility to the development of CAG.

Association of Helicobacter pylori infection with chronic atrophic gastritis: Meta-analyses according to type of disease definition.

Helicobacter pylori is a major risk factor for chronic atrophic gastritis (CAG). A large variety of definitions of CAG have been used in epidemiologic studies in the past. The aim of this work was to systematically review and summarize estimates of the association between H. pylori infection and CAG according to the various definitions of CAG. Articles on the association between H. pylori infection and CAG published until July 2007 were identified. Separate meta-analyses were carried out for studies defining CAG based on gastroscopy with biopsy, serum pepsinogen I (PG I) only, the pepsinogen I/pepsinogen II ratio (PG I/PG II ratio) only, or a combination of PG I and the PG I/PG II ratio. Numbers of identified studies and summary odds ratios (OR) (95% confidence intervals) were as follows: gastroscopy with biopsy: n = 34, OR = 6.4 (4.0-10.1); PG I only: n = 13, OR = 0.9 (0.7-1.2); PG I/PG II ratio: n = 8, OR = 7.2 (3.1-16.8); combination of PG I and the PG I/PG II ratio: n = 20, OR = 5.7 (4.4-7.5). Studies with CAG definitions based on gastroscopy with biopsy or the PG I/PG II ratio (alone or in combination with PG I) yield similarly strong associations of H. pylori with CAG. The association is missed entirely in studies where CAG is defined by PG I only.

Epidemiologic findings on serologically defined chronic atrophic gastritis strongly depend on the choice of the cutoff-value.

Chronic atrophic gastritis (CAG), a precursor of intestinal gastric cancer, is mostly ascertained noninvasively by serum pepsinogens in epidemiologic studies. However, serological definitions vary widely. We aimed to investigate the impact of this variation on estimated prevalence of CAG and its association with its main risk factors, age and Helicobacter pylori infection. Serum pepsinogen I and II and antibodies against H. pylori were measured by ELISA among 9,444 women and men aged 50-74 years in a population-based cohort study in Saarland/Germany. Application of the various definitions resulted in a wide range of prevalence estimates of CAG prevalence (2.1%-8.2%, with an outlier of 18.8% for one particular definition) and its associations with age and H. pylori infection (age adjusted odds ratios, OR, for CagA positive H. pylori infection: 0.98-4.48). Definitions of CAG based on both pepsinogen I and the pepsinogen I/II ratio or on the pepsinogen I/II ratio only revealed much clearer associations with both age and H. pylori infection than definitions of CAG based on pepsinogen I only (ORs for H. pylori infection: 1.45-4.48 and 0.86-1.30, respectively). Epidemiologic findings on CAG lack comparability due to the heterogeneity in serologic definitions of CAG. The association of age and H. pylori infection with CAG may be strongly underestimated in studies in which CAG is defined by pepsinogen I only.