cagA Status Research Articles

Helicobacter pylori cagA, vacA, and iceA genotypes and clinical outcomes: a cross-sectional study in central Vietnam.

Helicobacter pylori is the most common cause of gastroduodenal diseases. The concept that cagA-positive H. pylori is a risk factor for gastric cancer appears to be true only for H. pylori strains from Western countries. Other virulent genes may have a synergistic interaction with cagA during pathogenesis. This study aims to investigate H. pylori cagA, vacA, and iceA prevalence, genotypes, and their association to clinical outcomes in Vietnamese patients. The cagA status and vacA and iceA genotypes were determined using the PCR technique on DNA extracted from gastric biopsies of 141 patients with gastroduodenal diseases. After performing molecular analysis for cagA, vacA, and iceA genes, samples with mixed H. pylori strains, positivity, or negativity for both cagA and cagPAI-empty site, or unidentified genotypes were excluded. Finally, 107 samples were examined. The presence of the cagA, vacA, and iceA genes were detected in 77.6%, 100%, and 80.4% of cases, respectively. Notably, cagA( +) with EPIYA-ABD, vacA s1i1m1, vacA s1i1m2, iceA1, and iceA2 accounted for 73.8%, 44.9%, 33.6%, 48.6%, and 31.8% of cases, respectively. Four iceA2 subtypes (24-aa, 59-aa, 94-aa, and 129-aa variants) were found, with the 59-aa variant the most prevalent (70.6%). The cagA( +)/vacAs1i1m1/iceA1 and cagA( +)/vacAs1i1m2/iceA1 combinations were found in 26.2% and 25.1% of cases, respectively. A multivariable logistic regression analysis was performed, after adjusting for age and gender, with the gastritis group was used as a reference control. Statistically significant associations were found between the vacA s1i1m2 genotype, the iceA1 variant, and the cagA( +)/vacAs1i1m2/iceA1 combination and gastric cancer; the adjusted ORs were estimated as 18.02 (95% CI: 3.39-95.81), 4.09 (95% CI: 1.1-15.08), and 16.19 (95% CI: 3.42-76.66), respectively. Interestingly, for the first time, our study found that vacA s1i1m2, but not vacA s1i1m1, was a risk factor for gastric cancer. This study illustrates the genetic diversity of the H. pylori cagA, vacA, and iceA genes across geographical regions and contributes to understanding the importance of these genotypes for clinical outcomes.

Helicobacter pylori CagA-mediated ether lipid biosynthesis promotes ferroptosis susceptibility in gastric cancer

Helicobacter pylori, particularly cytotoxin-associated gene A (CagA)-positive strains, plays a key role in the progression of gastric cancer (GC). Ferroptosis, associated with lethal lipid peroxidation, has emerged to play an important role in malignant and infectious diseases, but the role of CagA in ferroptosis in cancer cells has not been determined. Here, we report that CagA confers GC cells sensitivity to ferroptosis both in vitro and in vivo. Mechanistically, CagA promotes the synthesis of polyunsaturated ether phospholipids (PUFA-ePLs), which is mediated by increased expression of alkylglycerone phosphate synthase (AGPS) and 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), leading to susceptibility to ferroptosis. This susceptibility is mediated by activation of the MEK/ERK/SRF pathway. SRF is a crucial transcription factor that increases AGPS transcription by binding to the AGPS promoter region. Moreover, the results demonstrated that CagA-positive cells are more sensitive to apatinib than are CagA-negative cells, suggesting that detecting the H. pylori CagA status may aid patient stratification for treatment with apatinib.

Distribution of vacA and cagA status of Helicobacter pylori from endoscopy referral patients of Benue State University Teaching Hospital Makurdi, Benue State Nigeria

Distribution of vacA and cagA status of Helicobacter pylori from endoscopy referral patients of Benue State University Teaching Hospital Makurdi, Benue State Nigeria

CagA toxin and risk of Helicobacter pylori-infected gastric phenotype: A meta-analysis of observational studies.

Helicobacter pylori (H. pylori) is frequently associated with non-cardia type gastric cancer, and it is designated as a group I carcinogen. This study aimed to systematically review and meta-analyze the evidence on the prevalence of CagA status in people with gastric disorders in the Indo-Pacific region, and to examine the association of CagA positive in the risk of gastric disorders. This study focused on the Indo-Pacific region owing to the high disability adjusted life-years related to these disorders, the accessibility of efficient treatments for this common bacterial infection, and the varying standard of care for these disorders, particularly among the elderly population in the region. Relevant studies were identified in the health-related electronic databases including PubMed, Ovid, Medline, Ovid Embase, Index Medicus, and Google Scholar that were published in English between 1 January 2000, and 18 November 2023. For pooled prevalence, meta-analysis of proportional studies was done, after Freeman-Tukey double arcsine transformation of data. A random-effect model was used to compute the pooled odds ratio (OR) and 95% confidence interval (CI) to investigate the relationship between CagA positivity and gastric disorders. Twenty-four studies from eight Indo-Pacific countries (Bhutan, India, Indonesia, Malaysia, Myanmar, Singapore, Thailand, Vietnam) were included. Overall pooled prevalence of CagA positivity in H. pylori-infected gastric disorders was 83% (95%CI = 73-91%). Following stratification, the pooled prevalence of CagA positivity was 78% (95%CI = 67-90%) in H. pylori-infected gastritis, 86% (95%CI = 73-96%) in peptic ulcer disease, and 83% (95%CI = 51-100%) in gastric cancer. Geographic locations encountered variations in CagA prevalence. There was a greater risk of developing gastric cancer in those with CagA positivity compared with gastritis (OR = 2.53,95%CI = 1.15-5.55). Findings suggest that the distribution of CagA in H. pylori-infected gastric disorders varies among different type of gastric disorders in the study countries, and CagA may play a role in the development of gastric cancer. It is important to provide a high standard of care for the management of gastric diseases, particularly in a region where the prevalence of these disorders is high. Better strategies for effective treatment for high-risk groups are required for health programs to revisit this often-neglected infectious disease.

Clinical manifestations and comorbid conditions in patients with chronic gastritis according to Helicobacter pylori CagA and VacA status

Objective — to determine the frequency of clinical manifestations and comorbidities in patients with Helicobacter pylori‑associated chronic gastritis, depending on the presence of H. pylori cytotoxin‑associated gene A and vacuolating cytotoxin A status. Materials and methods. This cross‑sectional study included 84 patients aged over 18 years with H. pylori‑associated chronic gastritis (CG). Patients were divided into two groups: 50 patients with the cytotoxin‑associated gene A (CagA) and vacuolating cytotoxin A (VacA) H. pylori strains and 34 patients with CagA‑ and VacA‑ H. pylori strains. H. pylori virulent strains (CagA+, VacA+) were detected using the polymerase chain reaction method. Solid‑phase enzyme‑linked immunosorbent assay (ELISA) was employed to detect immunoglobulins (IgA, IgG) against the CagA and VacA antigens of H. pylori. Analysis of medical records was conducted to assess clinical manifestations and the presence of comorbidities. Comorbid conditions were diagnosed using electrocardiography, abdominal ultrasound, and when necessary, computed tomography and magnetic resonance imaging, as well as videocolonoscopy. Statistical analysis was performed using the Stata 11 and Statistica 6 statistical software packages. Results. Patients with CagA+ and VacA+ H. pylori strains were more likely to have epigastric pain (60% vs. 35.3%, p=0.026) and constipation (52% vs. 20.6%, p=0.004) than patients with CagA‑ and VacA‑ H. pylori strains. Among the associated comorbid conditions in patients with H. pylori‑associated CG, the following were identified: gastroesophageal reflux disease — 33.3%, irritable bowel syndrome — 35.7%, non‑alcoholic fatty liver disease — 23.8%, autoimmune thyroiditis — 9.5%, arterial hypertension — 10.7%, and ischemic heart disease — 10.7%. The irritable bowel syndrome was significantly more prevalent in patients with CagA+ and VacA+ H. pylori strains, compared to those without CagA and VacA strains (46% vs. 20.6%, p=0.017). Other comorbid conditions occurred at similar frequencies among patients in both groups (p <0.05). Conclusions. Our study established that H. pylori virulent strains (CagA+, VacA+) could influence the clinical manifestations and associated conditions in patients with CG. Epigastric pain and constipation were more frequently observed in patients with H. pylori virulent strains (CagA+, VacA+), while the occurrence of irritable bowel syndrome was more pronounced among the associated conditions. The presence of H. pylori infection with CagA+ and VacA+ strains may be a risk factor for the development of irritable bowel syndrome. Eradication therapy could be considered as a preventive method for this comorbidity, but further research is needed to confirm this hypothesis.

Frequency of dyspeptic symptoms, anxiety, depression and health-related quality of life among patients with chronic gastritis according to Helicobacter pylori CagA and VacA status: a cross-sectional study

Objective — to determine the frequency of dyspeptic symptoms, anxiety and depression and to describe health‑related quality of life in patients with chronic gastritis according to Helicobacter pylori cytotoxin‑associated gene A and vacuolating cytotoxin A status.
 Materials and methods. This cross‑sectional study included a total of 84 patients with H. pylori‑associated chronic gastritis (CG). Based on H. pylori virulence factors status patients were categorized into 2 groups: 50 patients with the cytotoxin‑associated gene A (CagA) and vacuolating cytotoxin A (VacA)‑positive H. pylori strains (Group 1) and 34 patients with CagA‑ and VacA‑negative H. pylori strains (Group 2). The H. pylori virulence factors were determined by the polymerase chain reaction using paraffin stomach biopsies. Serum IgA and IgG antibodies to CagA and VacA were evaluated by solid‑phase enzyme‑linked immunoabsorbent assay. The Hospital Anxiety and Depression Scale (HADS) was used to identify anxiety disorders and depression. The MOS 36‑Item Short Form Health Survey (SF‑36) questionnaire was used to assess the health‑related quality of life (HRQoL). Statistical analysis was performed using Stata 11 and Statistica 6 software packages.
 Results. Patients with CagA‑ and VacA‑positive H. pylori strains were more likely to have epigastric pain than patients with CagA‑ and VacA‑negative H. pylori strains (60% vs. 35.3%, p=0.026). No statistical difference was observed between the frequency of epigastric burning, early satiety, and postprandial fullness in both groups (р >0.05). Anxiety and depression were significantly more prevalent in patients with CagA‑ and VacA‑positive H. pylori strains (p=0.041; р=0.032, respectively). Patients of Group 1 had significantly lower HRQoL in the domains of Role‑Physical (50 vs. 75; p=0.0001), Bodily Pain (57.5 vs. 77.5; p=0.0001), General Health (45 vs. 75; p=0.0001), Vitality (55 vs. 80; p=0.0011) and Mental Health (56 vs. 84; p=0.0001).
 Conclusions. H. pylori CagA and VacA‑positive status is an important factor that may have an impact on the clinical course of H. pylori‑associated gastritis. Higher frequency of epigastric pain, anxiety, and depression, as well as lower health‑related quality of life were observed in patients with CagA‑ and VacA‑positive H. pylori strains.

RELATIONSHIP OF HELICOBACTER PYLORI CAGA AND VACA STATUS TO MORPHOLOGICAL CHANGES OF GASTRIC MUCOSA AND PRIMARY CLARITHROMYCIN RESISTANCE RATE IN PATIENTS WITH CHRONIC GASTRITIS: A CROSS-SECTIONAL STUDY.

The aim: To investigate the relation of H. pylori CagA and VacA status to morphological changes of gastric mucosa and primary clarithromycin resistance rate in patients with chronic gastritis. Materials and methods: A cross-sectional study was conducted between May 2021 and January 2023, involving 64 patients with H. pylori-associated chronić gastritis. The patients were assigned to two groups according to the H. pylori virulence factors (CagA and VacA) status. The grades of inflammation, activity, atrophy, and metaplasia were determined according to the Houston-updated Sydney system. The identification of H. pylori genetic markers of antibiotic resistance and pathogenicity was performed by the polymerase chain reaction using paraffin stomach biopsies. Results: Patients with CagA- and VacA-positive H. pylori strains had significantly higher grades of inflammation both in the antrum and in the corpus of the stomach, activity of gastritis in the antrum, higher incidence and grade of atrophy in the antrum. Primary resistance to clarithromycin was significantly more prevalent in patients with CagA- and VacA-negative H. pylori strains (58.3% vs. 11.5%, p=0.002). Conclusions: Positive CagA and VacA status is related to more severe histopathological changes of gastric mucosa. In contrast, the rate of primary clarithromycin resistance is higher in patients CagA- and VacA-negative H. pylori strains.

The active form of Helicobacter pylori vacuolating cytotoxin induces decay-accelerating factor CD55 in association with intestinal metaplasia in the human gastric mucosa.

High‐level expression of decay‐accelerating factor, CD55, has previously been found in human gastric cancer (GC) and intestinal metaplasia (IM) tissues. Therapeutic effects of CD55 inhibition in cancer have been reported. However, the role of Helicobacter pylori infection and virulence factors in the induction of CD55 and its association with histological changes of the human gastric mucosa remain incompletely understood. We hypothesised that CD55 would be increased during infection with more virulent strains of H. pylori, and with more marked gastric mucosal pathology. RT‐qPCR and immunohistochemical analyses of gastric biopsy samples from 42 H. pylori‐infected and 42 uninfected patients revealed that CD55 mRNA and protein were significantly higher in the gastric antrum of H. pylori‐infected patients, and this was associated with the presence of IM, but not atrophy, or inflammation. Increased gastric CD55 and IM were both linked with colonisation by vacA i1‐type strains independently of cagA status, and in vitro studies using isogenic mutants of vacA confirmed the ability of VacA to induce CD55 and sCD55 in gastric epithelial cell lines. siRNA experiments to investigate the function of H. pylori‐induced CD55 showed that CD55 knockdown in gastric epithelial cells partially reduced IL‐8 secretion in response to H. pylori, but this was not due to modulation of bacterial adhesion or cytotoxicity. Finally, plasma samples taken from the same patients were analysed for the soluble form of CD55 (sCD55) by ELISA. sCD55 levels were not influenced by IM and did not correlate with gastric CD55 mRNA levels. These results suggest a new link between active vacA i1‐type H. pylori, IM, and CD55, and identify CD55 as a molecule of potential interest in the management of IM as well as GC treatment. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Clinical relevance of the cagA and vacA s1m1 status and antibiotic resistance in Helicobacter pylori: a systematic review and meta-analysis

BackgroundThe role of Helicobacter pylori (H. pylori) virulence factors of such as vacA s1m1 and cagA in designating clinical outcomes and eradication rate has been deeply challenged in the last decade. The goal of this analysis was to identify the potential relevance between cagA and vacA genotypes with reported antibiotic resistance observed in clinical H. pylori isolates.MethodsThis literature search was conducted in databases such as Clarivate analytics, PubMed, Scopus, EMBASE, DOAJ, and Google Scholar by April 2022, regardless of language restrictions and publication date. Quality of the included studies was assessed by the Newcastle–Ottawa scale. Statistical analysis of retrieved studies was fulfilled using Comprehensive Meta-Analysis software version 2.2. Following quality appraisal of eligible studies, potential association between the status of cagA and vacA genes with resistance to clarithromycin, metronidazole, amoxicillin, tetracycline, and levofloxacin was measured using odds ratio with 95% confidence interval. We also used sensitivity analyses and meta-regression to eliminate the source of heterogeneity from the overall estimates. Publication bias was assessed using funnel plot, Egger’s test, Begg’s test with the trim and fill procedure to assess the presence and magnitude of publication bias in the included studies.ResultsOur findings suggested that a significant relationship between cagA status ‎and increase resistance ‎to metronidazole (OR: 2.69; 95% CI: 1.24–5.83‎‏‎). In subgroup analysis, we ‎found that in the Western ‎population, infection with cagA-positive strains could be led to increase in ‎the resistance to ‎metronidazole (OR: 1.59; 95% CI: ‎0.78–3.21‎‏‎), ‎amoxicillin (OR: ‎19.68‎; 95% CI: 2.74–‎‎141.18), ‎and ‎levofloxacin (OR: ‎11.33; 95% CI: ‎1.39–‎‎91.85). After implementation of trim and fill method, the adjusted OR was not significantly differed from original estimates which in turn represented our subgroup analysis was statistically robust. On the other hand, vacA ‎genotypes usually ‎reduce the antibiotic resistance of this bacterium, so that vacA s1m1 significantly reduces the ‎resistance to ‎metronidazole (OR: 0.41; 95% CI: 0.20–0.86‎‏‎). Surprisingly, resistance of vacA s2m2 strains to antibiotics was low, the reason may be due ‎to the non-inflammatory properties of strains containing vacA s2m2. The meta-regression and sensitivity analyses successfully reduced the effect of heterogeneity from the overall estimates. In addition, although the pooled OR is reduced after trim and fill adjustment but results do not change the conclusion regarding vacA genotypes and antibiotic resistance.ConclusionsAccording to our findings, it was clearly demonstrated that cagA-positive strains are resistance to metronidazole, especially in Western countries. In Western countries, vacA s1m1 increases resistance to amoxicillin and levofloxacin. Based on the present findings, the vacA s1m1 genotype significantly increases resistance to metronidazole, while the vacA s1m2 decreases resistance to clarithromycin and metronidazole. Resistance to antibiotics in less virulent (vacA s2m2) strains is statistically significant lower than others.

Assessment of gastric caused by Helicobacter pylori and pathologic elements correlation with -511 IL1-β and -308 TNF-α polymorphisms in gastritis patients

Helicobacter pylori (H.pylori) is the main reason for gastric disorders including gastric lymphoma, ulcer disease, gastric carcinoma (GC), and chronic atrophic gastritis. H.pylori has two more significant virulence factors named cagA and vacA. Some host cytokines polymorphisms (Interleukin (IL-1) and tumor necrosis factor (TNF-α)) may contribute to H. pylori-related diseases. In the present study, we investigated the association of H. pylori gastritis and its pathogenic genes as well as the association of IL-1β and TNF-α polymorphisms in patients with gastritis. We collected gastric biopsy samples from patients with gastritis. After extracting DNA from biopsy specimens infected with H. pylori, cagA + and vacA + were detected by the polymerase chain reaction (PCR). To genotyping TNF-α polymorphism at position −308 and IL-1β polymorphism at position −511, PCR-based restriction fragment length polymorphism analysis was performed. Our study indicated that IL-1β-511 polymorphism, unlike TNF-α-308 polymorphism (P = 0.030), did not show a significant relationship between patients infected with H. pylori (p = 0.219). Also, our results indicated that alleles C and T of polymorphism of IL-1β-511 and alleles G of TNFα-308 were not significantly correlated with cagA status among patients infected with H. pylori (p = 0.793, p = 0.674, p = 0.179, respectively) unlike allele A of TNFα −308 (p = 0.016).

Helicobacter pylori cagA status and gastric mucosa-associated lymphoid tissue lymphoma: a systematic review and meta-analysis

BackgroundRecent studies have investigated the role of Helicobacter pylori infection in the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. It is estimated that approximately 0.1% of people infected with H. pylori develop gastric MALT lymphoma. However, the role of the CagA antigen, the highest causative agent of H. pylori, in increasing the risk of gastric MALT lymphoma remains unclear and controversial. A systematic review and meta-analysis were conducted to evaluate the effect of cagA status on the development of gastric MALT lymphoma.MethodsAll articles evaluating the status of the cagA gene in the development of gastric MALT lymphoma were collected using systematic searches in online databases, including PubMed, Scopus, Embase, and Google Scholar, regardless of publication date. The association between cagA and gastric MALT lymphoma was assessed using the odds ratio (OR) summary. In addition, a random-effects model was used in cases with significant heterogeneity.ResultsA total of 10 studies met our inclusion criteria, among which 1860 patients participated. No association between cagA status and the development of MALT lymphoma (extranodal marginal zone B-cell lymphoma) was found in this study (OR 1.30; 0.906–1.866 with 95% CIs; I2: 45.83; Q-value: 12.92). Surprisingly, a meaningful association was observed between cagA status and diffuse large B-cell lymphoma (OR 6.43; 2.45–16.84 with 95% CIs). We also observed an inverse association between vacA and gastric MALT lymphoma risk (OR 0.92; 0.57–1.50 with 95% CIs).ConclusionsIt seems that the infection with cagA-positive H. pylori strains does not have a meaningful effect on the gastric MALT lymphoma formation, while translocated CagA antigen into the B cells plays a crucial role in the development of diffuse large B-cell lymphoma.

Identifying the Profile of Helicobacter pylori-Negative Gastric Cancers: A Case-Only Analysis within the Stomach Cancer Pooling (StoP) Project.

The prevalence of Helicobacter pylori-negative gastric cancer (HpNGC) can be as low as 1%, when infection is assessed using more sensitive tests or considering the presence of gastric atrophy. HpNGC may share a high-risk profile contributing to the occurrence of cancer in the absence of infection. We estimated the proportion of HpNGC, using different criteria to define infection status, and compared HpNGC and positive cases regarding gastric cancer risk factors. Cases from 12 studies from the Stomach cancer Pooling (StoP) Project providing data on H. pylori infection status determined by serologic test were included. HpNGC was reclassified as positive (eight studies) when cases presented CagA markers (four studies), gastric atrophy (six studies), or advanced stage at diagnosis (three studies), and were compared with positive cases. A two-stage approach (random-effects models) was used to pool study-specific prevalence and adjusted odds ratios (OR). Among non-cardia cases, the pooled prevalence of HpNGC was 22.4% (n = 166/853) and decreased to 7.0% (n = 55) when considering CagA status; estimates for all criteria were 21.8% (n = 276/1,325) and 6.6% (n = 97), respectively. HpNGC had a family history of gastric cancer more often [OR = 2.18; 95% confidence interval (CI), 1.03-4.61] and were current smokers (OR = 2.16; 95% CI, 0.52-9.02). This study found a low prevalence of HpNGC, who are more likely to have a family history of gastric cancer in first-degree relatives. Our results support that H. pylori infection is present in most non-cardia gastric cancers, and suggest that HpNGC may have distinct patterns of exposure to other risk factors.

Helicobacter pylori infection and serum pepsinogen concentrations in an elderly population representative of Costa Rica

INTRODUCTION: Costa Rica has among the highest mortality rates from gastric cancer in the world, largely due to late detection. It is therefore important that economically and logistically sustainable screening is implemented in order to detect risk of developing cancer. We have previously shown that low pepsinogen (PG) values and infection with Helicobacter pylori-CagA+ are associated with risk of gastric atrophy and cancer in Costa Rican populations. OBJECTIVES: To determine how markers for gastric cancer risk are distributed in an elderly population representative of Costa Rica in order to design a screening strategy. METHODS: The population studied consists of 2,652 participants in a nationally representative survey of ageing. Information concerning epidemiologic, demographic, nutritional and life style factors is available. Serum PG concentrations as well as H. pylori and CagA status were determined by serology. Possible associations were determined by regression analyses. RESULTS: Antibodies to H. pylori were present in 72% of the population and of those, 58% were CagA positive. Infection with H. pylori was associated with higher PGI concentrations (p=0.000) and infection with H. pylori-CagA+ with lower PGI concentrations (p=0.025). Both showed association with lower PGI/PGII (p=0.006 and p=0.000). Higher age was associated with lower prevalence of H. pylori infection (OR=0.98; p=0.000) and CagA+ (OR=0.98; p=0.000) but not with PG values. Regions with high risk of gastric cancer showed lower PGI (p=0.004) and PGI/PGII values (p=0.021) as well as higher prevalence of H. pylori infection (OR=1.39; p=0.013) but not CagA+. Using cut-off values of PGI<100 µg/L and PGI/PGII<2.0, 2.5 and 3.0, 7-15% of the population would be considered at risk. CONCLUSIONS: H. pylori alone is not a useful marker for risk of gastric cancer. Screening using serum pepsinogen concentrations and infection with H. pylori-CagA+ is feasible in the general elderly population of Costa Rica but appropriate cut-off values have to be determined based on more clinical data and follow up capacity.

TAS2R38 polymorphisms, Helicobacter pylori infection and susceptibility to gastric cancer and premalignant gastric lesions.

Gastric cancer is worldwide the fourth more common cancer type by incidence, and the third by mortality. We analyzed three missense variants of TAS2R38 gene: rs713598 (A49P), rs1726866 (V262A), and rs10246939 (I296V). These variants and their combination in haplotypes (proline, alanine and valine/tasters or alanine, valine and isoleucine/nontasters) and diplotypes are responsible for individual differences in bitter perception. The single-nucleotide polymorphisms and the related phenotypes are known to be associated with susceptibility to Gram-negative bacterial infections, such as Helicobacter pylori , and with risk of various cancer types. An association between intermediate tasters (as defined by TAS2R38 diplotypes) and increased risk of gastric cancer was reported in a Korean population. We analyzed 2616 individuals of Latin American origin, representing the whole spectrum of lesions from gastritis to gastric cancer. Comparing cancer cases vs. noncancers we observed a decrease in risk associated with heterozygous carriers of rs10246939 ( P = 0.006) and rs1726866 ( P = 0.003) when compared with homozygotes of the more common allele. Also, the analysis of diplotypes/phenotypes reflected the same association, with super-tasters showing a borderline increased risk of developing gastric cancer compared to medium-tasters [odds ratio (OR) = 1.63; 95% confidence interval (CI), 1.04-2.56; P = 0.033]. Also, nontasters showed an increased risk when compared to medium-tasters although not reaching statistical significance (OR = 1.58; 95% CI, 0.80-2.87; P = 0.203). We also tested the interactions between the TAS2R38 genotypes and H. pylori cagA status in a subset of samples and found no interaction. In conclusion, our results suggest only a modest contribution of TAS2R38 gene genetic variability in gastric cancer etiology.

1447Gastric histopathology by Helicobacter pylori cagA status in Arctic Canada

Abstract Background Our community-driven projects address concerns of Canadian Arctic Indigenous communities about Helicobacter pylori (Hp) infection, responsible for elevated gastric cancer mortality in the region. Community research partners wished to learn whether bacterial characteristics determine severity of Hp-related disease in their communities. We aimed to describe gastric histopathology by cagA genotype of Hp isolated from residents of 7 Indigenous communities in the Northwest Territories and Yukon. Methods Participants underwent gastroscopy with 5-6 biopsies taken for histopathological assessment and 2 biopsies taken for tissue culture during 2008-2017. We used multiple PCR reactions and DNA sequence analysis to classify Hp genotypes as cagA+ or cagA-. A single pathologist used the updated Sydney classification system to grade severity of 5 gastric pathology outcomes: Hp density; chronic gastritis; active gastritis; atrophy; and intestinal metaplasia. We estimated prevalence of each outcome with 95% confidence intervals (CI) by gastric subsite and cagA status. Results Of 262 Hp isolates assessed, 142 (54%) were cagA+. Prevalence of moderate-high Hp density, severe chronic gastritis, moderate-severe active gastritis, atrophy, and metaplasia were (%[CI]): respectively, 78[70-85], 44[36-53], 65[56-72], 55[46-63], 25[18-33] in cagA+ participants and 61[52-70], 35[27-44], 31[23-40], 32[23-41], 8[4-15] in cagA- participants. cagA+ participants had higher prevalence of all outcomes in antrum and corpus. Conclusion Hp-infected Indigenous residents of Arctic Canada who harbored cagA-positive strains had higher prevalence of more severe gastric pathology than those with cagA-negative strains. Key messages Community-driven research answers questions posed by those who bear the disease burden.

Diagnosis of Helicobacter pylori Infection in a Routine Testing Workflow: Effect of Bacterial Load and Virulence Factors.

Reliable diagnostic methods are mandatory for effective management of Helicobacter pylori infection. Histology and culture are the most common invasive methods in current practice, even if molecular methods are gaining in importance. The performance of these conventional methods varies significantly. We conducted a retrospective study of 1540 adults and 504 children with gastric biopsies taken during endoscopy to assess the impact of bacterial load and the cagA virulence factor on the performance of H. pylori infection testing. The association between virulence and histology findings was also investigated. With 23S rRNA qPCR confirmed by glmM amplification as the gold standard, culture and histology had lower sensitivity, 74.4% and 73.3%, respectively. However, their sensitivity was enhanced (>90%) in biopsies with high bacterial load (qPCR Ct < 30). Positive cagA status of the strain was associated with high bacterial load (94.9%), thus resulting in more frequent positive culture (94.3%) and H. pylori histology detection (91.7%) and more severe lesions on histology (p < 0.001). Conversely, the cagA status of the strains was negative in 110/119 (92.4%) of biopsies with low bacterial load (qPCR Ct < 30), 82/90 (91.1%) with negative H. pylori histology detection and 119/131 (90%) with negative culture findings (p < 0.001). This study highlights the low sensitivity of conventional culture and histology that may lead to false negative diagnosis if used alone. H. pylori quantification associated with cagA genotyping in routine workflow are essential for a sensitive and reliable diagnosis, to identify patients at high risk and to manage eradication therapies.

CagE, cagA and cagA 3′ region polymorphism of Helicobacter pylori and their association with the intra-gastric diseases in Moroccan population

Helicobacter pylori infection is the most important etiological factor in gastroduodenal diseases development. Its evolution is influenced by several factors, including bacterial virulence genes such as cagA and cagE. This work aimed to evaluate the predictive value of cagE alone and in combination with cagA and CagA-EPIYA-C motifs number as a marker of the infection evolution. A total of 823 H. pylori DNA extracted from biopsies of consenting patients suffering from gastritis, peptic ulcer, or gastric cancer. The cagE, cagA status and cagA 3' region polymorphism were determined by PCR. The analysis shows that the risk of duodenal ulcer is 1.97-fold higher (CI = 1.18-3.30) in patients infected by strains cagA+/cagE+. And the risk of gastric cancer is 5.19-fold higher (CI = 1.18-22.70) in patients harboring strains cagE+/2EPIYA-C. The results suggest that cagE in combination with cagA-EPIYA-C motifs number can be used as predictive biomarker of H. pylori infection evolution.

Association between Helicobacter pylori and risk of childhood asthma: a meta-analysis of 18 observational studies

Objective: The association between Helicobacter pylori (H. pylori) and childhood asthma is unclear. Thus, the aim of this study was to explore the association between H. pylori and childhood asthma. Methods: A literature search, study selection, and data extraction were performed independently and in duplicate. Data were analyzed using STATA software. Results: Eighteen studies enrolling 17,196 children were analyzed. All studies were of moderate-to-high quality. Four studies subcategorized H. pylori infection according to CagA status. Overall, there was a significant negative association between H. pylori and risk for childhood asthma (OR = 0.68; 95% CI, 0.54–0.87; P = 0.002), with no/marginal publication bias identified by the Egger’s test and the Begg’s test (P = 0.162 and P = 0.198, respectively). The observed inverse association persisted for CagA(+) strains of H. pylori (OR = 0.58; 95% CI, 0.35–0.96; P = 0.034) but not for CagA(−) strains (OR = 0.52; 95% CI, 0.12–2.28; P = 0.387). There was no significant difference between studies with respect to study design, participant age, geographical region, and method of measuring H. pylori. Conclusion: The evidence suggests that H. pylori infection, particularly CagA(+) H. pylori infection, is inversely associated with the risk of childhood asthma. Supplemental data for this article can be accessed at publisher’s website.

The TNF-A–857*T Polymorphism is Associated with Gastric Adenocarcinoma Risk in a Costa Rican Population

BackgroundCosta Rica is ranked as one of the countries with highest incidence of gastric cancer worldwide. Previous studies in Costa Rican populations have revealed associations between gastric cancer risk and several cytokine polymorphisms that seem to play a role in the regulation of the expression of these proteins. In this study, we assessed associations of the polymorphisms IL-6-174 G/C, IFNGR1-56 C/T, IL-8-251 T/A and TNF-A (-857 C/T, -308 A/G) with gastric pathologies in a high-risk population of Latin America. MethodsDNA samples of 47 patients with gastric adenocarcinoma, 53 with chronic gastritis, 56 with duodenal ulcer and 94 healthy controls, were genotyped for the five mentioned SNPs. All participants were ≥50-years-old. Genotyping was performed by PCR-RFLP and 5’-nuclease PCR assay. H. pylori infection, CagA status, pepsinogen (PG) I and II blood levels were determined by ELISA. Logistic regression analysis was used to determine possible associations of the polymorphisms with cancer, gastritis and duodenal ulcer, and linear regression analysis to determine associations with blood PG levels. ResultsA total of 86.6% of the population was positive for H. pylori; of them, 51.6% was CagA+. Patients with the TNF-A-857*T allele had an increased risk for gastritis (OR: 3.67, p = 0.015) and gastric adenocarcinoma (OR:6.15, p = 0.001). Associations between other polymorphisms and gastric diseases, or PG levels, were not found. ConclusionsOur results indicate that the TNF-A-857*T SNP is among the risk factors associated with the risk of gastric cancer in Costa Rica.

THE H. PYLORI-RELATED VIRULENCE FACTOR CAGA INFLUENCES THE EXPRESSION OF CHEMOKINES CXCL10, CCL17, CCL20, CCL22, AND THEIR RECEPTORS BY PERIPHERAL BLOOD MONONUCLEAR CELLS FROM PEPTIC ULCER PATIENTS

During the Helicobacter pylori (HP) infection, the infiltration of the leukocytes into stomach mucosa is directed by locally produced chemokines that play a decisive role in infection outcome. The CagA is the most potent virulence factor of HP, so that the infection with CagA + strains is associated with more severe complications than infection with CagA - HP. The aim was to determine the expression of chemokines CXCL10, CCL17, CCL20 and CCL22, and their receptors by CagA + HP- and CagA - HP-derived crude extract (HP-CE)-stimulated peripheral blood mononuclear cells (PBMCs) from peptic ulcer (PU) patients. The serum and the PBMCs were collected from 20 HP-infected PU patients, 20 HP-infected asymptomatic subjects (HIA) and 20 non-infected healthy subjects (NHS). The PBMCs were cultured in absence of stimulator or with 10 µg CagA + HP crude extract (CagA + CE), 10 µg CagA - HP crude extract (CagA - CE). Chemokines and receptors were measured by ELISA and real time-PCR respectively. In PU patients, the production of chemokines CXCL10, CCL17, CCL20 and CCL22, and the expression of chemokine receptors CXCR3, CCR4 and CCR6 by CagA + CE-induced PBMCs were significantly higher than non-stimulated and CagA - CE stimulated cultures. The CXCL10 production by CagA + CE stimulated PBMCs from HIA subjects was significantly higher than the equal cultures from PU and NHS groups. The CCL17 and the CCL20 production by non-stimulated, CagA + CE stimulated, and CagA - CE stimulated PBMCs from PU subjects were significantly higher than the equal cultures from NHS and HIA groups. The CCL22 production by non-stimulated, CagA + CE stimulated and CagA - CE stimulated PBMCs from NHS group were significantly higher than the equal cultures from HIA and PU groups. The CagA + CE stimulated PBMCs from HIA subjects expressed lower amounts of CCR6 in comparison with CagA + CE stimulated PBMCs from NHS and PU groups. The serum levels CXCL10 and CCL20 in PU and HIA groups were significantly higher than NHS subjects. NHS and HIA groups displayed higher serum levels of CCL22 in comparison with PU patients. Results indicated that the CagA status of bacterium influence the expression of chemokines and receptors by HP-CE stimulated PBMCs from PU patients.