Two remarkable serine/leucine polymorphisms in Helicobacter pylori: functional importance for serine protease HtrA and adhesin BabA.

Single nucleotide polymorphisms (SNPs) account for significant genomic variability in microbes, including the highly diverse gastric pathogen Helicobacter pylori. However, data on the effects of specific SNPs in pathogen-host interactions are scarce. Recent functional studies unravelled how a serine/leucine polymorphism in serine protease HtrA affects the formation of proteolytically active trimers and modulates cleavage of host cell-to-cell junction proteins during infection. A similar serine/leucine mutation in the carbohydrate binding domain of the adhesin BabA controls binding of ABO blood group antigens, enabling binding of either only the short Lewis b/H antigens of blood group O or also the larger antigens of blood groups A and B. Here we summarize the functional importance of these two remarkable bacterial SNPs and their effect on the outcome of pathogen-host interactions.

Fourteen-day vonoprazan-based bismuth quadruple therapy for H. pylori eradication in an area with high clarithromycin and levofloxacin resistance: a prospective randomized study (VQ-HP trial).

Potassium-competitive acid blockers (P-CABs) provide potent acid inhibition, yet studies on P-CAB-based quadruple therapy for H. pylori eradication are limited. We theorized that integrating bismuth subsalicylate into a quadruple therapy regimen could enhance eradication rates. However, data on the efficacy of vonoprazan bismuth quadruple therapy are notably scarce. Therefore, the aim of this study was to evaluate the efficacy of vonoprazan-based bismuth quadruple therapy in areas with high clarithromycin and levofloxacin resistance. This was a prospective, single-center, randomized trial conducted to compare the efficacy of 7-day and 14-day vonoprazan-based bismuth quadruple therapy for H. pylori eradication between June 1, 2021, and March 31, 2022. Qualified patients were randomly assigned to the 7-day or 14-day regimen (1:1 ratio by computer-generated randomized list as follows: 51 patients for the 7-day regimen and 50 patients for the 14-day regimen). The regimens consisted of vonoprazan (20 mg) twice daily, bismuth subsalicylate (1024 mg) twice daily, metronidazole (400 mg) three times daily, and tetracycline (500 mg) four times daily. CYP3A4/5 genotyping and antibiotic susceptibility tests were also performed. Successful eradication was defined as 13negative C-UBTs 4 weeks after treatment. The primary endpoint was to compare the efficacy of 7-day and 14-day regimens as first-line treatments, which were assessed by intention-to-treat (ITT) and per-protocol (PP) analyses. The secondary endpoints included adverse effects. A total of 337 dyspeptic patients who underwent gastroscopy were included; 105 patients (31.1%) were diagnosed with H. pylori infection, and 101 patients were randomly assigned to each regimen. No dropouts were detected. The antibiotic resistance rate was 33.3% for clarithromycin, 29.4% for metronidazole, and 27.7% for levofloxacin. The CYP3A4 genotype was associated with 100% rapid metabolism. The H. pylori eradication rates for the 7-day and 14-day regimens were 84.4%, 95% CI 74.3-94.2 and 94%, 95% CI 87.4-100, respectively (RR difference 0.25, 95% CI 0.03-0.53, p value = 0.11). Interestingly, the 14-day regimen led to 100% eradication in the clarithromycin-resistant group. Among the patients in the 7-day regimen group, only two exhibited resistance to clarithromycin; unfortunately, neither of them achieved a cure from H. pylori infection. The incidence of adverse events was similar in both treatment groups, occurring in 29.4% (15/51) and 28% (14/50) of patients in the 7-day and 14-day regimens, respectively. No serious adverse reactions were reported. In conclusion, 14 days of vonoprazan-based bismuth quadruple therapy is highly effective for H. pylori eradication in areas with high levels of dual clarithromycin and levofloxacin resistance.

Differential cytokine expression in gastric tissues highlights helicobacter pylori's role in gastritis.

Helicobacter pylori (H. pylori), known for causing gastric inflammation, gastritis and gastric cancer, prompted our study to investigate the differential expression of cytokines in gastric tissues, which is crucial for understanding H. pylori infection and its potential progression to gastric cancer. Focusing on Il-1ß, IL-6, IL-8, IL-12, IL-18, and TNF-α, we analysed gene and protein levels to differentiate between H. pylori-infected and non-infected gastritis. We utilised real-time quantitative polymerase chain reaction (RT-qPCR) for gene quantification, immunohistochemical staining, and ELISA for protein measurement. Gastric samples from patients with gastritis were divided into three groups: (1) non-gastritis (N-group) group, (2) gastritis without H. pylori infection (G-group), and (3) gastritis with H. pylori infection (GH-group), each consisting of 8 samples. Our findings revealed a statistically significant variation in cytokine expression. Generally, cytokine levels were higher in gastritis, but in H. pylori-infected gastritis, IL-1ß, IL-6, and IL-8 levels were lower compared to H. pylori-independent gastritis, while IL-12, IL-18, and TNF-α levels were higher. This distinct cytokine expression pattern in H. pylori-infected gastritis underscores a unique inflammatory response, providing deeper insights into its pathogenesis.

Helicobacter pylori infection induces gastric cancer cell malignancy by targeting HOXA-AS2/miR-509-3p/MMD2 axis.

BACKGROUND: Helicobacter pylori (Hp) infection is considered to be the strongest risk factor for gastric cancer (GC). Long non-coding RNA HOXA cluster antisense RNA 2 (HOXA-AS2) has been indicated to be significantly related to Hp infection in GC patients. OBJECTIVE: To investigate the detailed role and molecular mechanism of lncRNA HOXA-AS2 in Hp-induced GC. METHODS: GC cells were treated with Hp filtrate for cell infection. Bioinformatics tools were utilized for survival analysis and prediction of HOXA-AS2 downstream molecules. Western blotting and RT-qPCR were utilized for assessing protein and RNA levels, respectively. Flow cytometry, colony formation and CCK-8 assays were implemented for testing HOXA-AS2 functions in Hp-infected GC cells. HOXA-AS2 localization in cells was determined by subcellular fractionation assay. The relationship between RNAs were measured by luciferase reporter assay. RESULTS: Hp infection induced HOXA-AS2 upregulation in GC cells. Knocking down HOXA-AS2 restrained cell proliferation but promoted cell apoptosis with Hp infection. HOXA-AS2 bound to miR-509-3p, and miR-509-3p targeted monocyte to macrophage differentiation associated 2 (MMD2). Overexpressing MMD2 reversed HOXA-AS2 depletion-mediated suppression on cell aggressiveness with Hp infection. CONCLUSION: Hp infection induces the aggressiveness of GC cells by regulating HOXA-AS2/miR-509-3p/MMD2 axis.

Retrospective cohort study of the MTHFR C677T/A1298C polymorphisms and human homocysteine levels in Helicobacter pylori infection.

This study avalited relationship between human Methylenetetrahydrofolate reductase (MTHFR) gene (C677T(rs1801133)/A1298C(rs1801131)) variants and homocysteine levels in 168 patients who are infected with Helicobacter pylori, diagnosed to PCR analysis. PCR-RFLP methods were performed to characterize the MTHFR gene C677T/A1298C variants in DNA samples obtained from gastric biopsies this patients. An immunoenzymatically assay was used for quantitative of total homocysteine and folate levels in the plasma of the same individuals. The adopted level statistical significance was to α = 0.05. The frequency of the C677T SNP was higher in infected individuals, wherein those with the CT/TT genotype presented a three-fold higher risk of acquiring Helicobacter pylori infection. The averages of the total homocysteine concentrations were associated with the TT genotype, advanced age and the male sex, but no dependence relationship was found with Helicobacter pylori infection.

Combined Use of Helicobacter pylori Genotyping and CDX2 Expression as a Predictor of Malignant Potential in Gastric Intestinal Metaplasia.

OBJECTIVE: Gastrointestinal metaplasia (GIM) has a close relationship with gastric cancer (GC), but it is unclear how to judge which GIM could develop into GC. This study aimed to assess the role of CDX2 and its association with Helicobacter pylori (H.pylori) genotypes in GIM. METHODS: CagA and vacA genes were identified via PCR in 466 H. pylori-positive gastric tissues, including gastritis (n=104), GIM diagnosed endoscopically (GIM-1; n=82), gastric cancer (GC; n=173), and paired adjacent GIM tumors resected surgically (GIM-2; n=107). GIM was subclassified per the HID- AB pH2.5-PAS as follows: type I (n=23), type II (n=43), and type III (n=16) in GIM-1; type I (n=8), type II (n=40), and type III (n=59) in GIM-2. CDX2 expression was evaluated immunohistochemically. RESULTS: In GIM-1, the infection rate of vacAm2 (55.8%) and vacAs1m2 (53.5%) was higher in subtype II than in others (P<0.05), while that of vacAm1 (49.2%) and vacAs1m1 (33.9%) was higher in subtype III than in others. The cagA+ rate was higher in subtypes I (75.0%) and III (64.4%) than in subtype II (40.0%; P<0.05) respectively. CDX2 was upregulated in subtype I than in subtypes II and III in GIM-1 and GIM-2. In GIM-2 and GC, CDX2 was downregulated in vacAm1, vacAs1m1, and cagA+ (P<0.05). The predominant genotype was vacAs1m2 in subtype II of GIM-1, CDX2 expression remaining unaltered; however, the predominant genotype was cagA+ vacAs1m1 in subtypes II and III of GIM-2, negatively correlated with CDX2 expression. CONCLUSION: These GIM subtypes (cagA+ vacAs1m1 H. pylori-positive GIM with negative CDX2 expression) resemble GC and should be evaluated similar to cancerous GIM.

High expression of TRIP13 is associated with tumor progression in H. pylori infection induced gastric cancer.

BACKGROUND/OBJECTIVE: H. pylori is a recognized bacterial carcinogen in the world to cause gastric cancer (GC). However, the molecular mechanism of H. pylori infection-induced GC is not completely clear. Thus, there is an urgent need to reveal the precise mechanisms regulating cancer development due to H. pylori infection. METHODS: GEO microarray databases and TCGA databases were extracted for the analysis of different expression genes (DEGs). Then, Kaplan-Meier Plotter was used for prognostic analysis. Functional enrichment analysis of TRIP13 was performed by metascape database and TIMER database. Specific role of TRIP13 in GC with H. pylori infection was confirmed by CCK8, cell cycle analysis and WB. RESULTS: A total 10 DEGs were substantially elevated in GC and H. pylori+ tissues and might be associated with H. pylori infection in GC and only the highly expressed TRIP13 was statistically associated with poor prognosis in GC patients. Meanwhile, TRIP13 were upregulated in both CagA-transfected epithelial cells and GC cells. And TRIP13 deficiency inhibited cell proliferation and arrested the cell cycle at the G1 phase. CONCLUSION: Our study suggested that high expression of TRIP13 can promote the proliferation, cell cycle in GC cells, which could be used as a biomarker for H. pylori infection GC.

Helicobacter pylori enhances HLA-C expression in the human gastric adenocarcinoma cells AGS and can protect them from the cytotoxicity of natural killer cells.

Helicobacter pylori (H. pylori) seems to play causative roles in gastric cancers. H. pylori has also been detected in established gastric cancers. How the presence of H. pylori modulates immune response to the cancer is unclear. The cytotoxicity of natural killer (NK) cells, toward infected or malignant cells, is controlled by the repertoire of activating and inhibitory receptors expressed on their surface. Here, we studied H. pylori-induced changes in the expression of ligands, of activating and inhibitory receptors of NK cells, in the gastric adenocarcinoma AGS cells, and their impacts on NK cell responses. AGS cells lacked or had low surface expression of the class I major histocompatibility complex (MHC-I) molecules HLA-E and HLA-C-ligands of the major NK cell inhibitory receptors NKG2A and killer-cell Ig-like receptor (KIR), respectively. However, AGS cells had high surface expression of ligands of activating receptors DNAM-1 and CD2, and of the adhesion molecules LFA-1. Consistently, AGS cells were sensitive to killing by NK cells despite the expression of inhibitory KIR on NK cells. Furthermore, H. pylori enhanced HLA-C surface expression on AGS cells. H. pylori infection enhanced HLA-C protein synthesis, which could explain H. pylori-induced HLA-C surface expression. H. pylori infection enhanced HLA-C surface expression also in the hepatoma Huh7 and HepG2 cells. Furthermore, H. pylori-induced HLA-C surface expression on AGS cells promoted inhibition of NK cells by KIR, and thereby protected AGS cells from NK cell cytotoxicity. These results suggest that H. pylori enhances HLA-C expression in host cells and protects them from the cytotoxic attack of NK cells expressing HLA-C-specific inhibitory receptors.

No potential causal link between HP infection and IBD: A 2way Mendelian randomization study.

Recent epidemiological research suggests a possible negative correlation between Helicobacter pylori infection and inflammatory bowel disease (IBD). However, conflicting studies have provided unclear evidence regarding these causal relationships. Therefore, recommending specific prevention and treatment strategies for H. pylori infection and IBD is challenging. We used various antibodies (anti-H. pylori IgG, VacA, and GroEl) related to H. pylori infection as indicators. We acquired relevant genetic variants from public databases within the Genome-wide Association Studies (GWAS) dataset using IBDs tool variables from 2 different GWAS datasets. We thoroughly examined the data and screened for IVs that fulfilled these criteria. Subsequently, Bidirectional Mendelian randomization (MR) was conducted to predict the potential causality between the 2. To ensure the accuracy and robustness of our results, we conducted a series of sensitivity analyses. Based on our comprehensive MR analysis, no potential causal relationship was observed between H. pylori infection and IBD. Across various methodologies, including IVW, MR-Egger, and weighted median, our findings showed P values > .05. The only exception was observed in the reverse MR analysis using the MR-Egger method, which yielded a P value of < .05. However, because the IVW method is considered the most statistically significant method for MR, and its P value was > .05, we do not believe that a potential causal relationship exists between them. Our sensitivity analysis did not suggest significant horizontal pleiotropism. Although heterogeneity was detected in the analysis of IBD (IIBDGC source) versus H. pylori GroEL antibody levels (MR-Egger, Qp = 0.038; IVW, Qp = 0.043), the results remained reliable because we selected IVW as a random-effects model in our MR analysis method. Based on our MR research, no direct correlation was observed between H. pylori infection and IBD risk. This implies that eradicating H. pylori may not provide substantial benefits in preventing or treating regional IBD, and vice versa. Nevertheless, the use of H. pylori serological index substitution has limitations, and further research using histological diagnosis and additional MR studies is required to comprehensively assess the link between H. pylori infection and IBD.

Lnc-PLCB1 is stabilized by METTL14 induced m6A modification and inhibits Helicobacter pylori mediated gastric cancer by destabilizing DDX21.

Helicobacter pylori (H. pylori) infection is considered to be an important factor in gastric cancer (GC). Long noncoding RNA (lncRNA) and m6A modification are involved in the occurrence and development of GC, but the role of lncRNA m6A modification in the development of GC mediated by H. pylori is still unclear. Here, we found that H. pylori infection downregulated the expression of lnc-PLCB1 through METTL14-mediated m6A modification and IRF2-mediated transcriptional regulation. Overexpression of lnc-PLCB1 inhibited the proliferation and migration of GC cells, while downregulation of lnc-PLCB1 promoted the proliferation and migration ability of GC cells. In addition, clinical analysis showed that lnc-PLCB1 is lower in GC tissues than in normal tissues. Further study found that lnc-PLCB1 reduced the protein stability of its binding protein DEAD-box helicase 21 (DDX21) and then downregulated the expression of CCND1 and Slug, thereby playing tumour suppressing role in the occurrence and development of GC. In conclusion, the METTL14/lnc-PLCB1/DDX21 axis plays an important role in H. pylori-mediated GC, and lnc-PLCB1 can be used as a new target for GC treatment.

ROS-mediated up-regulation of SAE1 by Helicobacter pylori promotes human gastric tumor genesis and progression.

Helicobacter pylori (H. pylori) is a major risk factor of gastric cancer (GC). The SUMO-activating enzyme SAE1(SUMO-activating enzyme subunit 1), which is indispensable for protein SUMOylation, involves in human tumorigenesis. In this study, we used the TIMER and TCGA database to explore the SAE1 expression in GC and normal tissues and Kaplan-Meier Plotter platform for survival analysis of GC patients. GC tissue microarray and gastric samples from patients who underwent endoscopic treatment were employed to detect the SAE1expression. Our results showed that SAE1 was overexpressed in GC tissues and higher SAE1 expression was associated with worse clinical characteristics of GC patients. Cell and animal models showed that H. pylori infection upregulated SAE1, SUMO1, and SUMO2/3 protein expression. Functional assays suggested that suppression of SAE1 attenuated epithelial-mesenchymal transition (EMT) biomarkers and cell proliferation abilities induced by H. pylori. Cell and animal models of ROS inhibition in H. pylori showed that ROS could mediate the H. pylori-induced upregulation of SAE1, SUMO1, and SUMO2/3 protein. RNA sequencing was performed and suggested that knockdown of SAE1 could exert an impact on IGF-1 expression. General, increased SUMOylation modification is involved in H. pylori-induced GC.

Investigation of Molecular Mechanisms of S-1, Docetaxel and Cisplatin in Gastric Cancer with a History of Helicobacter Pylori Infection.

Gastric cancer rates and fatality rates have not decreased. Gastric cancer treatment has historically included surgery (both endoscopic and open), chemotherapy, targeted therapy, and immunotherapy. One of the aggravating carriers of this cancer is Helicobacter pylori infection. Various drug combinations are used to treat gastric cancer. However, examining the molecular function of these drugs, depending on whether or not there is a history of Helicobacter pylori infection, can be a better help in the treatment of these patients. This study was designed as bioinformatics. Various datasets such as patients with gastric cancer, with and without a history of H. pylori, and chemotherapy drugs cisplatin, docetaxel, and S-1 were selected. Using Venn diagrams, the similarities between gene expression profiles were assessed and isolated. Then, selected the signal pathways, ontology of candidate genes and proteins. Then, in clinical databases, we confirmed the candidate genes and proteins. The association between gastric cancer patients with and without a history of H. pylori with chemotherapy drugs was investigated. The pathways of cellular aging, apoptosis, MAPK, and TGFß were clearly seen. After a closer look at the ontology of genes and the relationship between proteins, we nominated important biomolecules. Accordingly, NCOR1, KIT, MITF, ESF1, ARNT2, TCF7L2, and KRR1 proteins showed an important role in these connections. Finally, NCOR1, KIT, KRR1, and ESF1 proteins showed a more prominent role in the molecular mechanisms of S-1, Docetaxel, and Cisplatin in gastric cancer associated with or without H. pylori.

Association Study between SNPs in MST1 and MST2 and H. pylori Infection as well as Noncardia Gastric Carcinogenesis.

INTRODUCTION: Gastric cancer (GC) remains a global health challenge, and H. pylori infection is a main risk factor for noncardia GC. The present study aimed to investigate the association between single nucleotide polymorphisms (SNPs) in mammalian sterile 20-like kinase 1 (MST1) and MST2, H. pylori (H. pylori) infection, and the risk of noncardia gastric cancer (GC). METHODS: A case-control study was conducted using enzyme-linked immunosorbent assay (ELISA) and TaqMan method to detect the titer of anti-H. pylori antibody in normal human serum and genotype 9 SNPs of MST1 and MST2 genes among 808 samples. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between SNPs and H. pylori infection, as well as the risk of noncardia gastric cancer in codominant, dominant, overdominant, recessive, and log-additive genetic models. Haplotypes were constructed using the Haploview 4.2 software. RESULTS: The CC genotype of MST2 SNP rs10955176 was associated with a reduced risk of H. pylori infection compared to the TT + CT genotype. None of other SNPs were associated with H. pylori infection. The TT genotype of MST2 SNP rs7827435 was associated with a reduced risk of noncardia gastric cancer compared to the AA + AT genotype. None of the SNPs were associated with noncardia gastric cancer. There were no associations between haplotypes and H. pylori infection or the risk of noncardia gastric cancer. CONCLUSIONS: The CC genotype of rs10955176 and the TT genotype of rs7827435 may serve as protective factors against H. pylori infection and noncardia gastric cancer risk, respectively.

The causal effect of Helicobacter pylori infection on coronary heart disease is mediated by the body mass index: a Mendelian randomization study.

The association between Helicobacter pylori (H. pylori) infection and coronary heart disease (CHD) remains controversial, with an unclear causal link. This study employed bidirectional Mendelian randomization (MR) method, using H. pylori infection as the exposure, to investigate its causal relationship with CHD diagnosis, prognosis, and potential pathogenesis. H. pylori infection exhibited a causal association with body mass index (BMI) (ß = 0.022; 95% CI 0.008-0.036; p = 0.001). Conversely, there was no discernible connection between H. pylori infection and the diagnosis of CHD (OR = 0.991; 95% CI 0.904-1.078; p = 0.842; IEU database; OR = 1.049; 95% CI 0.980-1.118; p = 0.178; FinnGen database) or CHD prognosis (OR = 0.999; 95% CI 0.997-1.001; p = 0.391; IEU database; OR = 1.022; 95% CI 0.922-1.123; p = 0.663; FinnGen database). Reverse MR analysis showed no causal effect of CHD on H. pylori infection. Our findings further support that H. pylori infection exerts a causal effect on CHD incidence, mediated by BMI. Consequently, eradicating or preventing H. pylori infection may provide an indirect clinical benefit for patients with CHD.

Helicobacter pylori infection and gut microbiota in adolescents: Is there a relation?

Helicobacter pylori infection is a prevalent global infection associated with several complications such as peptic ulcer, upper gastrointestinal bleeding, and stomach cancer. An imbalance in the gut microbiota composition or the relationship between the microbiota and the host may be implicated in the infection. To investigate this, we studied the intestinal microbiota of 50 newly infected adolescents with H. pylori compared with 50 age-matched and sex-matched healthy controls. The gut microbiota composition was assessed using real-time polymerase chain reaction (RT-PCR), and the fecal bacterial diversity and composition were compared between groups. Our findings revealed that Clostridium difficile and Salmonella spp. were significantly higher in the patient group compared to the control group. Additionally, lower counts of eubacteria, Bacteroides fragilis, Lactobacillus spp., Escherichia coli, and Methanobrevibacter smithii, were observed in the gut of adolescents with H. pylori. Conversely, adolescents with H. pylori infection had non-significantly higher counts of Bifidobacterium spp., C. difficile, and Salmonella spp. Multiple logistic regression analysis revealed that a greater abundance of Bifidobacterium spp. and Salmonella spp., a higher prevalence of C. difficile, and a lower abundance of Lactobacillus spp. were predictive of H. pylori infection. Overall, our results suggest that H. pylori infection is associated with changes in fecal microbiome composition.

Interleukin-8 genetic polymorphism and its relation to Helicobacter pylori infection and Helicobacter pylori-associated gastric diseases.

Helicobacter pylori (H. pylori) infection has a variety of clinical outcomes, and host genetic factors play an important role in this process. Cytokines are important factors in mediating and controlling the inflammatory process during H. pylori infection. Interleukin-8 (IL-8) plays a critical role in the epithelial cell response to H. pylori infection and the development of H. pylori-related gastric disorders. The IL-8 gene has an A/T base pair polymorphism in the promoter region (-251), which has been linked to an increase in interleukin production by gastric epithelial cells. In this context, the goal of our study was to determine the polymorphism in the IL-8 gene and its relation to H. pylori infection and H. pylori-associated gastric diseases. Gastric biopsy specimens were collected from 44 patients with H. pylori infection and 29 patients without H. pylori infection. The rapid urease test and detection of the glmM gene were used to diagnose H. pylori infection. Polymerase chain reaction-restriction fragment length polymorphism was used to identify the polymorphism in the Il-8 gene (at position-251). The presence of the A/A and T/A genotypes of the IL-8 gene was found to be significantly associated with susceptibility to H. pylori infection (p = 0.012 and p = 0.004, respectively). Also, the IL-8 A allele was significantly associated with H. pylori infection in our study (p = 0.002). We did not find a significant association between IL-8 gene polymorphism and a higher risk of gastritis and peptic ulcer disease. In conclusion, IL-8 gene polymorphism at -251 position was significantly associated with H. pylori infection.

Impact of interaction between interleukin-6 gene polymorphism and Helicobacter pylori infection on susceptibility to gastric cancer.

OBJECTIVE: This study aimed to evaluate the association between four single nucleotide polymorphisms (SNPs) of the interleukin-6 (IL-6) gene and gastric cancer (GC), and impact of interaction between IL-6 SNPs and Helicobacter pylori (H. pylori ) infection on susceptibility to GC. METHODS: Logistic regression was used to test the relationships between four SNPs of IL-6 gene and GC susceptibility. A generalized multifactor dimensionality reduction (GMDR) model was employed to assess the interaction effect between IL-6 gene and H. pylori infection on GC risk. RESULTS: Logistic regression analysis indicated that the rs1800795-C allele was associated with increased GC risk, adjusted ORs (95% CI) were 1.80 (1.21-2.41) (CC vs. GG) and 1.68 (1.09-2.30) (C vs. G), respectively. The rs10499563-C allele was associated with decreased risk of GC, and adjusted ORs (95% CI) were 0.62 (0.31-0.93) (TC vs. TT), 0.52 (0.18-0.89) (CC vs. TT) and 0.60 (0.29-0.92) (C vs. T), respectively. GMDR methods found a two-dimensional model combination (including rs1800795 and H. pylori infection) was statistically significant. The selected model had testing balanced accuracy of 59.85% and the best cross-validation consistencies of 10/10 ( P  = 0.0107). Compared with H. pylori -negative subjects with rs1800795- GG genotype, H. pylori -positive participants with GC or CC genotype had the highest risk of GC, the OR (95% CI) was 3.34 (1.78-4.97). CONCLUSION: The rs1800795-C allele was associated with increased GC risk and the rs10499563-C allele was associated with decreased GC risk. The interaction between rs1800795 and H. pylori infection was also correlated with increased risk of GC.

Effects of RAD50 SNP, sodium intake, and H. pylori infection on gastric cancer survival in Korea.

BACKGROUND: Double-strand break repair protein (RAD50) gene plays important roles in genomic integrity, DNA double-strand break repair, cell cycle checkpoint activation, telomere maintenance, and meiotic recombination. The risk allele of RAD50 may negatively affect cancer by reducing the DNA repair capacity. Additionally, Sodium intake and Helicobacter pylori (H. pylori) infection are major risk factors for gastric cancer (GC). Our study investigated the association between polymorphisms in RAD50 gene and the risk of GC case-fatality. We evaluated whether the association differed with sodium intake or H. pylori infection. METHODS: We enrolled 490 patients from two hospitals between 2002 and 2006. Their survival or death was prospectively followed up until December 31, 2016, through a review of medical records and telephone surveys. The GC survival was assessed using the Cox proportional hazards regression analysis. RESULTS: In 319 GC cases, the total person-years were 1928.3, and the median survival years was 5.4 years. A total of 137 GC deaths were recorded. Our fully adjusted model showed that the GG type of RAD50 rs17772583 polymorphism is significantly associated with an increased risk of GC case-fatality (hazard ratio [HR] = 2.20, 95% confidence interval [CI] = 1.28-3.77) compared to that associated with the homozygous AA type. In the high sodium intake group, patients with the GG type of RAD50 rs17772583 showed a significantly higher GC case-fatality (HR = 8.61, 95% CI = 2.58-26.68) than that of patients with homozygous AA type. In the positive-H. pylori infection group, patients with GG-type RAD50 rs17772583 showed a significantly higher GC case-fatality (HR = 10.11, 95% CI = 2.81-36.35) than that of with AA homozygotes. CONCLUSIONS: Patients with GG-type RAD50 rs17772583, high sodium intake, or a positive-H. pylori infection are at a significantly increased risk of GC case-fatality compared to that associated with the absence of these risk factors.

A noninvasive multianalytical approach establishment for risk assessment and gastric cancer screening.

Effective screening and early detection are critical to improve the prognosis of gastric cancer (GC). Our study aims to explore noninvasive multianalytical biomarkers and construct integrative models for preliminary risk assessment and GC detection. Whole genomewide methylation marker discovery was conducted with CpG tandems target amplification (CTTA) in cfDNA from large asymptomatic screening participants in a high-risk area of GC. The methylation and mutation candidates were validated simultaneously using one plasma from patients at various gastric lesion stages by multiplex profiling with Mutation Capsule Plus (MCP). Helicobacter pylori specific antibodies were detected with a recomLine assay. Integrated models were constructed and validated by the combination of multianalytical biomarkers. A total of 146 and 120 novel methylation markers were found in CpG islands and promoter regions across the genome with CTTA. The methylation markers together with the candidate mutations were validated with MCP and used to establish a 133-methylation-marker panel for risk assessment of suspicious precancerous lesions and GC cases and a 49-methylation-marker panel as well as a 144-amplicon-mutation panel for GC detection. An integrated model comprising both methylation and specific antibody panels performed better for risk assessment than a traditional model (AUC, 0.83 and 0.63, P < .001). A second model for GC detection integrating methylation and mutation panels also outperformed the traditional model (AUC, 0.82 and 0.68, P = .005). Our study established methylation, mutation and H. pylori-specific antibody panels and constructed two integrated models for risk assessment and GC screening. Our findings provide new insights for a more precise GC screening strategy in the future.