ABSTRACT
BACKGROUND: Helicobacter pylori eradication therapy based on antimicrobial susceptibility in Vietnamese children currently get low efficiency. There are causes of treatment failure, among host genetic factors namely MDR1 C3435T and CYP2C19 affect the absorption and metabolism of proton pump inhibitors - a crucial component of eradication therapy. The study aimed to investigate the effect of MDR1 C3435T and CYP2C19 genetic polymorphisms on the cure rate. METHODS: 207 pediatric patients with gastritis and peptic ulcer infecting Helicobacter pylori completed the eradication therapy based on antimicrobial susceptibility with proton pump inhibitor esomeprazole. Eradication efficacy was assessed after at least 4 weeks by the urease breath test. MDR1 C3435T genetic polymorphism and CYP2C19 genotype were determined using a sequencing method based on Sanger's principle. RESULTS: Among 207 children recruited in this study, the ratio of CYP2C19 EM, IM, and PM phenotypes was 40.1%, 46.4%, and 16.9%, respectively. The patient with MDR1 3435 C/C polymorphism accounted for 43.0%, MDR1 3435 C/T was 40.1%, and MDR1 3435T/T was 16.9%. The cure rate of Helicobacter pylori infection in patients with CYP2C19 EM genotype was 78.3%; 83.3% of those with the IM genotype, and PM genotype was 96,4% (p = 0.07). Successful eradication rates for Helicobacter pylori were 85.4%, 86.7%, and 68.6% in patients with the MDR1 3435 C/C, C/T, and T/T, respectively (p = 0.02). Multiple logistic regression analysis found that MDR1 C3435T genetic polymorphisms of patients were significant independent risk factors for treatment failure, and CYP2C19 genotype did not affect Helicobacter pylori eradication. CONCLUSIONS: The Helicobacter pylori eradication rates by regimens based on antibiotic susceptibility and esomeprazole were not significantly different between the CYP2C19 phenotypes. The MDR1 C3435T polymorphism is one of the factors impacting Helicobacter pylori eradication results in children.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B , Cytochrome P-450 CYP2C19 , Gastritis , Helicobacter Infections , Helicobacter pylori , Peptic Ulcer , Proton Pump Inhibitors , Humans , Cytochrome P-450 CYP2C19/genetics , Helicobacter Infections/drug therapy , Helicobacter Infections/genetics , Helicobacter pylori/drug effects , Child , Male , Female , Vietnam , Gastritis/drug therapy , Gastritis/microbiology , Gastritis/genetics , Peptic Ulcer/drug therapy , Peptic Ulcer/genetics , Peptic Ulcer/microbiology , ATP Binding Cassette Transporter, Subfamily B/genetics , Proton Pump Inhibitors/therapeutic use , Adolescent , Child, Preschool , Genotype , Polymorphism, Genetic , Treatment Outcome , Esomeprazole/therapeutic use , Anti-Bacterial Agents/therapeutic useABSTRACT
Peptic ulcer disease (PUD) refers to acid-induced injury of the digestive tract, occurring mainly in the stomach (gastric ulcer (GU)) or duodenum (duodenal ulcer (DU)). In the present study, we conducted a large-scale, cross-ancestry meta-analysis of PUD combining genome-wide association studies with Japanese and European studies (52,032 cases and 905,344 controls), and discovered 25 new loci highly concordant across ancestries. An examination of GU and DU genetic architecture demonstrated that GUs shared the same risk loci as DUs, although with smaller genetic effect sizes and higher polygenicity than DUs, indicating higher heterogeneity of GUs. Helicobacter pylori (HP)-stratified analysis found an HP-related host genetic locus. Integrative analyses using bulk and single-cell transcriptome profiles highlighted the genetic factors of PUD being enriched in the highly expressed genes in stomach tissues, especially in somatostatin-producing D cells. Our results provide genetic evidence that gastrointestinal cell differentiations and hormone regulations are critical in PUD etiology.
Subject(s)
Duodenal Ulcer , Peptic Ulcer , Stomach Ulcer , Humans , East Asian People , Genome-Wide Association Study , Peptic Ulcer/genetics , Peptic Ulcer/complications , Stomach Ulcer/etiology , Duodenal Ulcer/genetics , Duodenal Ulcer/complications , Duodenal Ulcer/diagnosisABSTRACT
The association between osteoarthritis (OA) and gastrointestinal disorders was found in observational studies. However, the causality is still elusive. A bidirectional Mendelian randomization (MR) analysis using genome wide association studies data was conducted to assess the causal association between OA and gastrointestinal diseases [including peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD), and inflammatory bowel disease (IBD)]. A two-step MR (TSMR) was conducted between OA, gastrointestinal diseases and drugs to explore the mediating effects of non-steroidal anti-inflammatory drugs (NSAIDs) and opioids use. We used multivariable MR (MVMR) analysis to further validate the impact of prescription history on diseases. Results had statistical significance at a Bonferroni corrected P-value below 0.008. We observed that genetically predicted OA had a significant positive association with GORD [odds ratio (OR) = 1.26, P = 5e-05], but not with PUD or IBD. Regarding the other direction, gastrointestinal disorders as exposure had a null association with OA. Using TSMR, OA patients tended to increase the use of NSAIDs (OR = 1.45, P = 0.001) and opioids (OR = 1.77, P = 2e-05), but only the use of opioids increased the risk of GORD (OR = 1.43, P = 5e-09). Further MVMR analysis showed that the adverse effect of OA on GORD was significantly reduced after adjusting for opioids use (OR = 1.20, P = 0.038). This study provides evidence for the causal association between OA and increased risk of GORD, which is partly attributed to opioids use in OA patients but not NSAIDs.
Subject(s)
Gastroesophageal Reflux , Gastrointestinal Diseases , Inflammatory Bowel Diseases , Osteoarthritis , Peptic Ulcer , Humans , Genome-Wide Association Study , Mendelian Randomization Analysis , Gastrointestinal Diseases/genetics , Peptic Ulcer/genetics , Analgesics, Opioid , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Inflammatory Bowel Diseases/complications , Inflammatory Bowel Diseases/genetics , Osteoarthritis/genetics , Polymorphism, Single NucleotideABSTRACT
Objective: The pathogenesis of peptic ulcer diseases (PUDs) involves multiple factors, and the contribution of gut microbiota to this process remains unclear. While previous studies have associated gut microbiota with peptic ulcers, the precise nature of the relationship, whether causal or influenced by biases, requires further elucidation. Design: The largest meta-analysis of genome-wide association studies was conducted by the MiBioGen consortium, which provided the summary statistics of gut microbiota for implementation in the Mendelian randomization (MR) analysis. Summary statistics for five types of PUDs were compiled using the FinnGen Consortium R8 release data. Various statistical techniques, including inverse variance weighting (IVW), MR-Egger, weighted median (WM), weighted mode, and simple mode, were employed to assess the causal relationships between gut microbiota and these five PUDs. Result: In the intestinal microbiome of 119 known genera, we found a total of 14 causal associations with various locations of PUDs and reported the potential pathogenic bacteria of Bilophila et al. Among them, four had causal relationships with esophageal ulcer, one with gastric ulcer, three with gastroduodenal ulcer, four with duodenal ulcer, and two with gastrojejunal ulcer. Conclusion: In this study, the pathogenic bacterial genera in the gut microbiota that promote the occurrence of PUDs were found to be causally related. There are multiple correlations between intestinal flora and PUDs, overlapping PUDs have overlapping associated genera. The variance in ulcer-related bacterial genera across different locations underscores the potential influence of anatomical locations and physiological functions.
Subject(s)
Gastrointestinal Microbiome , Peptic Ulcer , Stomach Ulcer , Humans , Gastrointestinal Microbiome/genetics , Ulcer , Genome-Wide Association Study , Mendelian Randomization Analysis , Peptic Ulcer/geneticsABSTRACT
Helicobacter Pylori (H. Pylori) cause peptic ulcer disease (PUD), but the inflammasome's role in PUD is not well understood. Therefore this study has investigated inflammasome compartment expression and IL-1ß production in gastritis (G) and peptic ulcer disease. This study was based on gene expression of inflammasome compartments on stomach biopsies of 50 patients with PUD as cases and 50 individuals with gastritis as controls. The expression of NLRC4, ASC, IL-18, and serum IL-1ß decreased in the PUD group compared to the control group. AIM2 gene expression increased, and NLRP12 gene expression decreased in H. pylori-seropositive positive (HP+ ) individuals compared to H. pylori-seronegative (HP- ) individuals. The G-HP+ subjects had higher serum IL-1ß and AIM2 gene expression than G-HP- subjects but lower NLRP3 and NLRP12 gene expression. The PUD-HP+ had lower serum IL-1ß, but higher AIM2 and IL-18 expression than PUD-HP- . The PUD-HP- patients had decreased IL-18 expression than G-HP- group. The PUD-HP+ had lower serum IL-1ß and NLRC4 expression than G-HP+, while NLRP1 and NLRP3 were higher in expression in PUD-HP+ . The expression of caspase-1, NLRP3 and NAIP were correlated with IL-1ß and IL-18. In conclusion, a decrease in NLRC4, IL-18, ASC genes, and IL-1ß levels in PUD patients compared to gastritis may act in the development of PUD. H. pylori caused AIM2 induction and reduced NLRP12, indicating their contribution to bacterial responses. Decreased NLRC4 expression and IL-1ß protein, together with enhanced NLRP1, and NLRP3 expression, promotes H. pylori to develop peptic ulcers.
Subject(s)
Gastritis , Helicobacter Infections , Helicobacter pylori , Peptic Ulcer , Humans , Inflammasomes/genetics , Inflammasomes/metabolism , Interleukin-18/genetics , Interleukin-18/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Helicobacter Infections/complications , Peptic Ulcer/genetics , Gastritis/genetics , Gastritis/complications , Gastritis/pathology , Calcium-Binding Proteins/genetics , CARD Signaling Adaptor Proteins/genetics , CARD Signaling Adaptor Proteins/metabolism , DNA-Binding Proteins/geneticsABSTRACT
Developing rapid and non-invasive diagnostics for Helicobacter pylori (HP) is imperative to prevent associated diseases such as stomach gastritis, ulcers, and cancers. Owing to HP strain heterogeneity, not all HP-infected individuals incur side effects. Cytotoxin-associated gene A (CagA), and vacuolating cytotoxin A (VacA) genes predominantly drive HP pathogenicity. Therefore, diagnosing CagA and VacA genotypes could alert active infection and decide suitable therapeutics. We report an enhanced LbCas12a trans-cleavage activity with extended reporters and reductants (CEXTRAR) for early detection of HP. We demonstrate that extended ssDNA reporter acts as an excellent signal amplifier, making it a potential alternative substrate for LbCas12a collateral activity. Through a systematic investigation of various buffer components, we demonstrate that reductants improve LbCas12a trans-cleavage activity. Overall, our novel reporter and optimal buffer increased the trans-cleavage activity to an order of 16-fold, achieving picomolar sensitivity (171 pM) without target pre-amplification. Integrated with loop-mediated isothermal amplification (LAMP), CEXTRAR successfully attained attomolar sensitivity for HP detection using real-time fluorescence (43 and 96 aM), in-tube fluorescence readouts (430 and 960 aM), and lateral flow (4.3 and 9.6 aM) for CagA and VacA, respectively. We also demonstrate a rapid 2-min Triton X-100 lysis for clinical sample analysis, which could provide clinicians with actionable information for rapid diagnosis. CEXTRAR could potentially spot the 13C urea breath test false-negatives. For the first time, our study unveils an experimental outlook to manipulate reporters and reconsider precise cysteine substitution via protein engineering for Cas variants with enhanced catalytic activities for use in diagnostics and genetic engineering.
Subject(s)
Biosensing Techniques , Helicobacter Infections , Helicobacter pylori , Peptic Ulcer , Stomach Neoplasms , Humans , Antigens, Bacterial/metabolism , Bacterial Proteins/genetics , Helicobacter pylori/genetics , Helicobacter pylori/metabolism , Stomach Neoplasms/diagnosis , Stomach Neoplasms/genetics , Reducing Agents , CRISPR-Cas Systems , Early Detection of Cancer , Peptic Ulcer/diagnosis , Peptic Ulcer/genetics , Genotype , Cytotoxins/genetics , Helicobacter Infections/diagnosis , Helicobacter Infections/genetics , Helicobacter Infections/metabolismABSTRACT
BACKGROUND: Epidemiological evidence relating obesity to peptic ulcer disease (PUD) has been mixed. Here we sought to determine the causality in the association of obesity with PUD risk using the Mendelian randomization (MR) approach. METHODS: This study was based on summary-level data for body mass index (BMI), waist-to-hip ratio (WHR), and PUD derived from large genome-wide association studies (GWASs). Single nucleotide polymorphisms significantly associated with BMI and WHR (P < 5 × 10-8) were leveraged as instrumental variables. Causal estimates were pooled using several meta-analysis methods. In addition, multivariable MR was employed to account for covariation between BMI and WHR, as well as to explore potential mediators. RESULTS: Genetically predicted higher BMI has a causal effect on PUD, with an OR of 1.34 per SD increase in BMI (~ 4.8 kg/m2) (P = 9.72 × 10-16). Likewise, there was a 35% higher risk of PUD (P = 2.35 × 10-10) for each SD increase in WHR (0.09 ratio). Complementary analyses returned consistent results. Multivariable MR demonstrated that adjustment for WHR largely attenuated the BMI-PUD association. However, the causal association of WHR with PUD risk survived adjustment for BMI. Both the associations remained robust upon adjustment for several traditional risk factors. Replication analyses using different instrumental variants further strengthened the causal inference. Besides, we found no evidence for the causal association in the reverse analyses from PUD to BMI/WHR. CONCLUSIONS: This MR study revealed that obesity (notably abdominal obesity) is causally associated with higher PUD risk. Programs aimed at weight loss may represent therapeutic opportunities for PUD.
Subject(s)
Mendelian Randomization Analysis , Peptic Ulcer , Body Mass Index , Genome-Wide Association Study , Humans , Meta-Analysis as Topic , Obesity/complications , Obesity/genetics , Peptic Ulcer/complications , Peptic Ulcer/genetics , Polymorphism, Single Nucleotide , Waist-Hip RatioABSTRACT
BACKGROUND: Natural killer (NK) cells represent a critical component of the innate immune system's response against cancer and viral infections, among other diseases. To distinguish healthy host cells from infected or tumor cells, killer immunoglobulin receptors (KIR) on NK cells bind and recognize Human Leukocyte Antigen (HLA) complexes on their target cells. However, NK cells exhibit great diversity in their mechanism of activation, and the outcomes of their activation are not yet understood fully. Just like the HLAs they bind, KIR receptors exhibit high allelic diversity in the human population. Here we provide a method to identify KIR allele variants from whole exome sequencing data and uncover novel associations between these variants and various molecular and clinical correlates. RESULTS: In order to better understand KIRs, we have developed KIRCLE, a novel method for genotyping individual KIR genes from whole exome sequencing data, and used it to analyze approximately sixty-thousand patient samples in The Cancer Genome Atlas (TCGA) and UK Biobank. We were able to assess population frequencies for different KIR alleles and demonstrate that, similar to HLA alleles, individuals' KIR alleles correlate strongly with their ethnicities. In addition, we observed associations between different KIR alleles and HLA alleles, including HLA-B*53 with KIR3DL2*013 (Fisher's exact FDR = 7.64e-51). Finally, we showcased statistically significant associations between KIR alleles and various clinical correlates, including peptic ulcer disease (Fisher's exact FDR = 0.0429) and age of onset of atopy (Mann-Whitney U FDR = 0.0751). CONCLUSIONS: We show that KIRCLE is able to infer KIR variants accurately and consistently, and we demonstrate its utility using data from approximately sixty-thousand individuals from TCGA and UK Biobank to discover novel molecular and clinical correlations with KIR germline variants. Peptic ulcer disease and atopy are just two diseases in which NK cells may play a role beyond their "classical" realm of anti-tumor and anti-viral responses. This tool may be used both as a benchmark for future KIR-variant-inference algorithms, and to better understand the immunogenomics of and disease processes involving KIRs.
Subject(s)
Neoplasms , Peptic Ulcer , Alleles , Biological Specimen Banks , Genotype , Humans , Neoplasms/genetics , Peptic Ulcer/genetics , Receptors, KIR/genetics , United KingdomABSTRACT
OBJECTIVE: Periodontitis is a highly prevalent oral infectious disease and has been increasingly associated with H. pylori infection, gastric inflammation, and gastric cancer but little is known about epigenetic machinery underlying this potentially bidirectional association. The present study is aimed at identifying key deregulated miRNA, their associated genes, signaling pathways, and compounds linking periodontitis with H. pylori-associated peptic ulcer disease. METHODS: miRNA expression datasets for periodontitis-affected and H. pylori-associated peptic ulcer disease-affected tissues were sought from the GEO database. Differentially expressed miRNA (DEmiRNAs) were identified and the overlapping, shared-DEmiRNA between both datasets were determined. Shared-DEmiRNA-target networks construction and functional analyses were constructed using miRNet 2.0, including shared-DEmiRNA-gene, shared-DEmiRNA-transcription factor (TF), and shared-DEmiRNA-compound networks. Functional enrichment analysis for shared DEmiRNA-gene and shared DEmiRNA-TF networks was performed using the KEGG, Reactome, and Geno Ontology (GO) pathways. RESULTS: 11 shared-DEmiRNAs were identified, among which 9 showed similar expression patterns in both diseases, and 7 were overexpressed. miRNA hsa-hsa-mir-155-5p and hsa-mir-29a-3p were top miRNA nodes in both gene and TF networks. The topmost candidate miRNA-deregulated genes were PTEN, CCND1, MDM2, TNRC6A, and SCD while topmost deregulated TFs included STAT3, HIF1A, EZH2, CEBPA, and RUNX1. Curcumin, 5-fluorouracil, and the gallotanin 1,2,6-Tri-O-galloyl-beta-D-glucopyranose emerged as the most relevant linkage compound targets. Functional analyses revealed multiple cancer-associated pathways, PI3K pathways, kinase binding, and transcription factor binding among as enriched by the network-associated genes and TFs. CONCLUSION: Integrative analysis of deregulated miRNAs revealed candidate molecular mechanisms comprising of top miRNA, their gene, and TF targets linking H. pylori-infected peptic ulcer disease with periodontitis and highlighted compounds targeting both diseases. These findings provide basis for directing future experimental research.
Subject(s)
Helicobacter Infections/complications , Helicobacter pylori , MicroRNAs/genetics , Peptic Ulcer/microbiology , Periodontitis/microbiology , Helicobacter Infections/genetics , Humans , Peptic Ulcer/genetics , Periodontitis/geneticsABSTRACT
BACKGROUND: Low-dose aspirin can cause gastric and duodenal ulceration, hereafter called peptic ulcer disease (PUD). Predisposition is thought to be related to clinical and genetic factors; our aim was to identify genetic risk factors associated with aspirin-induced PUD. METHODS: Patients (n=1478) were recruited from 15 UK hospitals. Cases (n=505) were defined as patients with endoscopically confirmed PUD within 2 weeks of using aspirin and non-aspirin Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). They were compared to two control groups: patients with endoscopically confirmed PUD without any history of NSAID use within 3 months of diagnosis (n=495), and patients with no PUD on endoscopy (n=478). A genome-wide association study (GWAS) of aspirin-induced cases (n=247) was compared to 476 controls. The results were validated by replication in another 84 cases and 162 controls. FINDINGS: The GWAS identified one variant, rs12678747 (p=1·65×10-7) located in the last intron of EYA1 on chromosome 8. The association was replicated in another sample of 84 PUD patients receiving aspirin (p=0·002). Meta-analysis of discovery and replication cohort data for rs12678747, yielded a genome-wide significant association (p=3·12×10-11; OR=2·03; 95% CI 1·65-2·50). Expression of EYA1 was lower at the gastric ulcer edge when compared with the antrum. INTERPRETATION: Genetic variation in an intron of the EYA1 gene increases the risk of endoscopically confirmed aspirin-induced PUD. Reduced EYA1 expression in the upper gastrointestinal epithelium may modulate risk, but the functional basis of this association will need mechanistic evaluation. FUNDING: Department of Health Chair in Pharmacogenetics, MRC Centre for Drug Safety Science and the Barts Cardiovascular NIHR Biomedical Research Centre, British Heart Foundation (BHF).
Subject(s)
Aspirin/adverse effects , Intracellular Signaling Peptides and Proteins/genetics , Nuclear Proteins/genetics , Peptic Ulcer/genetics , Polymorphism, Single Nucleotide , Protein Tyrosine Phosphatases/genetics , Aged , Aged, 80 and over , Case-Control Studies , Down-Regulation , Endoscopy, Gastrointestinal , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Introns , Male , Middle Aged , Peptic Ulcer/chemically induced , Peptic Ulcer/pathology , United KingdomABSTRACT
OBJECTIVES: Observational studies indicate that insomnia may increase risk of peptic ulcer disease (PUD). Our purpose is to clarify the possible causal relationship between insomnia and PUD by Mendelian randomization analyses. METHODS: We carried out analyses using summary statistics data for genetic variants reported from a GWAS of insomnia (N = up to 1,331,010 individuals) and from a GWAS of PUD (N = up to 456,327 individuals). Three Mendelian randomization approaches were used to explore whether insomnia might play a causal role in PUD, and pathway and functional enrichment analyses were conducted to anticipate the underlying mechanisms. RESULTS: Conventional Mendelian randomization analysis showed clear causality between insomnia and PUD; 1 SD increased insomnia incident was related to a 19% higher risk of PUD (P = 6.69 × 10-16; OR, 1.19 (95% CI, 1.14-1.24)). The associations between insomnia and PUD were consistent in the other two analyses performed using the weighted median method (P = 7.75 × 10-7; OR, 1.16 (95% CI, 1.09-1.23)) and MR-Egger regression (P = 5.00 × 10-3; OR, 1.27 (95% CI, 1.07-1.50)). Moreover, no evidence indicated a reverse causality between PUD events and insomnia symptoms. Pathway and functional enrichment analyses indicated that the mechanisms of insomnia effect on PUD may be through various ways, such as the immune system and oxidative stress. CONCLUSIONS: This Mendelian randomization study suggests insomnia as a causal risk factor for PUD. The potential mechanisms included may be immune and oxidative stress. These findings indicate that improving sleep quality could have substantial health benefits.
Subject(s)
Mendelian Randomization Analysis/methods , Peptic Ulcer/epidemiology , Peptic Ulcer/genetics , Polymorphism, Single Nucleotide , Sleep Initiation and Maintenance Disorders/complications , Sleep Initiation and Maintenance Disorders/genetics , Causality , Chromosome Mapping/methods , Databases, Genetic , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Humans , Incidence , Multigene Family , Risk Factors , Sleep QualityABSTRACT
Peptic ulcer episodes cause damage to the stomach and intestine, with inflammatory cell infiltration and oxidative stress as the main players. In this study, we investigated the potential of anthocyanidin malvidin for preventive and curative peptic ulcer treatment. The anthocyanidin effects were examined in gastric ulcer mouse models induced by ethanol, non-steroidal anti-inflammatory drugs (NSAIDs), ischemia-reperfusion (IR), acetic acid and duodenal ulcer induced by polypharmacy. Expression levels of oxidative and inflammatory genes were measured to investigate the mechanism of anthocyanin activity. At a dose of 5 mg·kg-1, Malvidin prevented gastric ulcer induction by ethanol, NSAID and repaired the tissue after 6 days of IR. Moreover, the anthocyanidin accelerated the healing of acetic acid-induced ulcer, increased the gene expression of EGF and COX-1, and downregulated MMP-9. Anthocyanin treatment mitigated the effect of polypharmacy on inflammation and oxidative stress observed in the intestine. Additionally, the compound downregulated cytokine expression and TLR4 and upregulated HMOX-1 and IL-10, exhibiting protective activity in the mouse gut. Malvidin thus prevented gastric and duodenal ulcers due to prominent anti-inflammatory and antioxidative effects on the gastrointestinal tract that were related to gene expression modulation and an increase in endogenous defense mechanisms.
Subject(s)
Anthocyanins/therapeutic use , Inflammation/complications , Inflammation/drug therapy , Oxidative Stress , Peptic Ulcer/complications , Peptic Ulcer/drug therapy , Protective Agents/therapeutic use , Acetic Acid , Animals , Anthocyanins/pharmacology , Antioxidants/metabolism , Biomarkers/metabolism , Cyclooxygenase 1/genetics , Cyclooxygenase 1/metabolism , Disease Models, Animal , Duodenum/drug effects , Duodenum/pathology , Epidermal Growth Factor/genetics , Epidermal Growth Factor/metabolism , Ethanol , Gastric Mucosa/drug effects , Gastric Mucosa/pathology , Gene Expression Regulation/drug effects , Indomethacin , Inflammation/genetics , Male , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Mice , Oxidative Stress/drug effects , Oxidative Stress/genetics , Peptic Ulcer/genetics , Peptic Ulcer/immunology , Polypharmacy , Protective Agents/pharmacology , Reperfusion Injury/complications , Reperfusion Injury/drug therapy , Reperfusion Injury/pathology , Stomach Ulcer/chemically induced , Stomach Ulcer/drug therapy , Stomach Ulcer/genetics , Stomach Ulcer/immunology , Tight Junctions/drug effects , Tight Junctions/metabolism , Wound Healing/drug effectsABSTRACT
BACKGROUND: Helicobacter pylori infection is widespread, affecting about 50% of the global population. Polymorphisms in host genes such as the toll-like receptor 4 (TLR4) might affect the susceptibility and severity of infection and treatment success. OBJECTIVE: Investigate the susceptibility and severity of H pylori infection with host TLR4 (rs11536889, rs4986790, rs200109652, rs10759932), TLR5 (rs5744174, rs2072493, rs746250566), TLR10 (rs559182335, rs10004195) polymorphisms. DESIGN: Analytical, cross-sectional. SETTING: Endoscopy clinic at tertiary care center. PATIENTS AND METHODS: Genomic DNA was extracted from formalin-fixed paraffin-embedded tissues collected from H pylori-infected patients and healthy individuals. The single nucleotide polymorphisms (SNPs) within the targeted TLR genes were genotyped to assess the genetic association of various SNPs with disease severity. MAIN OUTCOME MEASURES: Effect of genotype distribution on H pylori infection. SAMPLE SIZE: 250 peptic ulcer patients and 217 controls. RESULTS: The TLR10 genotype showed no significant association with H pylori infection except for rs10004195 (T>A) (P=.002). The genotype frequency of Rs5744174 in TLR5 had a significant association with the presence of H pylori infection (P=.046, OR=0.52). Except for gender (P=.022), there were no significant associations between clinical and demographic variables and SNPs relating to the severity of the H pylori infections. CONCLUSIONS: Our findings are consistent with differences in severity of H pylori infection due to TLR SNPs in different ethnic groups. Understanding differences in genetic susceptibility could help in classifying patients and matching patients with various treatment options on a genetic basis. LIMITATIONS: Lack of H pylori pathogenicity features assessment. CONFLICTS OF INTEREST: None.
Subject(s)
Helicobacter Infections , Helicobacter pylori , Peptic Ulcer , Cross-Sectional Studies , Genetic Predisposition to Disease , Genotype , Helicobacter Infections/genetics , Humans , Jordan , Peptic Ulcer/genetics , Polymorphism, Single Nucleotide , Toll-Like Receptor 10 , Toll-Like Receptor 4/genetics , Toll-Like Receptor 5ABSTRACT
This study analyzed the association of functionally significant SNPs of matrix metalloproteinase (MMP) genes in the development of peptic ulcer disease (PUD) in Caucasians from Central Russia. Ten SNPs of the MMP-1, MMP-2, MMP-3, MMP-8, and MMP-9 genes were analyzed for association with PUD in a cohort of 798 patients with PUD (including 404 H. pylori-positive and 394 H. pylori-negative) and 347 H. pylori-negative controls using logistic regression and assuming the additive, recessive, and dominant genetic models. The variants of MMP-1, MMP-2, MMP-3, and MMP-8 did not manifest any significant associations with the diseases. Five SNPs of the MMP-9 gene demonstrated such association. Allele G of the rs17576 MMP-9 locus conferred a higher risk for PUD (ORadj = 1.31, pperm = 0.016), haplotype AACG of loci rs17576-rs3787268-rs2250889-rs17577 of the MMP-9 gene decreased risk for PUD (ORadj = 0.17, pperm = 0.003). Also, allele C of rs3918249, allele G of rs17576 and haplotype CG of rs3918249-rs17576 of the MMP-9 gene increased risk for H. pylori-positive PUD (ORadj = 1.82, pperm = 0.002; ORadj = 1.53-1.95 pperm = 0.001-0.013 and ORadj = 1.49 pperm = 0.009 respectively). The above loci and 50 linked to them possess significant regulatory effects and may affect the alternative splicing of four genes and the expression of 17 genes in various organs and tissues related to the PUD pathogenesis.
Subject(s)
Helicobacter Infections/genetics , Helicobacter pylori , Matrix Metalloproteinase 9/genetics , Peptic Ulcer/genetics , Polymorphism, Single Nucleotide , White People , Adult , Aged , Alleles , Female , Genetic Loci , Helicobacter Infections/enzymology , Humans , Male , Matrix Metalloproteinase 9/biosynthesis , Middle Aged , Peptic Ulcer/enzymology , RussiaABSTRACT
Genetic factors are recognized to contribute to peptic ulcer disease (PUD) and other gastrointestinal diseases, such as gastro-oesophageal reflux disease (GORD), irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Here, genome-wide association study (GWAS) analyses based on 456,327 UK Biobank (UKB) individuals identify 8 independent and significant loci for PUD at, or near, genes MUC1, MUC6, FUT2, PSCA, ABO, CDX2, GAST and CCKBR. There are previously established roles in susceptibility to Helicobacter pylori infection, response to counteract infection-related damage, gastric acid secretion or gastrointestinal motility for these genes. Only two associations have been previously reported for duodenal ulcer, here replicated trans-ancestrally. The results highlight the role of host genetic susceptibility to infection. Post-GWAS analyses for PUD, GORD, IBS and IBD add insights into relationships between these gastrointestinal diseases and their relationships with depression, a commonly comorbid disorder.
Subject(s)
Depression , Gastrointestinal Diseases/genetics , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study/methods , Helicobacter Infections/genetics , Helicobacter pylori/genetics , Peptic Ulcer/genetics , ABO Blood-Group System/genetics , Antigens, Neoplasm/genetics , CDX2 Transcription Factor/genetics , Duodenal Ulcer , Female , Fucosyltransferases/genetics , GPI-Linked Proteins , Galactosyltransferases , Gastroesophageal Reflux , Helicobacter Infections/complications , Humans , Inflammatory Bowel Diseases , Male , Mucin-1/genetics , Mucin-6/genetics , Neoplasm Proteins , Peptic Ulcer/complications , Galactoside 2-alpha-L-fucosyltransferaseABSTRACT
OBJECTIVES: To assess the correlation between a number of genetic variations of CYP2C19, TNF-α, NOD1, NOD2, and PPARγ genes with the severity of Helicobacter pylori (H. pylori) infections and peptic ulcers (PU). METHODS: A retrospective cross-sectional design was used in this study. Formalin-fixed paraffin-embedded (FFPE) tissue was used to extract genomic DNA that was collected from Jordanian patients who visited endoscopy clinics between 2014 to 2018 at the King Abdullah University Hospital (KAUH), Irbid, Jordan. Genotyping of the studied single nucleotide polymorphisms (SNPs) were applied using the sequencing protocol. Results: A total of 251 patients (mean age: 42.12 ± 16.09 years) and healthy controls (mean age: 52.76 ± 19.45 years) were enrolled in this study. This study showed no significant association between patients and the studied polymorphisms except for rs2075820 of the NOD1 (p=0.0046). It is hypothesized that the heterozygous genotype (TC); 44.8% in patients versus 61.3% in controls has a decreased risk of peptic ulcers (OR: 0.49). The alleles frequency association was insignificant in all studied SNPs with a p-value more than 0.05. CONCLUSION: This study provided evidence regarding the association of the rs2075820 with H. pylori infections. The other studied SNPs were not statistically significant.
Subject(s)
Cytochrome P-450 CYP2C19/genetics , Genetic Predisposition to Disease , Helicobacter Infections/complications , Helicobacter pylori , Nod1 Signaling Adaptor Protein/genetics , Nod2 Signaling Adaptor Protein/genetics , PPAR gamma/genetics , Peptic Ulcer/etiology , Peptic Ulcer/genetics , Polymorphism, Single Nucleotide/genetics , Tumor Necrosis Factor-alpha/genetics , Adolescent , Adult , Aged , Cross-Sectional Studies , Female , Genotyping Techniques/methods , Humans , Jordan , Male , Middle Aged , Paraffin Embedding , Retrospective Studies , Young AdultABSTRACT
BACKGROUND: Helicobacter pylori (H. pylori) infection causes inflammation and increases the risk of developing peptic ulcer disease (PUD); however, the exact molecular mechanisms of PUD development remain unclear. The aim of this study was to investigate the expression of CCL18, CCL28, and CXCL13 in H. pylori-positive subjects in comparison with H. pylori-negative subjects, and to determine its association with different clinical outcomes and virulence factors. METHODS: In total, 55 H. pylori-positive subjects with gastritis, 47 H. pylori-positive subjects with PUD, and 48 H. pylori-negative subjects were enrolled in this study. CCL18, CCL28, and CXCL13 expression were determined using real time polymerase chain reaction (PCR). The virulence factors of H. pylori such as cytotoxin-associated gene A (cagA), outer inflammatory protein A (oipA), blood group antigen-binding adhesin (babA), and vacuolating cytotoxin A (VacA) genes were evaluated using PCR. RESULTS: CCL18, CCL28, and CXCL13 expression in H. pylori-positive subjects were significantly higher than H. pylori-negative subjects. CCL18 and CXCL13 expression in H. pylori-positive subjects with oipA+ and babA2+were significantly higher than H. pylori-positive subjects with oipA¯ and babA2¯. CCL18 and CXCL13 expression were found to be significantly elevated in H. pylori-positive subjects with gastritis compared with H. pylori-positive subjects with PUD. CCL28 expression was significantly higher in H. pylori-positive subjects with PUD compared with H. pylori-positive subjects with gastritis. CONCLUSIONS: The increased of CCL18 and CXCL13 may be involved in the pathogenesis of H. pylori-associated gastritis, while the increased of CCL28 may be involved in the pathogenesis of H. pylori-associated PUD.
Subject(s)
Chemokine CXCL13/genetics , Chemokines, CC/genetics , Gastritis/genetics , Helicobacter Infections/genetics , Peptic Ulcer/genetics , Adult , Aged , Chemokine CXCL13/metabolism , Chemokines, CC/metabolism , Female , Gastritis/epidemiology , Gastritis/microbiology , Helicobacter Infections/epidemiology , Helicobacter Infections/microbiology , Helicobacter pylori/physiology , Humans , Iran/epidemiology , Male , Middle Aged , Peptic Ulcer/epidemiology , Peptic Ulcer/microbiology , Up-RegulationABSTRACT
Background: Haploinsufficiency A20 (HA20) is a newly described monogenic disease characterized by a wide spectrum of manifestations and caused by heterozygous mutations in TNFAIP3 which encodes A20 protein. TNFAIP3 mutation leads to disruption of the A20 ovarian tumor (OTU) domain and/or the zinc finger (ZnF) domain. This study aims at exploring the association between the various manifestations of HA20 and different domains disruption of A20. Methods: We reviewed the HA20 cases in previous literature and summarized the clinical features, TNFAIP3 mutation loci and the disrupted domains caused by different sites and patterns of mutations. Patients were classified into three groups according to the A20 domains disruption. Results: A total of 89 patients from 39 families with a genetic diagnosis of HA20 were included. Overall, the age at onset of HA20 was early (median:5.92, IQR:1-10). Patients in the ZnF group showed the earliest onset (median:2.5, IQR:0.6-5), followed by patients in the OTU+ZnF group (median:6, IQR:1-10) and patients in the OTU group (median:10, IQR:8-14). The main manifestations of HA20 patients were recurrent oral ulcers (70%), recurrent fever (42%), gastrointestinal ulcers (40%), skin lesion (38%), genital ulcers (36%), and musculoskeletal disorders (34%). The percentage of patients with musculoskeletal disorders was significantly different among the three groups (p = 0.005). Patients in the OTU+ZnF group and ZnF group were more likely to develop musculoskeletal disorders than patients in the OTU group (p = 0.002 and p = 0.035, respectively). Besides, forty-three percent of HA20 patients were initially diagnosed as Behcet's disease (BD). Compared to the ZnF group, the OTU+ZnF group and OTU group had a higher percentage of patients initially diagnosed as BD (p = 0.006 and p < 0.001, respectively). Conclusion: HA20 is characterized by early-onset and the most common symptoms of HA20 are recurrent oral ulcers, fever and gastrointestinal ulcers. The onset of HA20 in patients with the ZnF domain disruption is earlier than patients with the OTU domain disruption. Compared to the OTU domain, the ZnF domain may be more closely related to musculoskeletal disorders.
Subject(s)
Haploinsufficiency , Hereditary Autoinflammatory Diseases/genetics , Heterozygote , Mutation , Tumor Necrosis Factor alpha-Induced Protein 3/genetics , Adolescent , Age of Onset , Child , Child, Preschool , DNA Mutational Analysis , Diagnosis, Differential , Female , Fever/genetics , Fever/immunology , Genetic Predisposition to Disease , Hereditary Autoinflammatory Diseases/diagnosis , Hereditary Autoinflammatory Diseases/immunology , Humans , Infant , Male , Oral Ulcer/genetics , Oral Ulcer/immunology , Peptic Ulcer/genetics , Peptic Ulcer/immunology , Phenotype , Predictive Value of Tests , Tumor Necrosis Factor alpha-Induced Protein 3/immunologyABSTRACT
PAI genotyping for the G43A and 4G/5G polymorphisms was performed in 60 patients with peptic ulcer disease: 12 with an uncomplicated ulcer, 5 with perforation, the rest with ongoing bleeding. Fourteen patients had recurrent bleeding. The 5G/5G and G43A genotypes were not detected in patients with uncomplicated ulcers. All patients with ulcer perforation had the G43G genotype, 60% of patients had the 4G/4G genotype, and the rest of them had the 4G/5G and 5G/5G genotypes. The number of carriers of the 5G allele (86.05%) was higher in patients with bleeding than in ones with ulcer perforation (p=0.036) and ulcer without bleeding (p=0.021, χ2=5.32). The number of carriers of the 5G allele was higher in patients with recurrent bleeding (92.86%) than those without any relapses (82.76%) but there were no statistically significant differences (p=0.27, χ2=0.802). The G43G homozygous genotype was found in 94.12% of patients with peptic ulcer without bleeding, which was statistically significantly higher (p=0.02) than the ones with bleeding. The A allele was observed in 27.91% of patients with bleeding and 8.33% patients without any bleeding (p=0.05). The number of carriers of the A allele in patients with recurrent bleeding was statistically significantly higher than in ones without any bleeding (p=0.046). The 5G and A alleles in patients with a peptic ulcer can be used to predict the course of peptic ulcer disease and can be regarded as a predictor of the risk of bleeding relapse.
Subject(s)
Gastrointestinal Hemorrhage/genetics , Genetic Predisposition to Disease , Peptic Ulcer/genetics , Acute Disease , Adult , Aged , Aged, 80 and over , Female , Hemorrhage , Humans , Male , Middle Aged , Plasminogen Activator Inhibitor 1/genetics , Polymorphism, Single Nucleotide/genetics , Risk Factors , Young AdultABSTRACT
Background and objective: Although obesity is associated with an increased risk of peptic ulcer disease (PUD), no study has evaluated the association of PUD with sarcopenia. The aim of this study was to evaluate the association of sarcopenia and obesity with PUD. Material and Methods: Data from the Korean National Health and Nutrition Examination Survey (KNHANES) IV and V for 2007-2012 were used. PUD history, dietary, alcohol consumption, smoking, physical activity patterns, and other socioeconomic factors were analyzed. Sarcopenia index (appendicular skeletal muscle mass (kg) ÷ body mass index (kg/m2)) and body fat mass were determined by dual-energy X-ray absorptiometry. Univariate and multivariate analyses were performed to evaluate the association of sarcopenia with the prevalence of PUD. Results: The 7092 patients were divided into the sarcopenic obesity (SO, n = 870), sarcopenic non-obesity (n = 2676), non-sarcopenic obesity (NSO, n = 2698), and non-sarcopenic non-obesity (NSNO, n = 848) groups. The prevalence of PUD in these groups was 70 (7.9%), 170 (7.4%), 169 (6.3%), and 47 (3.8%), respectively (p < 0.001). A crude analysis revealed that the prevalence of PUD was 2.2-fold higher in the SO group than in the NSNO group (odds ratio (OR), 2.2; 95% confidence interval (CI), 1.5-3.2), the significance of which remained after adjustment for age, sex, body mass index, and HOMA-IR (homeostatic model assessment insulin resistance) score (OR, 1.9; 95% CI, 1.3-2.7). Conclusion: In conclusion, in this nationally representative cohort, the combination of muscle and fat mass, as well as obesity, was associated with an increased risk of PUD.