A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma

doi:10.1016/S0016-5085(03)00899-0

Gastroenterology

Volume 125, Issue 2, August 2003, Pages 364-371

https://doi.org/10.1016/S0016-5085(03)00899-0 Get rights and content

Abstract

Background & Aims:

Pro-inflammatory polymorphisms within the genes interleukin (IL)-1B and IL-1RN are associated with risk for gastric carcinoma (GC) in Helicobacter pylori—infected individuals. We aimed to determine the association between variation of the tumor necrosis factor (TNF)-α gene and the risk for chronic atrophic gastritis (CAG) and GC. We also investigated the extent to which the combined effect of proinflammatory genetic polymorphisms (IL-1B, IL-1RN, and TNF-α), and the combined effect of TNF-α and bacterial genotypes each influence such a risk.

Methods:

In a case-control study including 306 controls, 221 individuals with chronic gastritis, and 287 GC patients, the TNF-α-308 and IL-1B-511 bi-allelic polymorphisms, the IL-1RN variable number of tandem repeats (VNTR), and the H. pylori genes vacA (s and m regions) and cagA were genotyped.

Results:

We found that carriers of the TNF-α-308∗A allele are at increased risk for GC development with an odds ratio (OR) of 1.9 (95% confidence interval [CI], 1.3–2.7). For both CAG and GC, the odds of developing disease increased with the number of high-risk genotypes. Individuals carrying high-risk genotypes at the 3 loci are at increased risk for CAG and GC with an OR of 5.8 (95% CI, 1.1–31.0) and 9.7 (95% CI, 2.6–36.0), respectively. The risk for GC was not affected significantly by the combination of bacterial and TNF-α-308 genotypes.

Conclusions:

These findings show that a proinflammatory polymorphism in the TNF-α gene is associated with increased risk for GC, and that it is possible to define a specific genetic profile associated with highest risk for CAG and GC.

Section snippets

Study population

A total of 814 subjects from the north of Portugal were enrolled in this study, comprising unselected controls (n = 306), individuals with chronic gastritis (n = 221), and GC patients (n = 287). The control group consisted of healthy blood donors (mean age, 37 yr; median age, 35 yr; range, 18–64 yr; male:female ratio, 1.7:1). Individuals with chronic gastritis (mean age, 43 yr; median age, 43 yr; range, 24–62 yr; male:female ratio, 12.8:1) were recruited from among shipyard workers who had

Results

Genotype frequencies of the IL-1B-511, IL-1RN VNTR, and TNF-α-308 polymorphisms in the control group did not deviate significantly from those expected under Hardy-Weinberg equilibrium (P = 0.3, P = 0.6, and P = 0.8, respectively; Table 1). The genotype frequencies among chronic nonatrophic gastritis (CNAG) subjects, CAG subjects, and GC patients of all the individual loci studied are summarized in Table 1.

In the group of individuals with CAG we found that carriers of the proinflammatory allele

Discussion

The first consequence of H. pylori infection is the development of neutrophilic gastritis, which progresses to active chronic gastritis in most people.28 Recruitment and activation of immune cells in the underlying mucosa involves, among other molecules, proinflammatory cytokines such as IL-1β and TNF-α as part of nonspecific immunity.29 The complex network of cytokines implicated in these inflammatory responses includes counter-regulatory elements, such as IL-1ra, which act to down-regulate

References (33)

D.M Parkin
The global burden of cancer
Semin Cancer Biol
(1998)
E.J Kuipers et al.
Long-term sequelae of Helicobacter pylori gastritis
Lancet
(1995)
J.C Machado et al.
Interleukin 1B and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma
Gastroenterology
(2001)
C.A Dinarello
Biologic basis for interleukin-1 in disease
Blood
(1996)
I.R Hwang et al.
Effect of interleukin 1 polymorphisms on gastric mucosal interleukin 1beta production in Helicobacter pylori infection
Gastroenterology
(2002)
T Furuta et al.
Interleukin 1beta polymorphisms increase risk of hypochlorhydria and atrophic gastritis and reduce risk of duodenal ulcer recurrence in Japan
Gastroenterology
(2002)
C Zambon et al.
Helicobacter pylori virulence genes and host IL-1RN and IL-1β genes interplay in favouring the development of peptic ulcer and intestinal metaplasia
Cytokine
(2002)
K.M Kroeger et al.
Effects of stimulus and cell type on the expression of the -308 tumour necrosis factor promoter polymorphism
Cytokine
(2000)
J Parsonnet et al.
Helicobacter pylori infection and the risk of gastric carcinoma
N Engl J Med
(1991)
N Uemura et al.
Helicobacter pylori infection and the development of gastric cancer
N Engl J Med
(2001)

P Correa

Human gastric carcinogenesisa multistep and multifactorial process—first American Cancer Society Award Lecture on Cancer Epidemiology and Prevention

Cancer Res

(1992)

P Sipponen

Gastric cancer—a long-term consequence of Helicobacter pylori infection?

Scand J Gastroenterol Suppl

(1994)

E.M El-Omar et al.

Interleukin-1 polymorphisms associated with increased risk of gastric cancer (published erratum appears in Nature 2001;412:99)

Nature

(2000)

E.M El-Omar

The importance of interleukin 1beta in Helicobacter pylori associated disease

Gut

(2001)

L.A Noach et al.

Mucosal tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8 production in patients with Helicobacter pylori infection

Scand J Gastroenterol

(1994)

W.P Arend et al.

Interleukin-1 receptor antagonistrole in biology

Annu Rev Immunol

(1998)

Cited by (446)

Exploring the effect of Weifuchun capsule on the toll-like receptor pathway mediated HES6 and immune regulation against chronic atrophic gastritis
2023, Journal of Ethnopharmacology
Weifuchun capsule (WFC) is a traditional Chinese patent medicine for chronic atrophic gastritis (CAG) in clinic. However, the mechanism of action of WFC for CAG still remains unclear due to its complex composition.
The study was projected to uncover the mechanism of action of WFC and the corresponding pharmacodynamic substance of WFC against CAG as well as providing a standard example for the research of traditional Chinese medicine (TCM) from the perspective of the network and the system.
We identified the compounds of WFC through LC-MS/MS analysis and performed a systematic network targets analysis for WFC in the treatment of CAG which thoroughly described the mechanism of action of WFC for CAG. Based on analysis integrating omics data and algorithms, we focused on the specific immune regulatory role of WFC in the treatment of CAG, especially on a hub pathway, Toll-like receptor signaling pathway and thus deciphered the role of WFC in immune regulation, anti-inflammation and mediation of HES6. In experiments part, MNNG-GES-1-cell line and rat models were used to validate our findings.
In this study, compounds of WFC are identified through LC‒MS/MS and network target analysis is performed to dissect the specific immunoregulatory effect as well as mediation of HES6, a newly discovered biomolecule related to gastritis carcinoma progression, of WFC on CAG through the Toll-like receptor signaling pathway. Based on cell line and rat models, we verify the mechanism of action of WFC for CAG in inhibiting inflammatory cytokines, regulating immune cells like T cells and macrophages, related genes including TLR2 and CD14. It is also validated that WFC inhibits the expression of HES6 (P < 0.05).
Based on the combination of computational strategy and experiments, our study offers a comprehensive analysis to reveal the role of WFC in regulating immune response, inhibiting inflammation in the treatment of CAG, and provides a standard example for the research of TCM from the perspective of the network and the system.
Induction and Regulation of the Innate Immune Response in Helicobacter pylori Infection
2022, Cellular and Molecular Gastroenterology and Hepatology
Gastric cancer (GC) is the fifth most common cancer and the fourth most common cause of cancer-related death worldwide. The intestinal type of GC progresses from acute to chronic gastritis, multifocal atrophic gastritis, intestinal metaplasia, dysplasia, and carcinoma. Infection of the stomach by Helicobacter pylori, a Gram-negative bacterium that infects approximately 50% of the world’s population, is the causal determinant that initiates the gastric inflammation and then disease progression. In this context, the induction of the innate immune response of gastric epithelial cells and myeloid cells by H. pylori effectors plays a critical role in the outcome of the infection. However, only 1% to 3% of infected patients develop gastric adenocarcinoma, emphasizing that other mechanisms regulate the localized non-specific response, including the gastric microbiota and genetic factors. This review summarizes studies describing the factors that induce and regulate the mucosal innate immune response during H. pylori infection.
Network pharmacology to unveil the mechanism of Moluodan in the treatment of chronic atrophic gastritis
2022, Phytomedicine
Moluodan (MLD) is a traditional Chinese patent medicine for the treatment of chronic atrophic gastritis (CAG). However, the mechanism of action (MoA) of MLD for treating CAG still remain unclear.
Elucidate the MoA of MLD for treating CAG based on network pharmacology.
Integrate computational prediction and experimental validation based on network pharmacology.
Computationally, compounds of MLD were scanned by LC-MS/MS and the target profiles of compounds were identified based on network-based target prediction method. Compounds in MLD were compared with western drugs used for gastritis by hierarchical clustering of target profile. Key biological functional modules of MLD were analyzed, and herb-biological functional module network was constructed to elucidate combinatorial rules of MLD herbs for CAG. Experimentally, MLD's effect on different biological functional modules were validated from both phenotypic level and molecular level in 1- Methyl-3-nitro-1-nitrosoguanidine (MNNG)-induced GES-1 cells.
Computational results show that the target profiles of compounds in MLD can cover most of the biomolecules reported in literature. The MoA of MLD can cover most types of MoA of western drugs for CAG. The treatment of CAG by MLD involved the regulation of various biological functional modules, e.g., inflammation/immune, cell proliferation, cell apoptosis, cell differentiation, digestion and metabolism. Experimental results show that MLD can inhibit cell proliferation, promote cell apoptosis and differentiation, reduce the inflammation level and promote lipid droplet accumulation in MNNG-induced GES-1 cells.
The network pharmacology framework integrating computational prediction and experimental validation provides a novel way for exploring the MoA of MLD.
Single nucleotide polymorphisms of whole genes and atrophic gastritis susceptibility:a systematic review and meta-analysis
2021, Gene
Citation Excerpt :
In the smaller sample size subgroup, IL-8 rs4073 was positively linked to AG risk in four models (mutated homozygote vs. wild type: OR = 1.79, 95%CI = 1.26–2.55, P = 0.001; dominant model: OR = 1.42, 95%CI = 1.14–1.77, P = 0.002; recessive model: OR = 1.53, 95%CI = 1.10–2.13, P = 0.011; allelic model: OR = 1.33, 95%CI = 1.14–1.56, P < 0.001) (Table 3). No association was suggested between TNFA rs1800629 (Machado et al., 2003; Gao et al., 1990) and AG risk in overall analysis (Table 3). PSCA rs2294008 (Lochhead et al., 2011; Rizzato et al., 2013; Ichikawa et al., 2015), a member of Ly-6 gene family, could increase AG susceptibility in five genetic models (heterozygote vs. wild type: OR = 1.45, 95%CI = 1.19–1.77, P < 0.001, Fig. 6; mutated homozygote vs. wild type: OR = 1.60, 95%CI = 1.27–2.00, P < 0.001; dominant model: OR = 1.49, 95%CI = 1.24–1.80, P < 0.001; recessive model: OR = 1.21, 95%CI = 1.02–1.43, P = 0.032; allelic model: OR = 1.23, 95%CI = 1.11–1.37, P < 0.001, Fig. 7) (Table 3).
Atrophic gastritis (AG) is one of the important precancerous lesions of gastric cancer. Single nucleotide polymorphisms (SNPs) are closely related to AG susceptibility. However, the research conclusions on the predictive potential of SNPs are inconsistent. The study aims to retrospect the association between SNPs of whole genes and AG risk by meta-analysis.
Up to April 29, 2020, a systematic literature search for the relationship of SNPs with AG susceptibility was performed utilizing PubMed, Web of Science and Chinese National Knowledge Infrastructure. The overall and stratified meta-analyses on extracted data were conducted by Stata11.2.
33 case-control studies were enrolled containing 9951 AG patients and 17,252 healthy controls, and 17 SNPs in 12 different genes were systematically reviewed. The results indicated that 12 genes could be categorized based on their functions, including immune response, cell proliferation and apoptosis, and DNA damage repair. For the SNPs in immune response-related genes, the C allele of TLR1 rs4833095 T/C increased AG risk to 1.21-fold and the recessive model of TLR4 rs11536878 in the TLR gene family decreased AG susceptibility to 0.48-fold. The variant alleles of IL-10 rs1800871 (OR = 1.21) and IL-8 rs4073 (OR = 1.22) in the IL gene family were positively associated with AG risk. PSCA rs2294008 enhanced AG risk in all genetic models. SNPs associated with AG susceptibility were mainly focused on immune response-related genes.
These SNPs related to immune response could influence on AG risk and have potential to be AG predictive biomarkers. It is worth noting that the number of studies for each SNPs were insufficient due to the limited published researches and updated meta-analysis needs to be performed based on extensive relevant studies for more reliable results.
Helicobacter pylori in Childhood
2020, Pediatric Gastrointestinal and Liver Disease, Sixth Edition
Helicobacter pylori is a slow-growing, gram-negative organism that colonizes the gastric mucosa and can lead to antral gastritis and peptic ulcer disease. Infection is acquired during the first decade of life and unless eradicated causes lifelong infection. Although H. pylori infects children worldwide, approach to diagnosis, interventions, and treatment differ widely. The majority of children who are infected with H. pylori are asymptomatic, and investigation is only indicated if the intention is to treat a positive result. An updated guideline was published by the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) in 2017 to address the recommendations in the diagnosis and management of children with H. pylori infection. Pediatricians and pediatric gastroenterologists must consider carefully appropriate methods of investigation and therapeutic intervention, while ensuring appropriate utilization of preventive medicine in minimizing future ill health.
Network pharmacology based investigation into the effect and mechanism of Modified Sijunzi Decoction against the subtypes of chronic atrophic gastritis
2019, Pharmacological Research
Chronic atrophic gastritis (CAG) is a common digestive disease without specific treatment. According to syndrome differentiation, traditional Chinese medicine (TCM) classified it into different syndromes and has achieved significant therapeutic effects. In this study, immune repertoire sequencing techniques combined with symptom scores, electronic gastroscopy as well as pathologic changes were used to evaluate the effect and the underlying mechanism of Modified Sijunzi Decoction (MSD) in treating CAG. The results showed that MSD could relieve CAG symptoms, improve pathologic changes in CAG with fatigue and tiredness symptom, but with no help in CAG with reversal heat symptom. Moreover, MSD could regulate immune disorders in CAG with fatigue and tiredness symptom, and 7 TCR biomarkers were explored in CAG patients with immune disorders. All these results indicated that MSD is effective in treating CAG patients with fatigue and tiredness symptom by tonifying the spleen qi, suggesting that CAG treatment based on syndrome differentiation is reasonable.

View all citing articles on Scopus

^☆: Supported by the Fundação para a Ciência e Tecnologia (Programa Operacional Ciência, Tecnologia e Inovação/ESP/43650/1999; PRAXIS/C/SAU/35374/99; and Programa Operacional Ciência, Tecnologia e Inovação/CBO/41550/2001), by the Programa Operacional Ciência, Tecnologia e Inovação do Quadro Comunitário de Apoio II, by the Fundação Luso-Americana para o Desenvolvimento, and by Fundação Calouste Gulbenkian.

View full text

Clinical-alimentary tractA proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma☆

Abstract

Background & Aims:

Methods:

Results:

Conclusions:

Section snippets

Study population

Results

Discussion

Semin Cancer Biol

Lancet

Gastroenterology

Blood

Gastroenterology

Gastroenterology

Cytokine

Cytokine

Helicobacter pylori infection and the risk of gastric carcinoma

N Engl J Med

Helicobacter pylori infection and the development of gastric cancer

N Engl J Med

Human gastric carcinogenesisa multistep and multifactorial process—first American Cancer Society Award Lecture on Cancer Epidemiology and Prevention

Cancer Res

Gastric cancer—a long-term consequence of Helicobacter pylori infection?

Scand J Gastroenterol Suppl

Interleukin-1 polymorphisms associated with increased risk of gastric cancer (published erratum appears in Nature 2001;412:99)

Nature

The importance of interleukin 1beta in Helicobacter pylori associated disease

Gut

Mucosal tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8 production in patients with Helicobacter pylori infection

Scand J Gastroenterol

Interleukin-1 receptor antagonistrole in biology

Annu Rev Immunol

Clinical-alimentary tract
A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma☆