TLR1 and PRKAA1 Gene Polymorphisms in the Development of Atrophic Gastritis and Gastric Cancer

2018 ◽  
Vol 27 (4) ◽  
pp. 363-369 ◽  
Author(s):  
Gintare Dargiene ◽  
Greta Streleckiene ◽  
Jurgita Skieceviciene ◽  
Marcis Leja ◽  
Alexander Link ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Atrophic Gastritis ◽  
Genetic Polymorphisms ◽  
Association Studies ◽  
Control Group ◽  
Similar Distribution ◽  
Genome Wide Association Studies ◽  
Increased Risk ◽  
Infection Susceptibility ◽  
H Pylori

Background & Aims: Previous genome-wide association studies showed that genetic polymorphisms in toll-like receptor 1 (TLR1) and protein kinase AMP-activated alpha 1 catalytic subunit (PRKAA1) genes were associated with gastric cancer (GC) or increased Helicobacter pylori (H. pylori) infection susceptibility. The aim of this study was to evaluate the association between TLR1 and PRKAA1 genes polymorphisms and H.pylori infection, atrophic gastritis (AG) or GC in the European population.Methods: Single-nucleotide polymorphisms (SNPs) were analysed in 511 controls, 340 AG patients and 327 GC patients. TLR1 C>T (rs4833095) and PRKAA1 C>T (rs13361707) were genotyped by the real-time polymerase chain reaction. H. pylori status was determined by testing for anti-H. pylori IgG antibodies in the serum.Results: The study included 697 (59.2%) H. pylori positive and 481 (40.8%) H. pylori negative cases. We observed similar distribution of TLR1 and PRKAA1 alleles and genotypes in H. pylori positive and negative cases. TLR1 and PRKAA1 SNPs were not linked with the risk of AG. TC genotype of TLR1 gene was more prevalent in GC patients compared to the control group (29.7% and 22.3% respectively, p=0.002). Carriers of TC genotype had a higher risk of GC (aOR=1.89, 95% CI: 1.26–2.83, p=0.002). A similar association was observed in a dominant inheritance model for TLR1 gene SNP, where comparison of CC+TC vs. TT genotypes showed an increased risk of GC (aOR=1.86, 95% CI: 1.26–2.75, p=0.002). No association between genetic polymorphism in PRKAA1 gene and GC was observed.Conclusions: TLR1 rs4833095 SNP was associated with an increased risk of GC in a European population, while PRKAA1 rs13361707 genetic variant was not linked with GC. Both genetic polymorphisms were not associated with H. pylori infection susceptibility or the risk of AG.

scholarly journals Polymorphism in Toll-Like Receptors and Helicobacter Pylori Motility in Autoimmune Atrophic Gastritis and Gastric Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 648 ◽  
Author(s):  
Valli De Re ◽  
Ombretta Repetto ◽  
Mariangela De Zorzi ◽  
Mariateresa Casarotto ◽  
Massimo Tedeschi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Helicobacter Pylori ◽  
Atrophic Gastritis ◽  
Toll Like Receptors ◽  
Innate And Adaptive Immunity ◽  
Healthy Donors ◽  
Increased Risk ◽  
Host Cell Interactions ◽  
H Pylori ◽  
Autoimmune Atrophic Gastritis

Autoimmune atrophic gastritis (AAG) is associated with an increased risk of certain types of gastric cancer (GC). Helicobacter pylori (H. pylori) infection may have a role in the induction and/or maintenance of AAG and GC. Toll-like receptors (TLR) are essential for H. pylori recognition and subsequent innate and adaptive immunity responses. This study therefore aimed to characterize TLR polymorphisms, and features of bacterial flagellin A in samples from patients with AAG (n = 67), GC (n = 114) and healthy donors (HD; n = 97). TLR5 rs5744174 C/C genotype was associated with GC, lower IgG anti H. pylori response and a higher H. pylori flagellin A abundance and motility. In a subset of patients with AAG, H. pylori strains showed a reduction of the flagellin A abundance and a moderate motility compared with strains from GC patients, a prerequisite for active colonization of the deeper layers of the mucosa, host immune response and inflammation. TLR9 rs5743836 T allele showed an association with serum gastrin G17. In conclusion, our study suggests that alterations of flaA protein, moderate motility in H. pylori and two polymorphisms in TLR5 and TLR9 may favor the onset of AAG and GC, at least in a subset of patients. These findings corroborate the function of pathogen–host cell interactions and responses, likely influencing the pathogenetic process.

scholarly journals Endoscopic and histological evaluation of the mucous membrane of the stomach in relatives of people suffering from cancer of the stomach

2019 ◽  
Vol 16 (4) ◽  
pp. 391-403
Author(s):  
V. V. Karpenka ◽  
Ju. V. Gorgun ◽  
N. P. Mitkovskaya ◽  
V. V. Krasko
Keyword(s):  
Gastric Cancer ◽  
Gastric Mucosa ◽  
Atrophic Gastritis ◽  
Main Group ◽  
Alcoholic Beverages ◽  
Histological Evaluation ◽  
Control Group ◽  
Cancer Of The Stomach ◽  
Younger Age ◽  
H Pylori

The condition of gastric mucosa was assessed in relatives of patients with gastric cancer (RPGC). The study included 108 RPGC (main group) and 102 patients with no family history of gastric cancer who were screened for dyspepsia. All study participants were subjected to clinical examination, questioning and esophagogastroduodenoscopy (EGDS) with a biopsy, in which the gastric mucosa state was assessed according to the modified Sydney system, the OLGA and OLGIM systems, and the definition of Helicobacter pylori (H. pylori) infection. It was established that the prevalence of H. pylori infection in the main group was 58.3 % (95 % CI 48.8–67.7), in the control group – 56.0 % (95 % CI 46.1–65.6). At RPGC, atrophy of any localization (46.3 % (95 % CI 39.4–53.2) versus 26.5 % (95 % CI 20.4–32.6), respectively, was found more often than in the control group, respectively, p = 0.002), antral atrophic gastritis (41.6 % (95 % CI 34.8–48.4) versus 26.5 % (95 % CI 20.4–32.6), respectively, p = 0.020), and isolated atrophy in the stomach body (4.6 % (95 % CI 1.7–7.4) versus 0 % ( p = 0.03). In RPGC, atrophy developed at a younger age (48.0 years (95 % CI 44.0–52.0) versus 53.0 years in the control group (95 % CI 48.3–57.8) p = 0.000). There were no significant differences between the groups in the incidence of metaplasia and dysplasia. The following risk factors for development of atrophy were identified in the factor analysis: age over 6f0 years (odd ratio (OR) 53.0; 95 % CI 12.2–390.1; p < 0.001), age over 40 years (OR 4.0; 95 % CI 2.0–8.2; p < 0.001), heredity burdened by gastric cancer (OR 2.7; 95 % CI 1.4–5.7; p = 0.006) and the use of strong alcoholic beverages (OR 5.5; 95 % CI 1.6–21.6; p = 0.009). The frequency of the atrophy development of the gastric mucosa is increased in RPGC, and atrophic gastritis develops at a younger age in comparison with individuals without a burdened hereditary history. In addition to the hereditary factor, the risk of atrophy is associated with age and alcohol use.

scholarly journals Rejuvenation of Helicobacter pylori–Associated Atrophic Gastritis Through Concerted Actions of Placenta-Derived Mesenchymal Stem Cells Prevented Gastric Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Jong Min Park ◽  
Young Min Han ◽  
Ki Baik Hahm
Keyword(s):  
Gastric Cancer ◽  
Stem Cells ◽  
Helicobacter Pylori ◽  
Mesenchymal Stem Cells ◽  
Atrophic Gastritis ◽  
Conditioned Medium ◽  
Gastric Atrophy ◽  
Control Group ◽  
Therapeutic Effects ◽  
H Pylori

Chronic Helicobacter pylori infection causes gastric cancer via the progression of precancerous chronic atrophic gastritis (CAG). Therefore, repairing gastric atrophy could be a useful strategy in preventing H. pylori–associated gastric carcinogenesis. Although eradication of the bacterial pathogen offers one solution to this association, this study was designed to evaluate an alternative approach using mesenchymal stem cells to treat CAG and prevent carcinogenesis. Here, we used human placenta-derived mesenchymal stem cells (PD-MSCs) and their conditioned medium (CM) to treat H. pylori–associated CAG in a mice/cell model to explore their therapeutic effects and elucidate their molecular mechanisms. We compared the changes in the fecal microbiomes in response to PD-MSC treatments, and chronic H. pylori–infected mice were given ten treatments with PD-MSCs before being sacrificed for end point assays at around 36 weeks of age. These animals presented with significant reductions in the mean body weights of the control group, which were eradicated following PD-MSC treatment (p &lt; 0.01). Significant changes in various pathological parameters including inflammation, gastric atrophy, erosions/ulcers, and dysplastic changes were noted in the control group (p &lt; 0.01), but these were all significantly reduced in the PD-MSC/CM-treated groups. Lgr5+, Ki-67, H+/K+-ATPase, and Musashi-1 expressions were all significantly increased in the treated animals, while inflammatory mediators, MMP, and apoptotic executors were significantly decreased in the PD-MSC group compared to the control group (p &lt; 0.001). Our model showed that H. pylori–initiated, high-salt diet–promoted gastric atrophic gastritis resulted in significant changes in the fecal microbiome at the phylum/genus level and that PD-MSC/CM interventions facilitated a return to more normal microbial communities. In conclusion, administration of PD-MSCs or their conditioned medium may present a novel rejuvenating agent in preventing the progression of H. pylori–associated premalignant lesions.

scholarly journals Association of MUC1 5640G>A and PSCA 5057C>T polymorphisms with the Risk of Gastric Cancer in Northern Iran

2020 ◽  
Author(s):  
Reza Alikhani ◽  
Ali Taravati ◽  
Mohammad Bagher Hashemi-Soteh
Keyword(s):  
Gastric Cancer ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Mucin 1 ◽  
Northern Iran ◽  
Tissue Samples ◽  
Prostate Cell ◽  
Formalin Fixed Paraffin ◽  
Increased Risk ◽  
Formalin Fixed Paraffin Embedded

Abstract Background: Gastric cancer is the fourth most common cancer worldwide and the second leading cause of cancer-related death. Genome-Wide Association Studies (GWAS) have shown that genetic diversities MUC1 (Mucin 1) and PSCA (prostate cell surface antigen) genes are involved in gastric cancer. The aim of this study was to determine the association between rs4072037G>A polymorphism in MUC1 and rs2294008 C>T in PSCA gene with gastric cancer in northern Iran. Methods: DNA was extracted from 99 formalin fixed paraffin-embedded (FFPE) tissue samples of gastric cancer and 96 blood samples from healthy individuals (sex matched) as controls. DNA was extracted followed by PCR using specific primers. Two desired polymorphisms, 5640G>A and 5057C>T for MUC1 and PSCA genes were genotyped using PCR-RFLP method. Results: The G allele at rs4072037 of MUC1 gene was associated with a significant decreased gastric cancer risk (OR= 0.50, 95% CI: 0.32 –0.79, p=0.003). A significant decreased risk of gastric cancer was observed in people with either AG vs AA and AG+AA vs GG genotype of MUC1 polymorphism (OR= 4.29, 95% CI: 1.19–15.51, p=0.01) and (OR= 3.54, 95% CI: 0.99–12.61, p=0.04) respectively. People with CT or TT genotype in PSCA polymorphism did not show any increased risk (OR = 1.139, 95% CI = 0.634-2.047, P = 0.662). Conclusion: Results indicated that the MUC1 polymorphism could be a risk factor in gastric cancer and could be considered a potential molecular marker in gastric cancer.

scholarly journals Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation

2020 ◽  
Vol 9 (2) ◽  
pp. 372 ◽  
Author(s):  
Oliver Bundgaard Vad ◽  
Christian Paludan-Müller ◽  
Gustav Ahlberg ◽  
Silje Madeleine Kalstø ◽  
Jonas Ghouse ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Genetic Correlation ◽  
Early Onset ◽  
Association Studies ◽  
Cytoskeletal Proteins ◽  
Control Group ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Increased Risk ◽  
Genes Encoding

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with an increased risk of heart failure, stroke, dementia, and death. Recently, titin-truncating variants (TTNtv), which are predominantly associated with dilated cardiomyopathy (DCM), were associated with early-onset AF. Furthermore, genome-wide association studies (GWAS) associated AF with other structural genes. In this study, we investigated whether early-onset AF was associated with loss-of-function variants in DCM-associated genes encoding cytoskeletal proteins. Using targeted sequencing, we examined a cohort of 527 Scandinavian individuals with early-onset AF and a control group of individuals free of AF (n = 383). The patients had onset of AF before 50 years of age, normal echocardiogram, and no other cardiovascular disease at onset of AF. We identified six individuals with rare loss-of-function variants in three different genes (dystrophin (DMD), actin-associated LIM protein (PDLIM3), and fukutin (FKTN)), of which two variants were novel. Loss-of-function variants in cytoskeletal genes were significantly associated with early-onset AF when patients were compared with controls (p = 0.044). Using publicly available GWAS data, we performed genetic correlation analyses between AF and 13 other traits, e.g., showing genetic correlation between AF and non-ischemic cardiomyopathy (p = 0.0003). Our data suggest that rare loss-of-function variants in cytoskeletal genes previously associated with DCM may have a role in early-onset AF, perhaps through the development of an atrial cardiomyopathy.

scholarly journals Causal effect of adiposity on the risk of 19 gastrointestinal diseases: a Mendelian randomization study

2021 ◽  
Author(s):  
Min Seo Kim ◽  
Minku Song ◽  
Soyeon Kim ◽  
Beomsu Kim ◽  
Wonseok Kang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Liver Disease ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Association Studies ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Alcoholic Fatty Liver ◽  
Increased Risk

Objectives: We applied Mendelian randomization (MR) to investigate the causal associations of body mass index (BMI) and waist circumference (WC) with 19 gastrointestinal (GI) disorders. Design: MR study. Setting: The UK Biobank, Genetic Investigation of Anthropometric Traits (GIANT) Consortium, FinnGen consortium, and genome-wide association studies. Participants: Overall, >400,000 UK Biobank participants, >170,000 participants of Finnish descent, and numerous consortia participants with predominantly European ancestry. Interventions: Single-nucleotide polymorphisms associated with BMI and WC were used as instrumental variables to estimate the causal associations with the GI conditions. Main outcome measures: Risk of developing 19 GI diseases Results: After correction for multiple testing (Bonferroni-corrected threshold of P<0.05/19) and testing for consistencies using several MR methods with varying assumptions (inverse variance weighted, weighted median, MR-Egger, and MR-PRESSO), genetically predicted BMI was associated with increased risks of non-alcoholic fatty liver disease (NAFLD), cholecystitis, cholelithiasis, and primary biliary cholangitis. The odds ratio (OR) per one standard deviation (SD) increased in genetically predicted BMI (4.77 kg/m2) from 1.22 (95% confidence interval [CI] 1.12 to 1.34; P<0.0001) for NAFLD to 1.65 (95% CI 1.31 to 2.06; P<0.0001) for cholecystitis. Genetically predicted WC was associated with increased risks of NAFLD, alcoholic liver disease (ALD), cholecystitis, cholelithiasis, colon cancer, and gastric cancer. ALD was associated with WC even after adjustment for alcohol consumption in multivariable MR analysis. The OR per 1 SD increased in genetically predicted WC (12.52 cm) from 1.41 (95% CI 1.17 to 1.70; P=0.0015) for gastric cancer to 1.74 (95% CI 1.21 to 1.78; P<0.0001) for cholelithiasis. Conclusions: Higher BMI and WC are causally associated with an increased risk of GI abnormalities, particularly of hepatobiliary organs (liver, biliary tract, and gallbladder) that are functionally related to fat metabolism. Abdominal obesity measured by WC might be more influential and relevant with a diverse span of GI diseases than BMI, highlighting a possible pathophysiological role of visceral abdominal fats in the development of GI disorders and cancers.

P1231Loss of function in cytoskeletal genes associates with early onset atrial fibrillation

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
O Vad ◽  
G Ahlberg ◽  
L Refsgaard ◽  
J H Svendsen ◽  
A Tveit ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Early Onset ◽  
Association Studies ◽  
Dystrophin Gene ◽  
Cytoskeletal Proteins ◽  
Control Group ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Structural Genes ◽  
Increased Risk

Abstract Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia. It carries an increased risk of serious complications and an increased mortality. Genome Wide Association Studies have demonstrated that variants in several structural genes are associated with AF, and recently two landmark papers have implicated loss of function (LoF) variants in titin (TTN), a gene associated with dilated cardiomyopathy (DCM), in patients with early onset AF. An atrial cardiomyopathy syndrome has been proposed as a mechanism in the development of AF. Purpose We hypothesized that genes encoding structural proteins that were associated with DCM, could also be involved in atrial cardiomyopathy and contribute to AF. Materials and methods We performed targeted deep sequencing of structural genes associated with DCM. The genes were grouped by cellular function, and the burden of LoF variants was examined in a cohort of 540 early onset AF patients and compared to a control group (n=383). The patients were below age 49 with normal echo, and no other cardiovascular disease at onset of AF. Patient inclusion in the cohort is still ongoing, and we are working on obtaining a CRISPR/CAS9 modified zebra fish model with LoF variants in cytoskeletal proteins. Results We identified a total of 6 carriers of LoF variants in 3 genes thought to encode cytoskeletal proteins (DMD, PDLIM3 and FKTN). The burden of variants in cytoskeletal genes was significantly increased in patients with early onset AF compared with controls (p=0.0385). Four carriers had LoF variants in the dystrophin gene (DMD), while there was 1 carrier of LoF variants in PDLIM3 and FKTN respectively. All carriers with LoF variants in DMD developed persistent AF before age 30. Conclusion Our data suggest that rare mutations in cytoskeletal genes previously associated with DCM, may also play a role in the development of early onset AF. The data supports that AF is a part of an atrial cardiomyopathy syndrome. Acknowledgement/Funding Novo Nordisk Fonden Pre-Graduate Scholarships

scholarly journals Long non-coding RNA polymorphisms on 8q24 are associated with the prognosis of gastric cancer in a Chinese population

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8600 ◽  
Author(s):  
Yangyu Zhang ◽  
Yanhua Wu ◽  
Zhifang Jia ◽  
Donghui Cao ◽  
Na Yang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Chinese Population ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Chinese Populations ◽  
Risk Of Death ◽  
Non Coding Rna ◽  
Increased Risk ◽  
Long Non Coding Rna

Background Gastric cancer (GC) remains the third leading cause of cancer death in China. Although genome-wide association studies have identified the association between several single nucleotide polymorphisms (SNPs) on 8q24 and the risk of GC, the role of these SNPs in the prognosis of GC in Chinese populations has not yet been fully evaluated. Therefore, this study was conducted to explore the association between long non-coding RNA (lncRNA) polymorphisms on 8q24 and the prognosis of GC. Methods We genotyped 726 surgically resected GC patients to explore the association between eight SNPs in the lncRNAs CCAT1 (rs10087719, rs7816475), PCAT1 (rs1026411), PRNCR1 (rs12682421, rs13252298), and CASC8 (rs1562430, rs4871789, rs6983267) transcribed from the 8q24 locus and the prognosis of GC in a Chinese population. Results We found that the patients carrying rs12682421 AA genotypes survived for a shorter time than those with the GG/GA genotype (HR = 1.39, 95% confidence interval (CI) [1.09–1.78]). Compared with the CC/CT genotype, the TT genotype of rs1562430 was associated with an increased risk of death (HR = 1.38, 95% CI [1.06–1.80]). Furthermore, the results also identified the rs1026411 SNP as an independent prognostic factor for poor survival in GC patients. Patients carrying AA/AG variant genotypes had a 36% increased risk of death compared to those carrying the GG genotype (HR = 1.36, 95% CI [1.06–1.74]). These findings suggested that the rs12682421, rs1026411 and rs1562430 SNPs may contribute to the survival of GC and be prognostic markers for GC.

scholarly journals Polymorphism of HDAC9 Gene Is Associated with Increased Risk of Acute Coronary Syndrome in Chinese Han Population

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Zhenhua Han ◽  
Xin Dong ◽  
Chaoying Zhang ◽  
Yue Wu ◽  
Zuyi Yuan ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Association Studies ◽  
Chinese Han Population ◽  
Control Group ◽  
Allele Carrier ◽  
Genome Wide Association Studies ◽  
Chinese Han ◽  
Han Population ◽  
Coronary Syndrome ◽  
Increased Risk

Recent genome-wide association studies (GWAS) have indicated an association of histone deacetylase 9 (HDAC9) genetic variant with large-vessel stroke and coronary artery disease, among the European population. However, whether HDAC9 gene is associated with an increased susceptibility to acute coronary syndrome (ACS) in Chinese Han population is not known. A total of 472 patients, including patients with ACS (N=309), and those with chest pain syndrome (controls,N=163) were enrolled. Genotyping for HDAC9 gene was performed using the ligation detection reaction assay. A series of statistical analyses were performed to investigate the correlation between HDAC9 gene SNPs and the susceptibility to ACS. The results revealed a significant association of rs2240419 with ACS risk in which the A allele (P= 0.047) and the A allele carriers (AA + AG) (P= 0.037) were more likely to be in ACS group as compared to those in the control group. None of two other SNPs, rs2389995 and rs2107595, were significantly associated with ACS risk (P> 0.05). Logistic regression analyses further revealed an increased risk for ACS in A allele carrier among rs2240419 genotypes, as compared to those with GG homozygotes (odds ratio: 1.869, 95% CI 1.143, 3.056,P= 0.013). A significant correlation between rs2240419 polymorphism of HDAC9 gene and the susceptibility to ACS in Chinese Han population was observed in this study.

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