Polymorphisms in IL-10 and TGF-? gene promoter are associated with lower risk to gastric cancer in a Mexican population.
ABSTRACT: BACKGROUND:Helicobacter pylori infection is recognized as the main risk factor for gastric cancer (GC), the fifth most common neoplasia worldwide. H. pylori interacts with the immune system, disrupting the cytokine network and inducing chronic inflammation. This work aimed to evaluate the association between single nucleotide polymorphisms (SNPs) in selected cytokine gene promoters and GC. METHODS:The study included 359 subjects, 125 GC patients, 109 intestinal metaplasia (IM) patients and 125 asymptomatic controls. DNA was extracted from white blood cells and nine SNPs in cytokine gene promoters were genotyped using predesigned 5'-endonulease assays. The association of the SNPs with IM and GC was evaluated using multinomial regression models. RESULTS:Both genotypes, TC (OR =?0.51, 95% CI?=?0.27-0.98) and TT (OR =?0.42, 95% CI?=?0.20-0.91) in the locus -?509 of the TGF-? promoter were significantly associated with GC. The TT genotype in the locus -?819 of the IL-10 promoter was also significantly associated with GC (OR = 0.37, 95% CI?=?0.17-0.81). No significant association was found with SNPs IL-4 -590?T/C (rs1800629), IL-6 -573G/C (rs1800796), IL-10 -592C/A (rs1800872), IL-10 -1082A/G (rs1800896), and, IFN-? -1615C/T (rs2069705). CONCLUSIONS:SNPs in TGF? (-?509 C/T, rs1800469) and IL-10 (-?819 C/T, rs1800871) promoters were associated with a lower risk for GC in a Mexican population.
Project description:BACKGROUND: Potential functional allele T/C single nucleotide polymorphism (SNP) of Interleukin 10 (IL-10) promoter -819 (rs1800871) has been implicated in gastric cancer risk. We aimed to explore the role of T/C SNP of IL-10 -819 in the susceptibility to gastric cancer through a systematic review and meta-analysis. METHODS: Each initially included article was scored for quality appraisal. Desirable data were extracted and registered into databases. 11 studies were ultimately eligible for the meta-analysis of IL-10 -819 T/C SNP. We adopted the most probably appropriate genetic model (recessive model). Potential sources of heterogeneity were sought out via subgroup and sensitivity analyses, and publication biases were estimated. RESULTS: IL-10 -819 TT genotype is associated with the overall reduced gastric cancer risk among Asians and even apparently observed among high quality subgroup Asians. IL-10-819 TT genotype is not statistically associated with the overall reduced gastric cancer susceptibility in persons with H. pylori infection compared with controls without H. pylori infection. IL-10 -819 TT genotype is reversely associated with diffuse-subtype risk but not in intestinal-subtype risk. IL-10 -819 TT genotype is not reversely associated with non-cardia or cardia subtype gastric cancer susceptibility. CONCLUSIONS: IL-10 -819 TT genotype seems to be more protective from gastric cancer in Asians. Whether IL-10 -819 TT genotype may be protective from gastric cancer susceptibility in persons infected with H. pylori or in diffuse-subtype cancer needs further exploring in the future well-designed high quality studies among different ethnicity populations. Direct sequencing should be more used in the future.
Project description:BACKGROUND: Intestinal metaplasia (IM) is an important precursor lesion in the development of gastric cancer (GC). The aim of this study was to investigate genetic factors previously linked to GC risk for their possible association with IM. A total of 18 polymorphisms in 14 candidate genes were evaluated in a Singapore-Chinese population at high risk of developing GC. METHODS: Genotype frequencies were compared between individuals presenting with (n = 128) or without (n = 246) IM by both univariate and multivariate analysis. RESULTS: Carriers of the NQO1 609 T allele showed an association with IM in individuals who were seropositive for Helicobacter pylori (HP+; OR = 2.61, 95%CI: 1.18-5.80, P = .018). The IL-10 819 C allele was also associated with IM in HP+ individuals (OR = 2.32, 95%CI: 1.21-4.43, P = 0.011), while the PTPN11 A allele was associated with IM in HP- individuals (OR = 2.51, 95%CI: 1.16-5.40, P = 0.019), but showed an inverse association in HP+ subjects (OR = 0.46, 95%CI: 0.21-0.99, P = 0.048). CONCLUSION: Polymorphisms in NQO1, IL-10 and PTPN11, in combination with HP status, could be used to identify individuals who are more likely to develop IM and therefore GC.
Project description:The aim of this study is to clarify the associations between IL-1B31C/T, IL-1B-511C/T, IL-8-251T/A gene polymorphisms and the risk of Helicobacter pylori (H. pylori) infection together with H. pylori-related gastric cancer (GC), peptic ulcer disease (PUD).All eligible literature published up to July 2016 were identified by searching Pubmed, Embase, Web of Science and CNKI. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated using a fixed or random effects model.29 case-control studies were eligible, and each of them may focus on more than one gene polymorphism. Ultimately, there were 21 studies (3159 cases and 2816 controls) for IL-1B-31C/T, 16 studies (2486 cases and 1989 controls) for IL-1B-511C/T polymorphisms, 9 studies (1963 cases and 1205 controls) for IL-8-251T/A polymorphisms. Overall, an increased risk of H. pylori infection was found for IL-1B-31C/T polymorphisms in total population [OR = 1.134, 95%CI = 1.008-1.275 for recessive model; OR = 1.145, 95%CI = 1.007-1.301 for TT vs CC model]. While, for IL-1B-511C/T and IL8-251T/A polymorphisms, no evidence indicated that they were associated with the risk of H. pylori infection in all genetic models. Furthermore, we found an increased risk of H. pylori-related GC with IL-1B-511C/T polymorphisms [OR = 1.784, 95%CI = 1.289-2.469 for recessive model; OR = 1.772, 95%CI = 1.210-2.594 for TT vs CC model] and IL8-251A/T polymorphisms [OR = 1.810, 95%CI = 1.229-2.667 for recessive model; OR = 1.717, 95%CI = 1.143-2.580 for TT vs AA model], an increased risk of H. pylori-related PUD with IL8-251T/A polymorphisms [OR = 1.364, 95%CI = 1.010-1.843 for recessive model; OR = 1.427, 95%CI = 1.039-1.959 for AA vs TT model].IL-1B-31C/T gene polymorphisms might increase H. pylori infection risk. IL-1B-511-C/T and IL-8-251T/A gene polymorphisms might act as a risk factor to H. pylori-related diseases including GC or PUD.
Project description:The risk of gastric cancer (GC) declines after Helicobacter pylori (H. pylori) eradication and long-term aspirin use. We evaluated the effects of H. pylori eradication (Cohort 1) and aspirin use (Cohort 2) on the methylation of microRNAs (miRNAs), such as miR-34c, miR-124a-3, miR-129-2, and miR-137, in the gastric mucosa with and without GC, i.e., in atrophic mucosal glands without intestinal metaplasia (non-IM) and intestinal metaplastic glands (IM). DNA was isolated from non-IM and IM separately using laser caption microdissection. In Cohort 1, H. pylori eradication was associated with a significant reduction of miR-124a-3 methylation only in non-IM, but not in IM. miR-129-2 methylation in non-IM may be a surrogate marker of GC in H. pylori-infected patients. In Cohort 2, aspirin did not reverse miRNA methylation in either non-IM or IM, irrespective of H. pylori infection. miR-129-2 methylation in non-IM was an independent predictive marker of GC in H. pylori-infected but not -eradicated patients. These results indicate that H. pylori eradication and aspirin use were less effective for improving methylation in IM than in non-IM; thus, these interventions are recommended at an early stage prior to the development of IM to prevent GC development. In addition, the effects of the interventions were not uniform for each miRNA gene.
Project description:The risk of gastric cancer (GC) remains in precancerous conditions, including atrophic mucosa and intestinal mucosa (IM), even after H. pylori treatment. To define the molecular changes following H. pylori eradication, molecular alterations in the gastric mucosa with and without GC were evaluated in a long-term follow-up study. A total of 232 biopsy specimens from 78 consecutive patients, including atrophic gastritis patients with follow-up ?3?y after successful H. pylori eradication (AG group), patients who developed early GC after successful eradication (?3?y) (GC group), and patients with H. pylori-positive atrophic gastritis (Hp group), were analyzed. H. pylori eradication was associated with significant reductions of methylation of several genes/loci in atrophic mucosa (non-IM), but not in IM. In contrast, the incidence of CpG island methylator phenotype (CIMP) in IM was significantly higher in the GC group than in the AG group. miR-124a-3 methylation and miR-34c methylation were more frequently identified in IM, with very few in non-IM mucosa among the three groups. H. pylori eradication can reverse methylation only in non-IM mucosa. CIMP in IM may have potential as a surrogate maker of GC development, and methylation of miR-124a-3 and miR-34c is a molecular event in IM that may not be associated with GC development.
Project description:<h4>Background</h4>Rheumatoid arthritis (RA) is characterized by systemic synovitis with bone erosion and joint cartilage degradation. Although the analysis of polymorphisms in cytokine-encoding genes is important or understanding the pathophysiology of RA and selecting appropriate treatment for it, few studies have examined such single-nucleotide polymorphisms (SNPs) specifically in Japanese patients. This study was established to investigate the associations between polymorphisms in cytokine-encoding genes, autoantibodies and therapeutic responses in Japanese RA patients.<h4>Methods</h4>The subjects in this study consisted of 100 RA patients and 50 healthy controls. We extracted data on sex, age, disease duration, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibody, and therapeutic responses, including to methotrexate (MTX) and biological disease-modifying antirheumatic drugs (DMARDs). Genomic DNA was isolated from peripheral blood, which was genotyped for IL-10, TNF-?, TGF-?<sub>1</sub>, and IFN-? polymorphisms.<h4>Results</h4>Regarding IL-10 (-592 C/A and -819 C/T), significant decreases in the frequencies of the IL-10 (-592) CC genotype and (-819) CC genotype were found in RA patients compared with the levels in controls. For IFN-? (+874 T/A), a significant decrease in the frequency of the TT genotype was found in RA patients compared with that in controls. Regarding TGF-?<sub>1</sub> (+869 T/C), patients with positivity for anti-CCP antibody had a significantly lower frequency of the CC genotype than those with negativity for it. Furthermore, the IL-10 (-592) CC genotype and (-819) CC genotype might be related to the biological DMARD-response.<h4>Conclusion</h4>Our results suggest that the analysis of polymorphisms in cytokine-encoding genes may be useful when selecting treatment for Japanese RA patients.
Project description:Gene-environment interactions may increase gastric cancer (GC) risk. Seven susceptibility loci identified by genome-wide association studies (GWASs) suggest that genetic factors play a role in gastric carcinogenesis. Meanwhile, Helicobacter pylori (H. pylori) infection, smoking, and alcohol drinking are also important environmental factors for gastric cancer. However, studies to explore the role of gene-environment interactions in gastric carcinogenesis, and particularly the relationship between the seven susceptibility loci and their potential interactions with H. pylori infection, smoking, and alcohol drinking in risk of GC, and severe intestinal metaplasia (IM)/dysplasia, have been inconclusive. A total of 1273 subjects in a Chinese population were recruited, and genotyping was carried out using the competitive allele-specific PCR (KASP) method. Unconditional logistic regression was applied to model the associations between genetic polymorphisms and the disease risk. Effect modifications by H. pylori infection, smoking and alcohol drinking were evaluated. PSCA rs2294008/rs2976392 showed a significant, multiplicative interaction with H. pylori infection in risk of GC. Meanwhile, PRKAA1 rs13361707 had an additive interaction with H. pylori infection. SLC52A3 rs13042395 showed an interaction with alcohol drinking in risk of GC. Moreover, three SNPs, MUC1 rs4072037, ZBTB20 rs9841504 and PRKAA1 rs13361707, were associated with precancerous gastric lesions (severe IM/dysplasia). Our data suggest that genetic predisposition factors identified by GWAS may interact with environmental risk factors, Particularly for H. pylori infection and alcohol consumption, to increase the risk of GC.
Project description:Leprosy is a chronic bacterial disease caused by Mycobacterium leprae. Cytokines are known to play vital role as a peacekeeper during inflammatory and other immunocompromised conditions such as leprosy. This study has tried to bridge the gap of information on cytokine gene polymorphisms and its potential role in the pathogenesis of leprosy. Interleukin-10 (IL-10) is an immunosuppressive cytokine, found to be elevated in leprosy that accounted for the suppression of host's immune system by regulating the functions of other immune cells. T helper cells and T regulatory (Tregs) cells are the major source of IL-10 in lepromatous leprosy patients. In this study, we have documented the association of IL-10 cytokine gene polymorphism with the disease progression. A total of 132 lepromatous leprosy patients and 120 healthy controls were analyzed for IL-10 cytokine gene polymorphisms using PCR-SSP assay and flow cytometry was used to analyze IL-10 secretion by CD4 and Tregs in various genotype of leprosy patients. The frequencies of IL-10 (-819) TT and IL-10 (-1082) GG genotypes were significantly higher in leprosy patients as compared to healthy controls. This observation advocates that these genotypes were associated with the susceptibility and development of the disease. In addition, flow cytometry analysis demonstrated an increased number of IL-10 producing CD4 and Treg cells in IL-10 (819) TT genotype compared to CT and CC genotypes. These observations were further supported by immunohistochemical studies. Therefore, we can conclude that IL-10 cytokine gene polymorphisms by affecting its production can determine the predilection and progression of leprosy in the study population.
Project description:Background/Aims:Helicobacter pylori (Hp) suppresses gastric acid secretion by repressing the expression of the H+, K+-adenosine triphosphatase (H+, K+-ATPase) and stimulating interleukin-1 (IL-1?; encoded by IL-1B). This study was aimed at evaluating the expression of the H+, K+-ATPase and IL-1? after Hp eradication. Methods:Two hundred twentyone subjects were categorized as Hp-negative (n=84) or Hppositive (n=137) according to the results of Hp tests (histology, CLO test, culturing, and serology). The mRNA expression levels of IL-1B and ATP4A (the gene encoding the ?-subunit of H+, K+-ATPase) were measured in biopsy specimens from the gastric corpus using real-time polymerase chain reaction. Results:The Hp-positive group had significantly higher IL-1B mRNA levels than the whole Hp-negative group and the intestinal metaplasia (IM)-negative subgroup. After Hp eradication, the difference between the Hp-negative and Hperadicated groups disappeared, including in the IM-negative subgroup. The IL-1B mRNA level did not significantly change from the baseline level. Within the gastric cancer (GC)/dysplasia subgroup, the IL-1B mRNA levels at 1, 2, 3-4, and ?5 years after Hp eradication were significantly lower than the baseline level. The difference in ATP4A mRNA levels between the Hp-negative and Hp-positive groups was not significant at baseline, and the changes in the ATP4A mRNA levels after Hp eradication compared to the baseline levels in the whole group and subgroups stratified by the presence of IM and GC/dysplasia were not significant. Conclusions:Infection with Hp has an effect on the level of IL-1B mRNA in IM-negative subjects. The continuous reduction in the IL-1B mRNA level in patients with GC/dysplasia after Hp eradication contributes to the prevention of metachronous GC after Hp eradication.
Project description:Influence of folate metabolism has long been studied in cancer and copies evidences have suggested that the key genes involved were correlated with GC risk and prognosis. However, their genetically association and contribution for GC prognosis are still elusive. To evaluate the effect of folate metabolism related genes polymorphisms on the prognosis of gastric cancer (GC), the genotype of seven single nucleotide polymorphisms (SNPs) of three genes were selected and genotyped in a cohort of 664 GC patients, including genes of Methylenetetrahydrofolate reductase (MTHFR), Methionine synthase reductase (MTRR), and Methionine synthase (MTR). Kaplan-Meier Curve, long-rank tests and multivariate Cox proportional hazard model were used for prognosis analysis. The results demonstrated that TT or CT/TT genotypes of SNP rs1532268 in MTRR gene coding region are significantly associated with a poorer overall survival (OS) when compared with CC genotype (HR=2.340, 95% CI: 1.240-4.414, p=0.009; or HR=1.502, 95% CI: 1.083-2.085, p=0.015, respectively). Furthermore, comparing to that of the CC genotype, the detrimental effect of rs1532268 TT genotype was also evident in the special subgroups of GC patients, especially in patients with BMI<24 and H. pylori infection. Moreover, significant association between increased relapse and TT genotype of rs1532268 was also observed in patients who are females, BMI<24 and without chemotherapy. In addition, the joint analysis demonstrated that integration of rs1532268 genotypes and BMI, H. pylori infection status, clinical stage and tumor site may significantly improve the predictive abilities for predicting OS of GC patients. In conclusion, it suggested that the MTRR rs1532268 polymorphism is significantly associated with clinical outcomes of GC patients, especially in those with lower BMI (BMI<24) or positive H. pylori infection status, which warrants further validation. And the polymorphism of MTRR rs1532268 may be a potential prognostic factor for GC patients.