RESUMEN
Chronic inflammation induced by Helicobacter pylori is a key process in gastric carcinogenesis. We hypothesized that genetic polymorphisms in important mediators of H. pylori-induced inflammation may influence the risk of developing various grades of precancerous lesions. We studied the associations between single nucleotide polymorphisms (SNPs) in cyclooxygenase 1 and 2 (PTGS1 and PTGS2), inducible nitric oxide synthase (NOS2A), interferon gamma (IFNG) and its receptor (IFNGR1), and risk of gastric precancerous lesions in a Venezuelan population characterized by high rates of H. pylori infection. We found no association of precancerous lesions with SNPs in PTGS1 and in IFNG. A nonsynonymous SNP of NOS2A (Ser608Leu) and an SNP located in the promoter of IFNGR1 (C-56T) were associated with higher risk of atrophic gastritis [odds ratio (OR)=1.37, 95% confidence interval (CI)=1.01-1.86, and OR=1.49, 95% CI=1.01-2.19, respectively]. Two SNPs of PTGS2 were associated with risk of dysplasia (OR=1.60, 95% CI=1.01-2.54, and OR=0.66, 95% CI=0.43-0.99). We conclude that genetic variability in the genes we studied does not play a major role in the early stages of gastric carcinogenesis.
Asunto(s)
Infecciones por Helicobacter/complicaciones , Neoplasias Gástricas/genética , Neoplasias Gástricas/microbiología , Adulto , Anciano , Ciclooxigenasa 1/genética , Ciclooxigenasa 2/genética , Femenino , Infecciones por Helicobacter/epidemiología , Helicobacter pylori , Humanos , Inflamación , Interferón gamma/genética , Masculino , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo II/genética , Polimorfismo de Nucleótido Simple , Lesiones Precancerosas/genética , Receptores de Interferón/genética , Factores de Riesgo , Neoplasias Gástricas/epidemiología , Venezuela/epidemiología , Receptor de Interferón gammaRESUMEN
As Helicobacter pylori (HP) is a Gram-negative bacterium, we investigated the associations between several functional polymorphisms in genes involved in lipopolysaccharide (LPS) signaling and the prevalence of various stages of gastric premalignant lesions in a Venezuelan population. The two NOD2 polymorphisms, del3020insC and Gly908Arg, were too infrequent to study their associations with gastric lesions. The risk of intestinal metaplasia (IM) was significantly increased among subjects with the CD14 T-260 allele compared to those without this allele. A similar, but nonsignificant increase in risk for dysplasia was observed among homozygotes of this allele. There was no association between TLR4 Asp299Gly polymorphism and any type of lesions, except for a slight nonsignificant increase in risk of IM associated with the AA genotype among subjects with a higher histological HP score. These results suggest that genetic polymorphisms in HP LPS signaling may be implicated in the development of intermediate stages of gastric premalignant lesions.
Asunto(s)
Helicobacter pylori/genética , Receptores de Lipopolisacáridos/genética , Lipopolisacáridos/metabolismo , Proteína Adaptadora de Señalización NOD2/metabolismo , Peptidoglicano/metabolismo , Polimorfismo Genético , Lesiones Precancerosas/genética , Neoplasias Gástricas/genética , Receptor Toll-Like 4/genética , Adulto , Femenino , Gastroscopía , Genotipo , Infecciones por Helicobacter , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/microbiología , Venezuela/epidemiologíaRESUMEN
OBJECTIVES: The aim of the study was to assess the effects of genetic polymorphisms in anti-inflammatory mediators, i.e., IL10, IL4 and IL4R on the prevalence of gastric precancerous lesions and their interactions with other environmental factors. METHODS: The study population consisted of 2,033 Venezuelan subjects known to have extremely high Helicobacter Pylori (HP) infection rates. The odds ratios (OR) and 95% confidence intervals (CI) associated with these polymorphisms were estimated by multinominal logistic regression models for gastric precursor lesions. RESULTS: We found a 60% increase in risk of intestinal metaplasia (IM) and dysplasia combined (OR 1.62, 95% CI: 1.10-2.38) among the carriers of the IL10-1082 low activity allele. This increased risk was more pronounced for dysplasia than for IM. On the other hand, homozygotes with the low activity allele of the A398G polymorphism in the IL4R gene had a modest increase in risk of atrophic gastritis (OR = 1.52, 95% CI: 1.05-2.21), compared with homozygotes of the high activity allele. There were no statistically significant synergetic interactions between these polymorphisms and environmental risk factors (low fruit intake, high starchy vegetable intake and cigarette smoking) for these lesions. CONCLUSION: While the results of the present study suggest roles of genetic variability in these anti-inflammatory mediators in different stages of gastric carcinogenesis, there is high likelihood that they were chance findings due to multiple comparisons.
Asunto(s)
Citocinas/genética , Mediadores de Inflamación , Polimorfismo de Nucleótido Simple , Lesiones Precancerosas/genética , Transducción de Señal/genética , Neoplasias Gástricas/genética , Adulto , Anciano , Citocinas/metabolismo , Femenino , Gastritis/epidemiología , Gastritis/genética , Gastritis/microbiología , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/genética , Humanos , Interleucina-10/genética , Interleucina-4/genética , Intestinos/microbiología , Intestinos/patología , Modelos Logísticos , Masculino , Metaplasia , Persona de Mediana Edad , Lesiones Precancerosas/epidemiología , Lesiones Precancerosas/microbiología , Prevalencia , Receptores de Interleucina-4/genética , Medición de Riesgo , Factores de Riesgo , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/microbiología , Venezuela/epidemiologíaRESUMEN
Helicobacter pylori (HP) infection affects over 50% of the world's population. The prevalence is over 90% in populations at high risk for gastric cancer, but clinical outcomes of the infection are highly variable and thus host genetic factors have been suggested to play a role in its outcomes in addition to bacterial factors. In this study, we examined the effects of common functional genetic polymorphisms of several proinflammatory cytokines known to be overexpressed in HP-infected gastric mucosa on the risk of various stages of gastric premalignant lesions. The odds ratios (ORs) and 95% confidence intervals (CI) for atrophic gastritis, intestinal metaplasia and dysplasia were estimated by multinominal logistic regression analysis among 2,033 Venezuelan subjects. There was a significant effect of IL8 -251A allele on the prevalence of dysplasia (p = 0.021). The OR associated with the A-allele was 1.34 (95% CI: 0.82-2.18) for heterozygotes and 2.00 (95% CI: 1.13-3.56) for homozygotes, compared with the TT genotype. Furthermore, there was a statistically significant interaction between the number of A-alleles and HP cag A genotype (p = 0.009), suggesting that the A-allele increased the risk of dysplasia only when cag A was present. The OR for the AA compared with TT genotype was 3.22 (95% CI: 1.60-6.52) in this group. There were no associations with other proinflammatory cytokines studied, i.e., IL1 beta, IL6, monocyte chemoattractant protein 1 (MCP1) and TNF alpha, or with other stages of premalignant lesions. The present study provides important evidence suggesting host-bacterial interactions in the development of gastric precancerous lesions.