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Helicobacter pylori (HP) colonizes the human stomach and induces acute gastritis, peptic ulcer disease, atrophic gastritis, and gastric adenocarcinoma. Increased virulence in HP isolates derives from harboring the cag (cytotoxin-associated genes) pathogenicity island (cagPAI). We analyzed the microvariants in cagPAI genes with the hypothesis that they may play an important role in determining HP virulence. We tested DNAs from cagA positive patients HP isolates; a total of 74 patients with chronic gastritis (CG, N = 37), intestinal metaplasia (IM, N = 21) or gastric cancer (GC, N = 16) from Mexico and Colombia. We selected 520 non-synonymous variants with at least 7.5% frequency in the original sequence outputs or with a minimum of 5 isolates with minor allele. After adjustment for multiple comparisons, no variants were statistically significantly associated with IM or GC. However, 19 non-synonymous showed conventional P-values < 0.05 comparing the frequency of the alleles between the isolates from subjects with gastritis and isolates from subjects with IM or GC; 12 of these showed a significant correlation with the severity of the disease. The present study revealed that several cagPAI genes from Latin American Western HP strains contains a number of non-synonymous variants in relatively high frequencies which could influence on the clinical outcome. However, none of the associations remained statistically significant after adjustment for multiple comparison.

Helicobacter pylori (Hp) infects the stomach of about half of the human population and is strongly associated with the risk of gastric cancer (GC) and its premalignant precursors. The cag pathogenicity island (cagPAI) is a region of the Hp genome encoding for key molecular machinery involved in the infection process. Following a sequencing study, we selected 50 genetic polymorphisms located in seven cagPAI genes and tested their associations with the risk of advanced gastric premalignant lesions and GC in 1220 subjects from various Latin American populations showing the whole spectrum of phenotypes from gastritis to GC. We found that three polymorphisms of cagA are associated with the risk of advanced gastric premalignant lesions (incomplete intestinal metaplasia [ie, Type 2 and 3] or dysplasia), and that six polymorphisms located in cagA, cagL and cagI were associated with risk of GC. When corrected for multiple testing none of the associations were statistically significant. However, scores built by integrating the individual polymorphisms were significantly associated with the risk of advanced gastric premalignant lesions and GC. These results have the potential of establishing markers for risk stratification in the general population, in view of targeting Hp eradication to high-risk population groups.

El cáncer gástrico es una de las principales causas de muerte por cáncer en el mundo y la infección con Helicobacter pylori es uno de los principales factores de riesgo, asociados a su aparición. H. pylori es una bacteria que coloniza la mucosa gástrica, infectando alrededor de la mitad de la población mundial. Los efectos patológicos ocasionados por la infección con H. pylori dependen, en buena parte, de un sistema de secreción tipo IV, codificado en el islote de patogenicidad cag (cagPAI). En esta revisión, se describe la composición del cagPAI, la alteración de las vías de señalización celular mediadas por el cagPAI, que regulan respuestas celulares oncogénicas, que pueden incrementar el riesgo de transformación maligna asociada a la infección y la importancia de los polimorfismos en genes del cagPAI, como posibles marcadores de progresión a cáncer gástrico. Gastric cancer is one of the main causes of death by cancer in the world and the infection with Helicobacter pylori is one of the main risk factors associated with its appearance. Helicobacter pylori is a bacterium that colonizes the gastric mucosa, infecting about half of the world ́s population. The pathological effects caused by infections with H. pylori greatly depend on an IV type secretion system encoded in the cag pathogenicity island (cagPAI). In this review, we describe the composition of the cagPAI, the alterations of cellular signaling pathways mediated by cagPAI which regulate oncogenic cellular responses that may increase the risk of malignant transformation associated with the infection and the importance of polymorphisms in cagPAI genes as potential markers of progression to gastric cancer. Incluye referencias bibliográficas

Resumen Objetivo Evaluar la asociacion de los polimorfismos de alguna de las citocinas mas estudiadas en relacion con el cancer gastrico (IL-1B-511, IL-1RN intron-2-VNTR, TNF-α-308, IL-10-819 e IL-10-1082) y la presencia de anticuerpos hacia la proteina cagA de Helicobacter pylori con las lesiones preneoplasicas gastricas en pacientes colombianos. Materiales y metodos Se estudiaron 185 pacientes con lesiones preneoplasicas (gastritis atrofica, metaplasia intestinal y displasia), y 154 controles (gastritis no atrofica), provenientes de hospitales de una zona de riesgo alto y otra de riesgo bajo para cancer gastrico. Se obtuvieron biopsias gastricas y muestras de sangre; la genotipificacion de los polimorfismos se hizo por discriminacion alelica usando PCR en tiempo real y por PCR convencional y electroforesis en agarosa (VNTR del intron 2 de IL-1RN); la serologia de Helicobacter pylori y Helicobacter pylori cagA se determino por ELISA. Se utilizo regresion logistica multinomial en el analisis estadistico. Resultados El genotipo IL-1B-511TT ( odds ratio = 4,05; intervalo de confianza 95% 1,35-12,10) se asocio a metaplasia intestinal; no se observaron otras asociaciones entre los diferentes polimorfismos y las lesiones preneoplasicas. La infeccion por Helicobacter pylori cagA positivo se asocio a gastritis atrofica, metaplasia intestinal y displasia (OR = 2,66; 13,70; 40,29, respectivamente). Conclusion Los resultados sugieren que entre los genotipos proinflamatorios el genotipo IL-1B - 511TT estaria asociado a la metaplasia intestinal, y la serologia de Helicobacter pylori cagA positivo seria un biomarcador util para intervenir y prevenir la presencia de lesiones preneoplasicas. Se necesitan otros estudios con poblacion colombiana que evaluen la asociacion hallada de IL1B-511 con la metaplasia intestinal.

Background: There is an association of interleukin (IL)1B polymorphism with gastric cancer risk. However systematic reviews of the existing evidence have shown that such association varies across populations with different genetic ancestry. Aim: To evaluate the association of IL-1B-511 and IL-1RN polymorphism and Helicobacter pylori IgG antibodies CagA, with gastric cancer in two Colombian cities located in a high risk area for gastric cancer. Material and Methods: A case-control study including 46 gastric cancer cases and 99 controls with non-atrophic gastritis from a high risk zone for gastric cancer. Polymorphism genotyping was carried out by polymerase chain reaction (PCR) and IgG CagA status by ELISA. Results: IgG CagA seropositive individuals had an increased gastric cancer risk (odds ratio (OR) = 11.56; 95% confidence intervals (CI) 2.62-50.91 in Tunja and OR = 19.66, 95%CI 0.98-395 in Bogotá). IL-1B-511TT carriers in Tunja had increased risk of gastric cancer (OR = 11.31; 95%CI 1.20-106.54)), while IL-1RN*2 alelle carriers in Bogotá showed an inverse association with gastric cancer risk (OR = 0.03; 95%CI 0.01-0.65). Conclusions: This study adds evidence to the positive association of Helicobacter pylori CagA positive strains with non-cardial gastric cancer etiology. There is a possible heterogeneity in the association of IL-1B gene polymorphism with cancer, in populations of similar ethnic background and settled in the same risk area.

Resumen Objetivo Determinar la asociacion entre los polimorfismos IL-1B-511, IL-1RN, TNF-α-308, IL-10-819 e IL-101082 y la infeccion por Helicobacter pylori CagA positivo en un grupo de pacientes con cancer gastrico y ulcera duodenal en diferentes poblaciones en Colombia. Metodos Estudio de casos y controles con 341 pacientes: con gastritis no atrofica, 194; con cancer gastrico, 58; ulcera duodenal con lesiones preneoplasicas, 54; y con ulcera duodenal, 35. La genotipificacion de los polimorfismos se hizo por discriminacion alelica usando PCR en tiempo real, y la del IL-1RN, por PCR convencional y electroforesis en agarosa. La infeccion por Helicobacter pylori CagA se determino mediante ELISA. Se utilizo la regresion logistica en el analisis estadistico. Resultados Ser portador del genotipo IL-1B-511TT (OR = 4,69; IC 95% 1,22-18,09) y tener una infeccion por Helicobacter pylori CagA positivo (OR = 4,43; IC 95% 1,72–11,4) se asociaron a cancer gastrico. Tener una infeccion por Helicobacter pylori CagA positivo (OR = 4,39; IC95% 1,82–10,59) se asocio a la presencia de ulcera duodenal con lesiones preneoplasicas, y ser portador del genotipo IL-1B-511CT se asocio a ulcera duodenal (OR = 0,30; IC 95% 0,10–0,91). Conclusion Los resultados sugieren que la respuesta pro-inflamatoria y la genetica virulenta de la bacteria son factores relacionados con los diferentes desenlaces ocasionados por la infeccion por Helicobacter pylori en la poblacion estudiada; asi, el polimorfismo IL-1B-511 es un factor relacionado con cancer gastrico y ulcera duodenal, y la infeccion por Helicobacter pylori CagA positivo es un factor asociado a cancer gastrico y ulcera duodenal con lesiones preneoplasicas.

Helicobacter pylori is a Gram-negative microaerophilic bacterium. It has been estimated that it colonizes half of the human population (1, 2). The prevalence of the infection correlates with the socioeconomic status of the populations studied, more frequently affecting developing rather than developed countries (3). The infection is associated with the development of chronic gastritis, gastric ulcer, and stomach cancer (4), although in most cases the infection persistsin the gastric mucosa without affecting the individual’s health (5). In this communication, we present the genome sequence of the strain Col2025. This strain was isolated from a 36-year-old man diagnosed with diffuse antral gastritis from Tibaná, Boyacá, a region with high gastric cancer risk in Colombia (6). Interestingly, neither CagA phosphorylation nor interleukin 8 (IL-8) secretion was detected when the strain Col2025 was cultured with AGS cells. To obtain a genome sequence, 1 g of DNA was fragmented by Covaris, and the fragments were repaired by attaching an A to the 3= end. Illumina adaptors were ligated to the fragments and selected for sizes between 400 and 500 bp. The size-selected fragments were amplified by PCR and the final products validated in an Agilent Bioanalyzer. The short reads were assembled using SOAPdenovo (7). Finally, the sequences were annotated in GenBank using the NCBI Prokaryotic Genomes Automatic Annotation Pipeline (PGAAP) according to the submission guidelines (http://www.ncbi.nlm.nih.gov/genbank/genomesubmit.html). Overall, this whole-genome shotgun sequencing revealed the following data: scaffolds, 54; contigs, 73; N50, 60,455; L50, 9; genome size, 1.64; GC content, 38.9%; proteins, 1,451; rRNAs, 3; tRNAs, 36; genes, 1,543; pseudogenes, 52. This genome and others sequenced using strains isolated in Colombia (8, 9) will be the basis for evolutionary computational studies. Nucleotide sequence accession number. This whole-genome shotgun project has been deposited in DDBJ/ENA/GenBank under the accession no.

The overall prevalence of Helicobacter pylori infection is high in Colombia; however, in the country´s Andean region, gastric cancer rates far surpass those in coastal areas. Helicobacter pylori genotypes cagA positive and vacA s1 and m1 are associated with an increased risk of gastric cancer.To compare the distribution of H. pylori genotypes associated with virulence in two regions in Colombia with opposing risk for gastric cancer.Four hundred and one gastric antral biopsies were obtained and analyzed from 401 individuals diagnosed with non-atrophic gastritis, atrophic gastritis and intestinal metaplasia: 256 came from the high-risk area cities of Tunja and Bogotá, and 145 from the low-risk area cities of Barranquilla, Santa Marta and Cartagena. Genotyping of virulence genes vacA and cagA was performed by PCR.No difference was observed in the frequency of H. pylori infection between the two areas (77.3% vs 77.9 %, p=non significant, ns). The presence of cagA was higher in the low-risk area (77.9% vs. 69.2 %, p=ns). The vacA s1 allele was also more prevalent in the low-risk area (61.8 % vs 72.0 %, p=ns). The vacA m1 allele was more prevalent in the high-risk area (57.2 % vs 42.8 %, p=ns). The cagA positive s1m1 combination was also more frequent in the low-risk area (48.9% vs 38.9%, p=ns).The differences in the risk of gastric cancer in these two geographic areas cannot be explained by differences in the prevalence of infection by H. pylori or by differences in the virulence of circulating strains.

There is an association of interleukin (IL)1B polymorphism with gastric cancer risk. However systematic reviews of the existing evidence have shown that such association varies across populations with different genetic ancestry.To evaluate the association of IL-1B-511 and IL-1RN polymorphism and Helicobacter pylori IgG antibodies CagA, with gastric cancer in two Colombian cities located in a high risk area for gastric cancer.A case-control study including 46 gastric cancer cases and 99 controls with non-atrophic gastritis from a high risk zone for gastric cancer. Polymorphism genotyping was carried out by polymerase chain reaction (PCR) and IgG CagA status by ELISA.IgG CagA seropositive individuals had an increased gastric cancer risk (odds ratio (OR) = 11.56; 95% confidence intervals (CI) 2.62-50.91 in Tunja and OR = 19.66, 95%CI 0.98-395 in Bogotá). IL-1B-511TT carriers in Tunja had increased risk of gastric cancer (OR = 11.31; 95%CI 1.20-106.54)), while IL-1RN*2 alelle carriers in Bogotá showed an inverse association with gastric cancer risk (OR = 0.03; 95%CI 0.01-0.65).This study adds evidence to the positive association of Helicobacter pylori CagA positive strains with non-cardial gastric cancer etiology. There is a possible heterogeneity in the association of IL-1B gene polymorphism with cancer, in populations of similar ethnic background and settled in the same risk area.