Variations in cag pathogenicity island genes of Helicobacter pylori from Latin American groups may influence neoplastic progression to gastric cancer

Abstract

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.Gastric cancer has the third highest mortality rate and the fifth highest incidence worldwide 1 . The two regions of the world with highest mortality rate for gastric cancer are Asia and Latin America accounting for almost two thirds of all gastric cancer deaths 2 . Within the US, ethnic minorities, e.g., Asians, Blacks, Hispanics and Native Americans, experience an incidence almost twice as high as non-Hispanic Whites 3 . Some Asian countries, such as Japan, have nation-wide screening programs for early detection of gastric cancer, whereas most other high-risk countries, such as Latin American countries, do not have such programs, nor does the US for ethnic minorities 4-6 . Although Helicobacter pylori (HP) is an established cause of gastric cancer 7 , eradication of HP in general asymptomatic populations has not been advised, because of the large number of persons already infected in high risk populations (>90%), high reinfection rates in endemic areas 8 , antibiotic resistance, high cost of the treatment 9 and the increased risk of esophageal cancer associated with HP-negative/eradicated individuals 10-12 . Thus, new strategies for gastric cancer prevention are warranted and may help reduce health disparities, mainly in the most affected and underdeveloped regions of the world 13 . All considered identification of new HP variants potentially useful to predict gastric cancer risk will be invaluable not only for vaccine development, but also to target antibiotic treatment to high-risk individuals.HP has a remarkably high level of genetic diversity due to rec...

Genetic polymorphisms in the cag pathogenicity island of Helicobacter pylori and risk of stomach cancer and high‐grade premalignant gastric lesions

“…Finally, we also removed 46 subjects with duodenal ulcer, leaving a total number of 1220 samples for analysis. We checked that allelic frequencies of all polymorphisms were in general agreement with those observed in the sequencing analysis reported in our previous work 13 …”

“…Additionally, this work did not include large structural variations. However, we studied EPIYA and CM motifs in our sequencing study and we did not observe any association with risk of IM and/or GC 13 . Moreover, structural variations are meaningfully studied only by sequencing, which most of our samples are unsuitable for.…”

“…They were chosen because their functions have been well characterized in the T4SS, including CagA, 22 CagE 23 and Cagγ, 24 or because they are present extracellularly (ie, as pilus or bacterial surface‐related proteins), suggesting possible interactions with host cells, like CagC, 23,25 CagI, 26 CagL, 27 CagX 25 and CagY 28 . Variants on these genes were identified by a whole‐genome sequencing study performed on 74 Hp strains isolated from patients from Mexico and Colombia, 37 CG, 21 with IM and 16 with GC 13 . We selected candidate polymorphisms from SNPs with at least 7.5% frequency in the 74 sequenced strains (ie, observed in at least five strains), then applied the following criteria: for nonsynonymous variants, OR of ≥1.5 or ≤0.67 for GC + IM compared to CG, and OR ≥ 3.0 or OR ≤ 0.33 for synonymous variants.…”

Análisis polimórfico de interleucina IL-1β en pacientes con diagnóstico de Helicobacter pylori, en Tabasco, México

“…Los resultados obtenidos muestran una asociación entre el polimorfismo de interleucina IL-1β+3954(C>T) y el cáncer gástrico. Ya que diversos estudios han identificado y relacionado con un incremento en la producción de la interleucina frente a patógenos, ya que es una molécula proinflamatoria importante en la señalización y amplificación de la respuesta frente a la infección por Helicobacter pylori, produciendo un proceso inflamatorio que puede desencadenar la transformación maligna de la mucosa, a través de cambios moleculares y morfológicos (21,22 (24). En el análisis estadístico de Odds ratio, los valores de OR con IC 95% se calcularon con respecto al homocigoto normal de cada polimorfismo estudiado.…”

Helicobacter pylori Virulence Factor Cytotoxin-Associated Gene A (CagA)-Mediated Gastric Pathogenicity

“…In a recent study, polymorphisms on the nucleotide level in cagA , such as cagA 1283 and cagA 2551, have been associated with high-grade premalignant lesions, and the polymorphisms such as cagA 2419 and cagA 3435 together with polymorphism in cagL , such as cagL 400, have been associated with the risk of gastric cancer development [ 30 ]. Moreover, amino acid variations in CagA such as V52I, S194F, and Q/R427K have been associated with the risk of intestinal metaplasia, whereas N467G has been associated with the development of gastric cancer [ 31 ]. The studies have found the development of gastric cancer only in 1–2% of H. pylori -infected individuals and MALT lymphoma in even less than 0.1% of individuals [ 32 , 33 ].…”