Association of IL 1 B-511 C /-31 T haplotype and Helicobacter pylori vacA genotypes with gastric ulcer and chronic gastritis

Background: The association between proinflammatory cytokine gene polymorphisms and gastric diseases related to Helicobacter pylori varies by population and geographic area. Our objective was to determine if the IL-1B -511 T>C and -31 C>T polymorphisms and H. pylori vacA genotypes are associated with risk of chronic gastritis and gastric ulcer in a Mexican population. Methods: We conducted endoscopic studies in 128 patients with symptoms of dyspepsia. We took two biopsies from the body, antrum, or ulcer edge from each patient, and classified our histopathological findings according to the Sydney System. H. pylori infection and vacA genotyping were accomplished via PCR from total DNA of the gastric biopsies. We confirmed the presence of anti-H. pylori serum IgG and IgM in 102 control subjects. In both case subjects and control subjects, the IL-1B -511 T>C polymorphism was genotyped by PCR-RFLPs and the IL-1B -31 C>T polymorphism was genotyped by pyrosequencing. Results: Sixty-two point seven (62.7%) of the 102 control subjects were H. pylori-seropositive. Among the case subjects, 100 were diagnosed with chronic gastritis and 28 with gastric ulcer. We found that 77% of the patients with chronic gastritis and 85.7% of the patients with gastric ulcer were H. pylori-positive. The predominant H. pylori genotype was vacA s1m1 (58.4%) and the most frequent subtype was vacA s1. The -511 TC, (rs16944 -511 T>C) genotype and the -511C allele were associated with chronic gastritis (OR = 3.1, 95% CI = 1.4-6.8 and OR = 3.0, 95% CI = 1.4-6.0, respectively). The subjects carrying -31T (rs1143627 -31 C>T) were found to be at a higher risk of having chronic gastritis (OR = 2.8, 95% CI = 1.3-5.8). The IL-1B -511C/-31T haplotype was associated with chronic gastritis (OR = 2.1, 95% CI = 1.2-3.8) but not with gastric ulcer. Conclusions: The H. pylori vacA genotypes identified herein were similar to those reported for other regions of Mexico. The vacA s1m1 genotype was not associated with gastric ulcer. In the southern Mexican population, the IL-1B -511C and -31T alleles and the -511C/-31T and -511T/-31T haplotypes are associated with increased risk of chronic gastritis and gastric ulcer. Background Helicobacter pylori infection is related to the inflammatory response of the gastric mucosa. While most infected individuals remain asymptomatic, persistent colonization and chronic inflammation increase the risk of developing atrophic gastritis, peptic ulcers, and distal gastric adenocarcinoma [1]. The development of chronic gastritis is the initiating event in the process that leads to stomach cancer. The risk of malignancy increases with severity, chronicity, and duration of the inflammatory process [2,3]. Clinical outcome of H. pylori infection is determined by the genetic characteristics of the host and bacteria as well as environmental factors [4]. While H. pylori is considered to be a class I carcinogen, it is accepted that some genotypes have greater virulence. The strains * Correspondence: gferti@hotmail.com Laboratorio de Investigación Clínica, Unidad Académica de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero. Av. Lázaro Cárdenas S/N. Ciudad Universitaria, Colonia Haciendita, Chilpancingo, Guerrero. C.P. 39090, México Full list of author information is available at the end of the article Martínez-Carrillo et al. BMC Gastroenterology 2010, 10:126 http://www.biomedcentral. com/1471-230X/10/126 © 2010 Martínez-Carrillo et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. that express cytotoxin-associated gene A (CagA) and large quantities of vacuolating cytotoxin (VacA) are most frequently found in patients with peptic ulcers and gastric carcinoma [2,5,6]. It has been observed that H. pylori vacA s1/m1 strains produce high levels of the cytotoxin, strains s1/m2 produce moderate levels, and strains s2/m2 produce little or no toxin [7,9]. The vacA s1 subtype is related to higher disease severity and a higher risk of developing ulcers and stomach cancer [5,6,10]. H. pylori induce production of IL-1b in the gastric mucosa. IL-1b modulates the expression of other proinflammatory cytokine genes such as TNF-a, IL-2, IL-6 and IL-12, which increase the magnitude of inflammation [11]. The concentration of IL-1b produced by the inflamed epithelium is influenced by two biallelic polymorphisms in positions -511T>C (rs16944) and -31C>T (rs1143627). These polymorphisms are in almost total genetic disequilibrium, and -31 is a TATA-box polymorphism that significantly affects DNA-protein interactions in vitro. Thus, these single-nucleotide polymorphisms (SNPs) can modulate production of IL-1b, directly affecting transcription [12,13]. Given that IL-1b is a strong inhibitor of gastric acid secretion and may contribute to dispersion of H. pylori from the pylorus to the corpus of the stomach, polymorphisms in the IL-1b gene can be considered a key genetic factor in determining the pattern of gastritis that develops and one risk of malignant transformation [13,14]. The IL-1B -511T and -31C alleles are associated with high levels of the cytokine and with severe inflammation or stomach cancer, in comparison to -511C and -31T, which are associated with low levels of IL-1b. This association with H pylori infection or stomach cancer has not been significant in all populations [2,4,6,11,13-20]. In combination, bacterium virulence factors and IL-B polymorphisms (cagA+/vacA+/IL-1B-511T/IL-RN*2) are associated with severe histological changes in the gastric mucosa of some populations [1,4]. However, the variability of results across populations and geographic areas has been a source of ongoing controversy [2,13,14]. While gastritis, ulcer, and duodenitis constitute the fourth leading cause of disease in the Mexican population [21], the genetic basis for inter-individual variations in inflammatory response and cytokine production, in the context of H. pylori infection, has not been well studied in the Mexican population. Genotyping of H. pylori vacA and IL-1B polymorphisms could be important in the early identification of individuals at high risk for developing severe gastric diseases. The objective of this study was to evaluate the relationship between IL-1B -511 T>C and -31 C>T polymorphisms and the presence of chronic gastritis and gastric ulcer, and to analyze the relationship of H. pylori vacA genotypes with gastric ulcer. Methods