Polimorfismos genéticos de interleucinas e enzimas de reparo e genes de virulência de helicobacter pylori na progressão das doenças gástricas: investigação de biomarcadores.

Abstract

Gastric diseases are very frequent and diverse, and may eventually develop into cancer. Factors such as H. pylori infection and host genetic polymorphisms may be involved in the outcome of the disease. In this way, we evaluated the influence of H. pylori genes and genetic polymorphisms of interleukins IL6-174, IL8-251, IL1β-511 and IL1RN on non-malignant gastric lesions and the DNA repair system enzymes APE1 T2197G, XRCC1 G28152A, XRCC3 T18067C, MLH1-93 G> A and MGMT A533G in gastric lesions of different severities. In the first trial, biopsy specimens from patients submitted to endoscopy were analyzed. In the second investigation, we included patients referred for gastrectomy. Detection of presence and H. pylori genes and IL1RN genotyping were performed by PCR and the genotypes of the other interleukins and repair enzymes were identified by RFLP-PCR. In study I, we used 192 samples, 40 cases of chronic inactive gastritis (ICG), 112 cases of chronic active gastritis (GCA) and 40 cases of intestinal metaplasia (MI). For the IL6 and IL8 polymorphisms we found an association of the heterozygous genotype and the polymorphic allele, respectively, with GCI, mainly in women. While polymorphic IL8 was associated with GCA. H. pylori strains positive for the cagA, cagE and virB11 genes were more frequent in GCA and the cagE gene was more associated with MI. In the parasite-host interaction, patients carrying the polymorphic alleles of IL1B, IL1RN or IL8 were infected with more virulent strains. In study II, 504 samples were used, 102 GCI, 178 GCA, 74 MI and 150 intestinal gastric cancers (CG). In this study, patients with the XRCC1 polymorphic allele were associated with a decreased risk for the development of MI and GC (O.R. 0.43), especially in men, while for XRCC3 the heterozygous women showed a reduced risk for MI (O.R. 0.38). On the other hand, the heterozygote genotype of MLH1 was associated with CG in women (O.R. 6.69). In a haplotypic analysis, we verified that the XRCC1 heterozygote in several combinations (XRCC1 GA + MGMT AA, APE TT and TG, MLH1 GG) decreases the risk for MI and CG. Individuals with wild-type MLH1 homozygous genotypes were associated to GCI while polymorphic homozygotes progressed to GCA in the presence of less virulent strains (without cagPAI/s2m2). The polymorphisms studied may be biomarkers of stomach cancer when evaluated in conjunction with H. pylori genes.