ABSTRACT
OBJECTIVES: Conflicting data from studies on the potential role of multidrug resistance 1 gene polymorphisms in inflammatory bowel disease may result from the analysis of genetically and geographically distinct populations. Here, we investigated whether multidrug resistance 1 gene polymorphisms are associated with inflammatory bowel diseases in patients from Rio de Janeiro. METHODS: We analyzed 123 Crohn's disease patients and 83 ulcerative colitis patients to determine the presence of the multidrug resistance 1 gene polymorphisms C1236T, G2677T and C3435T. In particular, the genotype frequencies of Crohn's disease and ulcerative colitis patients were analyzed. Genotype-phenotype associations with major clinical characteristics were established, and estimated risks were calculated for the mutations. RESULTS: No significant difference was observed in the genotype frequencies of the multidrug resistance 1 G2677T/A and C3435T polymorphisms between Crohn's disease and ulcerative colitis patients. In contrast, the C1236T polymorphism was significantly more common in Crohn's disease than in ulcerative colitis (p = 0.047). A significant association was also found between the multidrug resistance 1 C3435T polymorphism and the stricturing form of Crohn's disease (OR: 4.13; p = 0.009), whereas no association was found with penetrating behavior (OR: 0.33; p = 0.094). In Crohn's disease, a positive association was also found between the C3435T polymorphism and corticosteroid resistance/refractoriness (OR: 4.14; p = 0.010). However, no significant association was found between multidrug resistance 1 gene polymorphisms and UC subphenotypic categories. CONCLUSION: The multidrug resistance 1 gene polymorphism C3435T is associated with the stricturing phenotype and an inappropriate response to therapy in Crohn's disease. This association with Crohn's disease may support additional pathogenic roles ...
Subject(s)
Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , Humans , Male , Middle Aged , Young Adult , Colitis, Ulcerative/genetics , Crohn Disease/genetics , Genes, MDR/genetics , Polymorphism, Genetic/genetics , Gene Frequency , Genetic Association Studies , Phenotype , Polymorphism, Single NucleotideABSTRACT
A carcinogênese é um processo altamente complexo do qual participam fatores de risco herdados e fatores de risco ambientais, tais como a alimentaçäo, o hábito de fumar, a ocupaçäo, e a exposiçäo a radiaçäo e a agentes químicos. A toxicologia experimental identifica as substâncias químicas potencialmente carcinogênicas e torna possível medidas regulatórias que objetivam reduzir a exposiçäo humana a elas. A carcinogênese pode ser vista como consistindo de três seqüências distintas: a iniciaçäo, a promoçäo e a progressäo. A conversäo neoplásica (iniciaçäo) ocorre quando um evento genético (mutaçöes, rearranjos cromossômicos, inserçöes ou deleçöes de genes e amplificaçäo de genes) resulta em ativaçäo de oncogenes e/ou em falta de expressäo - ou inativaçäo de produtos - de genes supressores de tumores. A promoçäo envolve a expansäo clonal das células "iniciadas" e exige a proliferaçäo celular. Estratégias efetivas para reduzir os riscos de câncer gástrico e os riscos de neoplasias de outras localizaçöes devem incluir o controle de carcinógenos conhecidos, assim como a quimioprevençäo, por meio de intervençöes racionais no processo carcinogênico. Neste sentido, o desafio a ser enfrentado pelo toxicologista envolve o desenvolvimento de ensaios preditivos melhores e mais baratos e a elucidaçäo dos mecanismos subjacentes à carcinogênese química.