Estudo dos polimorfismos C1236T, G2677T e C3435T do gene MDR1 em pacientes portadores de doenças inflamatórias intestinais

Abstract

Recent studies have evaluated the presence of multidrug resistant gene 1 polymorphisms (MDR1) that encodes the efflux membrane transporter called P-glycoprotein, its potential role in susceptibility to inflammatory bowel disease (IBD) and possible correlations with clinical features of IBD. Conflicting data may result from genetic analysis of distinct populations. We investigated whether polymorphisms of MDR1 gene are associated with IBD in the population of southeastern Brazil and its possible correlations with phenotypes, disease activity, response to treatment and side effects. As methods, this research worked with 146 patients with Crohn's Disease (CD) and 90 with Idiopathic Ulcerative Colitis (UC) who were recruited through established diagnostic criteria. The polymorphisms of MDR1 most commonly described in the literature, C1236T, G2677T and C3435T, were evaluated by PCR. The genotypic frequencies of patients with UC and DC were analyzed in the study population. Genotype-phenotype associations with clinical characteristics were established and estimated risks for the mutations were calculated. No significant difference was observed in genotype frequencies for polymorphisms G2677T / A and C3435T of MDR1 in DC or UC. The C1236T polymorphism was significantly more common in CD than in UC (p = 0.036). At UC, C1236T and G2677T polymorphisms were found more in men in the group of heterozygotes. Significant associations were found between the C3435T polymorphism of the MDR1 gene in patients with stricturing phenotype in CD (OR: 3.16, p = 0.036), as opposed to penetrating behavior (OR: 0.31, p = 0.076). In DC, positive associations were also found between the C3435T polymorphism, activity moderate / severe disease (OR: 3.54, p = 0.046), and resistance to corticosteroids (OR: 3.29, p = 0.043) in the polymorphic homozygote group. No significant association was found between polymorphisms of MDR1 and phenotypic classes of disease activity or response to treatment of UC. In conclusion, the present results suggest that MDR1 gene polymorphisms could be involved in susceptibility to DC and stricturing phenotype, as well as being associated with an inadequate response to treatment in a group of patients with CD. The strong evidence with DC supports the existence of additional roles for MDR1 specific mechanisms underlying the pathogenesis of DC, such as regulating gut-microbiota interactions and mediating fibrosis. Further, understanding the effects of different drugs associated with these variants can contribute to the MDR1 custom prescription regimens.