Associação do polimorfismo no gene codificador da enzima MTHFR com a artrite idiopática juvenil

Abstract

Objective: The mthfr (methylenetetrahydrofolate reductase) gene has a strong impact on DNA methylation, biosynthesis and repair of proliferating cells, and its most common mutation (C677T) has been linked to a reduced enzymatic activity, and consequently involved in various inflammatory diseases probably due to the homocysteine accumulation (Hcy). Methotrexate (MTX) is an antifolate agent widely used as a disease-modifying anti-rheumatic drug (DMARD) for treatment of juvenile idiopathic arthritis (JIA). The objective is to analyze the association between allelic and genotypic distribution of the C677T polymorphism of the gene encoding MTHFR and susceptibility to JIA. Method: A cross-sectional study included 38 patients with JIA and 22 healthy controls, with age range from 3 to 22 years. JIA patients were under MTX treatment, and were monitored for adverse events. Laboratorial analyses and clinical examinations, including toxicity data, were performed during 16 months. Patients underwent peripheral blood sampling for DNA extraction and subsequent analysis by Polymerase Chain Reaction and Sequencing to determine if there were changes in the amplified region. Results: JIA occurrence was significantly associated with the 677T allele and its genotypes (P<0.01). The odds ratios for T allele and genotypes (CT and TT) were eight-times higher towards the disease manifestation, suggesting a dominance effect of the T allele. There was no significant correlation between the C677T polymorphism and laboratorialy analyses and medical history (p>0.05), which was not associated with adverse reactions to MTX therapy (p>0.05) either. We found a new polymorphism was 678 not yet described in the literature. Conclusion: JIA was significantly affected by the polymorphism in the MTHFR gene at the C677T genomic region. The increased prevalence of CT and TT genotypes in JIA patients indicated a dominance effect of the T allele. However, this polymorphism was not associated with MTX intolerance, suggesting that accumulation of substrate is not related to the incapacity of patients to sequester MTX and prevent cellular detoxification.