The Relationship Between The Single Nucleotide Polymorphism Of 5,10-Methylenetetrahydrofolate Reductase Gene And The Treatment Of Methotrexate In Rheumatoid Arthritis

Background Rheumatoid arthritis(RA) is an inflammatory and immune-mediated diseases involving joints and a variety of major organ systems.In China the prevalence of RA is 0.32-0.36 percent.RA is one of the important reasons which cause the destruction of joints and the loss of function.Methotrexate(MTX) is believed to be related to the inhibition of folate pathway enzymes,and has proven to reduce disease activity and delay or stabilize the development of bone erosions.MTX is also cheap and can be in combination with other disease modifying antirheumatic(DMARD) or biological agents,so it is the most widely used DMARD for the treatment of RA. However,only 45%-65%of the patients experience good clinical response,and 10%-30%discontinue therapy due to side effects.Based on the progress of pharmaco-genetics research in the past ten years,the difference of individual gene is the main factor of efficacy and toxicity of treatment.Methylenetetrahydrofolate reductase (MTHFR) is the best studied of the genes in the intemational and domestic research about the efficacy and toxicity of MTX.The report from individual may vary.The C677T and A1298C polymorphisms of the MTHFR gene were analysed by real-time fluorescent quantitative polymerase chain reaction.The aim of the current study was to determine associations between the efficacy and toxicity of MTX and SNPs in gene coding for the folate pathway enzyme MTHFR in patients with RA and to provide the initiatory clues for the individualized therapy in RA.Objectives To determine the allele frequencies of two common coding the single nucleotide Polymorphisms(677C/T 1298A/C) in the 5,10-methylenetetrahydrofolate reductase gene in RA patients,RA patients with cardiovascular complication and controls,the relationship between it and the treatment of methotrexate in rheumatoid arthritis.Methods A total of 184 patients with RA were divided into MTX group,MTX+other DMARDs group,other DMARDs with no MTX group,who were diagnosed as having RA as defined by the American College of Rheumatology 1987 revised criteria.The clinical and laboratory measurements were evaluated before observation and 24 weeks later.Efficacy and toxicity of the drugs were also collected.The patients were diagnosed as cardiovascular complication who had the symptoms such as cardiopalmus,chest distress,stethalgia accompanied with hypertension or EKG or color Doppler ultrasound changing.Real-time fluorescent quantitative PCR was conducted to test gene mutation in RA patients and 100 healthy controls.Results1.There was no significant difference of frenquency among 677CC,CT,TT and 1298AA,AC,CC between RA patients and the healthy controls.2.There was significant difference of frenquency among 677CC,CT,TT between RA patients with cardiovascular complication and the healthy controls.3.In MTX group,there was significant difference of frenquency of 1298AC,CC between the group in which MTX was effectual and the other group in which MTX was not effectual,the incidence of side effect of MTX on the patients with 677TT was more than that without mutation(CC).4.In MTX+other DMARDs group,the incidence of the side effect of MTX in the patients with 677TT and CT was higher than that without mutation(CC).5.In other DMARDs with no MTX group,there was no relationship between the polymorphism of 677C/T,1298A/C and the efficacy and toxicity of MTX. Conclusion1.There was no relationship between the pathogenesis of RA and the 677C/T,1298A/C mutation of MTHFR gene.2.MTHFR gene C677T mutation was the associated with the toxicity of MTX and 1298C alle was associated with the efficacy of MTX.3.MTHFR gene C677T mutation was probably one of the genetic risk factors for the cardiovascular complication of RA patients.