***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: OBJECTIVES We examined the association between c and i date single nucleotide polymorphisms ( SNPs ) and disease activity in RA patients on MTX .  METHODS Our population was drawn from the Brigham and Women 's Hospital Rheumatoid Arthritis Sequential Study ( BRASS ) , a prospect i ve , observational cohort of RA patients . A total of 556 participants were genotyped using the Affymetrix 100 K platform . Two hundred and sixty-two participants were on MTX therapy , including 120 on MTX monotherapy .  The primary outcome was the disease activity score in 28 joints ( DAS28-CRP ) . High disease activity was defined as DAS28-CRP > 3.2 . Low disease activity was defined as DAS28-CRP < or = 3.2 . We studied three c and i date alleles in the ATIC , ITPA and MTHFR genes for association with DAS28-CRP . RESULTS Among participants on MTX monotherapy  , those carrying the minor allele of ATIC SNP rs4673993 were more likely to have low disease activity ( P = 0.01 ) . None of the other SNPs was associated with disease activity . Among patients on any MTX ( combination or monotherapy ) , the minor allele of ATIC rs4673993 was also associated with low disease activity ( P = 0.04 ) . CONCLUSIONS In this cross-sectional analysis , ATIC SNP rs4673993 was associated with low disease activity in patients on MTX .  Further studies are needed to clarify the relationship between ATIC polymorphisms , disease activity and treatment response The folate antagonist methotrexate ( MTX ) is a drug currently used in the treatment of rheumatoid arthritis ( RA ) . MTX enters the cells through the reduced folate carrier ( RFC-1 ) and is activated to polyglutamates . Previous studies have shown that RFC-1 expression may influence the efficacy of therapy with MTX . The studies suggest that G80A polymorphism in RFC-1 is associated with altered folate/antifolate levels and the subjects carrying homozygous mutant 80AA genotype tend to have higher plasma folate and MTX concentrations and higher erythrocyte polyglutamate levels compared with those with the wild type or heterozygous genotype . It is possible that this polymorphism might influence MTX treatment outcome in patients with RA . In the present study , we examined the association between RFC-1 G80A polymorphism and treatment outcome in patients with RA administered MTX .  The study was carried out on 174 patients diagnosed with RA treated with MTX ( 7.5–15.0 mg weekly ) plus low doses of methylprednisone .  The RFC-1 80G > A polymorphism ( result ing in a histidine-to-arginine substitution at codon 27 of RFC-1 ) was detected using a polymerase chain reaction-restriction fragment length polymorphism method . The probability of remission of RA symptoms was 3.32-fold higher in carriers of 80AA genotype as compared with patients with 80GG genotype ( P=0.021 , OR=3.32 , 95 % CI : 1.26–8.79 ) . The frequency of A allele among MTX responders was 62.1 , compared to 47.8 % in a group of poor MTX responders ( P=0.013 , OR=1.78 , 95 % CI : 1.13–2.81 ) . Moreover , the increase of aminotransferase activity was noted more frequently in carriers of 80AA genotype . The present data suggest that evaluation of RFC-1 gene 80G > A polymorphism may be a useful tool to optimize MTX therapy in patients with RA Methotrexate ( MTX ) exhibits large inter-individual and inter-ethnic differences in the dose required for its anti-rheumatic effect . To maintain low disease activity , patients may require increased MTX doses or co-administration of biologic disease-modifying anti-rheumatic drugs ( bDMARDs ) . The availability of a marker predicting the effect of MTX will make it possible to increase the MTX dose and prescribe bDMARDs to patients at an early stage . To establish individualized medication for rheumatoid arthritis ( RA ) , we investigated genetic polymorphisms of the folate pathway in Japanese RA patients . Eighty-nine patients were treated with MTX alone ( MTX group ) .  MTX and bDMARDs were co-administered to 81 patients because of insufficient  MTX efficacy  ( MTX + bDMARDs group ) ; an equally stable therapeutic effect was achieved in both groups . Polymorphism analyses using bDMARD co-treatment as the objective variable revealed a significant association between age and the G80A polymorphism of the reduced folate carrier 1 gene ( RFC1 ) as an explanatory variable . Compared to patients with the A allele , patients with the G allele may have less intracellular MTX uptake and , therefore , poor efficacy ; a greater number of them were found to be bDMARD concomitant cases . The results of this study suggest that the RFC1 G80A polymorphism may be a useful marker for predicting  MTX efficacy in Japanese patients with RA 
    Output:
    
Only SLC19A1 rs1051266 was replicated in an independent cohort and promising for predicting methotrexate efficacy