***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: Methylenetetrahydrofolate reductase ( MTHFR ) gene polymorphisms have been reported to be associated with response to methotrexate ( MTX ) in certain population s of patients with rheumatoid arthritis ( RA ) . This study aims at investigating any relationship of two single nucleotide polymorphisms ( SNPs ) in MTHFR gene , C677 T and A1298C with response to therapy with MTX in Pakistani RA patients . Allelic frequencies of the two polymorphisms ( C677 T and A1298C ) were determined in 67 RA patients ( 9 males and 58 females ; mean age 42.87 ± 13.5 years ) who had previously participated in a prospect i ve clinical trial . Fifty-one patients had received MTX and were followed up for response up to 6 months . Genotyping of the two MTHFR polymorphisms was carried out using PCR-RFLP , while fasting concentration of plasma homocysteine was determined using a kit method . Twenty-eight patients were found to be " good responders " , while twenty-three were " poor responders " . MTHFR 1298C and MTHFR 677 T alleles ' frequencies in " good responders " were not different from frequencies in " poor responders " ( 0.574 vs. 0.521 ; p=0.6 and 0.197 vs. 0.196 ; p=0.75 , respectively ) . Plasma homocysteine levels in female RA patients were significantly higher compared to general population in Karachi ( 13.1 ± 6.7 µmol/l vs. 11.4 ± 5.3 µmol/l ; p<0.001 ) . MTHFR C677 T and A1298C polymorphisms are not associated with response to MTX in a population of Pakistani RA patients INTRODUCTION Methotrexate ( MTX ) , widely used in the treatment of rheumatoid arthritis ( RA ) , inhibits dihydrofolate reductase and folate-dependent enzymes . Methylenetetrahydrofolate reductase ( MTHFR ) is involved in folate metabolism and has been shown to be polymorphic , affecting the enzyme activity . METHODS To examine the association between 677C > T and 1298A > C MTHFR polymorphisms and  MTX efficacy in the treatment of RA , a total of 174 RA patients , treated with MTX plus methylprednisone 4 mg and folic acid 5 mg were analyzed . RESULTS In univariate regression analysis model , the MTHFR 677 T allele was associated with significantly higher frequency of remission , whereas in the case of the 1298C allele , a tendency for higher remission rate was observed . In multivariate regression analysis , the presence of both 677 T and 1298C alleles was associated with an increased frequency of remission . CONCLUSION The results of our study suggest that the MTHFR 677 T and 1298C alleles may be associated with an increased rate of RA remission in patients treated with MTX receiving high doses of folic acid supplementation 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:
    
However , for the polymorphisms not being associated following meta- analysis could still be associated if larger cohorts were used , and studies of other polymorphisms are necessary in large cohorts and a rigorous way , which may provide more accurate results for the effect of the gene polymorphisms on the  MTX response