677C>T and 1298A>C MTHFR polymorphisms affect methotrexate treatment outcome in rheumatoid arthritis

Abstract

The results of our study suggest that the MTHFR 677T 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.

Genetic Determinants of Methotrexate Toxicity in Tunisian Patients with Rheumatoid Arthritis: A Study of Polymorphisms Involved in the MTX Metabolic Pathway

“…Each meta-analysis includes eight studies where seven are similar [37][38][39][40][41][42][43] and two are different [34,44]. Indeed, Fisher and Cronstein (2009) reported an association of MTHFR polymorphisms with MTX-related toxicities and concluded that the C677T polymorphism, contradictory to A1298C polymorphism, was associated with increased toxicity (p \ 0.001).…”

MTHFR gene polymorphisms and outcome of methotrexate treatment in patients with rheumatoid arthritis: analysis of key polymorphisms and meta-analysis of C677T and A1298C polymorphisms

“…Data from 27 studies investigating MTHFR SNPs and MTX related efficacy and toxicity in RA patients were initially identified through the database searches [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][45][46][47][48][49][50][51][52][53][54] and combined with results from our study, leaving 28 studies for review. From these, 11 studies were excluded due to lack of available data, leaving 17 studies including the present study published between 2001 and 2010 meeting the eligibility criteria, which were included in the meta-analysis: [18][19][20][22][23][24][25][26][27][28]32,33,45,46,53,54 For the C677T SNP, 10 studies were included for the efficacy analysis and 13 studies for the toxicity analysis (Table 2) and for the A1298C SNP 8 studies were included for the efficacy analysis and 8 studies for the toxicity analysis (Table 3).…”

“…From these, 11 studies were excluded due to lack of available data, leaving 17 studies including the present study published between 2001 and 2010 meeting the eligibility criteria, which were included in the meta-analysis: [18][19][20][22][23][24][25][26][27][28]32,33,45,46,53,54 For the C677T SNP, 10 studies were included for the efficacy analysis and 13 studies for the toxicity analysis (Table 2) and for the A1298C SNP 8 studies were included for the efficacy analysis and 8 studies for the toxicity analysis (Table 3). Studies were conducted in different populations: six were conducted in populations of East Asian ethnicity, 18,20,22,23,26,27 seven involved European and Jewish populations 19,24,25,32,33,46,53 and three studies were conducted in American populations. 28,45,54 All used validated genotyping methods.…”

“…Association of the 677T allele with MTX toxicity (worse clinical outcome) have been confirmed by some [18][19][20][21][22] but not all studies, [23][24][25][26][27][28][29][30][31] there being less confirmatory evidence for an association with efficacy. 31,32 There is less data investigating the role of the A1298C SNP modulating response to MTX therapy but most studies have reported that the C allele is associated with reduced AE/ increased efficacy 18,20,24,25,33 or demonstrate no association. 26,27 The variability in individual study findings may arise due to the fact that each includes a small sample size thereby reducing the power to accurately estimate effect sizes.…”

A Perspective on Nutritional Genomics

“…121 The C>T and A>C alleles yield higher rates of rheumatoid arthritis remission in patients treated with MTX if they also receive high doses of folic acid. 122 The A>C polymorphism protects against overall MTX toxicity without minimizing efficacy of the drug. 123…”