Polymorphisms C677T and A1298C in the MTHFR gene in Mexican patients with rheumatoid arthritis treated with methotrexate: implication with elevation of transaminases

Abstract

Rheumatoid arthritis (RA) is the prototype of the rheumatic diseases worldwide. Methotrexate (MTX) is the drug of first choice in the treatment of this disease due to its immunosuppressant effect. However, side events are present in 30% of the patients. The C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene are involved in the metabolism of MTX. Earlier studies reported an association between these polymorphisms and elevation of hepatic enzymes. We analyzed the frequencies of both polymorphisms and the presence of transaminasemia in 70 Mexican patients with rheumatic arthritis treated with MTX. The 19% (13/70) of patients had an increase in the serum level of transaminases. The A1298C polymorphism was associated with elevation of transaminases (P ¼ 0.024). The identification of MTHFR genotypes for C677T and A1298C polymorphisms could lead clinicians to identify patients in risk of elevation of transaminases, and give them an individualized treatment, as is a goal of pharmacogenetics.

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

“…There was reduced heterogeneity detected for the toxicity studies among the five pooled Caucasian studies 19,24,28,53 (I 2 ¼ 51.1% P ¼ 0.08), but the mean effect across studies suggested no association with toxicity (OR ¼ 1.12 95% CI ¼ 0.69-1.82). Significant heterogeneity remained between the eight studies restricted to nonCaucasian populations 18,20,22,23,[25][26][27]54 (I 2 ¼ 74.62% Po0.001) but again, no association with toxicity was detected (OR ¼ 1.56 95% CI ¼ 0.83-2.93).…”

“…Significant heterogeneity remained between the four studies restricted to non-Caucasian populations 18,20,26,27 (I 2 ¼ 60.4% P ¼ 0.05) but again, on average there was no association with efficacy detected (OR ¼ 0.63 95% CI 0.30-1.33) (Figure 3). In terms of toxicity outcomes the heterogeneity was moderate, albeit nonsignificant for both Caucasian (I 2 ¼ 43.5% P ¼ 0.13) 32,53 and non-Caucasian (I 2 ¼ 59.2% P ¼ 0.086) 18,20,25,27,54 populations and the mean effect across studies for both Caucasian (OR ¼ 1.49 95% CI 0.84-2.62) and non-Caucasian (OR ¼ 0.98 95% CI 0.57 -1.70) populations was not statistically significant ( Figure 4). Meta-regression results did not suggest a significant association between the effect size and the study co-variates tested (data not shown).…”

“…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.…”

“…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. Overall, including information from our own patient cohort, the analysis included data from 1375 patients for the C677T polymorphism efficacy analysis and 2043 for the toxicity analysis and for the A1298C polymorphism, data from 1140 patients were included in the efficacy analysis and 1239 in the toxicity analysis.…”