Pharmacogenetic Polymorphisms Contributing to Toxicity Induced by Methotrexate in the Southern Spanish Population with Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a common illness of global significance for public health. Methotrexate (MTX) is the most broadly used disease-modifying antirheumatic drug for the treatment of RA, but it displays marked person-to-person variation in its propensity for toxicity. Several studies have suggested that polymorphisms in methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, reduced folate carrier (RFC1) G80A, and ABCB1 C3435T, could be related to methotrexate toxicity. This prospective study examined the different frequencies of MTHFR, RFC1, and ABCB1 pharmacogenetic variations between patients who have RA and those without RA. We also sought to assess the association between these polymorphisms and MTX toxicity. Four single-nucleotide polymorphisms (SNPs) were genotyped: C677T and A1298C from MTHFR, G80A from RFC1, and C3435T from ABCB1. The efficacy and toxicity of MTX were evaluated through clinical follow-up during 1 year of treatment. RA patients showed a higher frequency of the T allele at MTHFR C677T than patients without RA (p=0.049). There was a significant association between the presence of both the T allele at MTHFR C677T (p=0.006), and the C allele at ABCB1 C3435T (p=0.046), with toxicity development after 12 months of MTX treatment. However, there was no correlation between MTX toxicity and either the A allele at MTHFR A1298C or the G allele at RFC1 A80G. These data suggest that the presence of the MTHFR C677T and ABCB1 C3435T SNPs contribute to MTX toxicity in patients with RA. These observations contribute to a rapidly-growing knowledge base on the pharmacogenetics of RA and personalized medicine.

Multidrug resistance 1 (MDR1) 3435C>T gene polymorphism influences the clinical phenotype and methotrexate-induced adverse events in South Indian Tamil rheumatoid arthritis

“…It was found that patients carrying the MDR1 3435 TT genotype undergo a 4. [21], MDR1 3435C allele was high in patients with toxicity than in those without any toxicities (58.2 vs 41.8 %, p=0.046). Though the involvement of MDR1 3435 C and T alleles in the development of adverse events is unclear, MDR1 mutation could result in reduced expression of P-glycoprotein.…”

“…Pawlik et al [19] found that the risk of having an active form of RA was 2.89-fold greater in patients with 3435CC and CT genotypes when compared to patients with 3435 TT genotype (OR 2.89, 95 % CI 0.87-0.97, p<0.05). Grabar et al, from a retrospective cohort of 213 Caucasians with RA [20] and Plaza et al, in a prospective cohort of 67 naïve patients with RA [21] reported that MDR1 3435C>T gene polymorphism was associated with MTX-induced toxicity. The contribution of MDR1 3435 C and T alleles in disease activity, refractoriness to therapy, and MTX-induced adverse events remains varied across diverse ethnicities.…”

Association of the ABCB1 C3435T polymorphism with responsiveness to and toxicity of DMARDs in rheumatoid arthritis

“…Five studies were excluded because they discussed other polymorphisms or were review articles. Thus, in total 9 studies consisting of 14 comparisons met our inclusion criteria ( [11,12,13,14,15,16,17,18,19], . Fig.…”

“…Several studies have examined the potential contribution of the ABCB1 C3435T polymorphism in RA [11,12,13,14,15,16,17,18,19]. However, it remains controversial whether the ABCB1 C3435T polymorphism may be a marker of efficacy and toxicity of DMARDs including MTX.…”

Farmacogenética del metotrexato en artritis reumatoide. Revisión sistemática

“…Estudios de cohorte. En los estudios de cohorte se estableció una relación entre el polimorfismo y la disminución de la efectividad del MTX, el estudio de Plaza et al 26 , 2012 estableció que presenta una asociación de riesgo de toxicidad con el MTX, OR 3,21 IC95% (1,45-7,10), en el estudio de Urano et al 28 , 2002 se estableció una relación para la disminución de la efectividad del MTX para el control de la enfermedad, OR 2,18 IC 95% (1,17-4,06). En los estudios de casos y controles la asociación no es consistente.…”