Genetic polymorphisms in key methotrexate pathway genes are associated with response to treatment in rheumatoid arthritis patients

Abstract

We investigated the effect of Single Nucleotide Polymorphisms (SNPs) spanning 10 methotrexate (MTX) pathway genes, namely AMPD1, ATIC, DHFR, FPGS, GGH, ITPA, MTHFD1, SHMT1, SLC19A1 (RFC) and TYMS on the outcome of MTX treatment in a UK rheumatoid arthritis (RA) patient cohort. Tagging SNPs were selected and genotyping performed in 309 patients with predefined outcomes to MTX treatment. Of the 129 SNPs tested, 11 associations were detected with efficacy (p-trend ≤ 0.05) including four SNPs in the ATIC gene (rs12995526, rs3821353, rs7563206 and rs16853834), 6 SNPs in the SLC19A1 gene region (rs11702425, rs2838956, rs7499, rs2274808, rs9977268, rs7279445) and a single SNP within the GGH gene (rs12681874). Five SNPs were significantly associated with adverse events; three in the DHFR gene (rs12517451, rs10072026, and rs1643657) and two of borderline significance in the FPGS gene. The results suggest that genetic variations in several key MTX pathway genes may influence response to MTX in RA patients. Further studies will be required to validate these findings and if confirmed these results could contribute towards a better understanding of and ability to predict MTX response in RA.

γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells

“…High GGH expression was shown to be associated with a higher risk of developing advanced toxicity to pemetrexed, a multi-targeted antifolate, in patients with advanced breast cancer (Llombart-Cussac et al 2007). Furthermore, several recently identified and characterized functionally significant genetic and epigenetic polymorphisms of GGH have been reported to predict response to and toxicity of antifolate-based treatment in patients with several cancers (Cheng et al 2004;Kim et al 2008;Koomdee et al 2012;Silva et al 2013;Smit et al 2012;Wang et al 2014) and inflammatory arthritis (Dervieux et al 2004;Hayashi et al 2009;Jekic et al 2013;Owen et al 2012;van der Straaten et al 2007;Yanagimachi et al 2011). Our data herein provide evidence that GGH modulation significantly influences expression and CpG DNA methylation of genes involved in important biological pathways that might account for the observed effects of GGH modulation on cancer risk, prognosis, and treatment response.…”

Low expression of CD39 on regulatory T cells as a biomarker for resistance to methotrexate therapy in rheumatoid arthritis

“…Polymorphisms in the SCL19A1 (solute carrier family 19, member 1) gene encoding the protein folate transporter 1 have also been described to implicate the therapeutic efficacy of the MTX (28). However, subsequent investigations produced conflicting results (29,30). Thus, the mechanisms of, and functional biomarker for, the development of MTX resistance remains poorly understood (31).…”

Impacto de polimorfismos genéticos de la vía metabólica del metotrexato sobre la sobrevida de niños mexicanos con leucemia linfoblástica aguda (LLA)

“…El SNP (rs2274808) mostró genotipo mayoritario silvestre o "wild type" (WT) en el grupo de niños con LLA (59%), mientras que los portadores heterocigotos (HT) y homocigotos mutados (HM) estuvieron en frecuencias elevadas causando el desequilibrio de Hardy Weinberg. Sin embargo, el OR de 1,540(IC95%; 0,871-2,719) indica bajo riesgo de padecer LLA, aunque no se descartaría la probabilidad de ser responsable en parte, de la aparición de eventos adversos mediados por MTX, tal como lo reportó Owen et al (13). El polimorfismo SLC19A1 (rs2838956) se encontró en un importante número de pacientes con HT y HM; lo cual favorecería la posible presentación de reacciones gastro-intestinales adversas por MTX, como se ha asociado en población portuguesa (22,23).…”

“…Un grupo importante de estas proteínas está constituido por los transportadores de folato reducido de tipo 1 (Reduced Folic Carrier type 1-RFC1) codificados por el gen SLC19A1 que esencialmente se encargan de introducir el folato y antifolatos a la célula, localizándose a lo largo de la membrana celular (13). Existen otros transportadores, igualmente distribuidos en la región membranal, que participan en el eflujo activo de sustancias extrañas o de desecho conocidas como proteínas de resistencia a fármacos que usan la energía de ATP, tales como Multi-drug resistance proteins (MDR1) y Multidrug related resistance proteins (MRP5) codificados por ABCB1 y ABCC5 respectivamente (14), genes altamente polimórficos que modifican consecuentemente su función y su sobre-expresión (15).…”