Polymorphisms and pharmacogenomics for the toxicity of methotrexate monotherapy in patients with rheumatoid arthritis: A systematic review and meta-analysis

Abstract

Background: Methotrexate (MTX) is widely used and considered a first-line disease modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). However, 10% to 30% of patients discontinue therapy within a year of starting the treatment, usually because of undesirable side effects. Many of the relevant genes have been investigated to estimate the association between gene polymorphisms and MTX toxicity in RA patients, although inconsistent results have been reported.

Methods: We searched EMBASE and PubMed in February 2016 for polymorphisms and pharmacogenomics study of the toxicity of MTX monotherapy in RA patients. The meta-analysis was stratified by whether genetic variants associated with MTX toxicity.

Results: A total of 42 publications that included 28 genes with 88 gene SNPs associated with the transporters, enzymes, and metabolites of MTX or the progression of RA were included in the SR, and 31 studies were included in 7 meta-analyses. The meta-analysis showed a significant association between the toxicity of MTX and the RFC-1 80G > A (rs1051266) polymorphism in the European RA patients.

Conclusion: RFC-1 80G > A (rs1051266) polymorphism was associated with MTX toxicity, and larger and more stringent study designs may provide more accurate results for the effect of these SNPs on the MTX toxicity.

Figure 1

Study selection flow diagram adapted from the Preferred Reporting Items for SRs and Meta-Analyses (PRISMA) Statement.

Figure 2

Distribution of countries in 31 studies that measured the association between polymorphisms and the toxicity to MTX in RA. MTX = methotrexate, RA = rheumatoid arthritis.

Figure 3

Distribution of ancestry in 31 studies that measured the association between polymorphisms and the toxicity to MTX in RA. MTX = methotrexate, RA = rheumatoid arthritis.

Figure 4

Summary of detected genes associated with the MTX toxicity in RA patients in previous studies. Schematic representation of the intracellular folate biosynthetic pathway and the genes detected in previous studies (in green). ABCC1–4, ABCB1, and ABCG2 = adenosine triphosphate-binding cassette (ABC) transporters, ADA = adenosine deaminase, ADP = adenosine diphosphate, AICAR = 5-aminoimidazole-4-carboxamide ribonucleotide, AMP = adenosine monophosphate, ATIC = -aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase, ATP = adenosine triphosphate, CBS = cystathionine-β-synthase, CCND1 = cyclin D1, CH3 = methyl group, CL = cystathionine lyase, DHF = dihydrofolate, DHFR = dihydrofolate reductase, dTMP = deoxythymidine-5′-monophosphate, dUMP = deoxyuridine-5′-monophosphate, FAICAR = 10-formyl-AICAR, FPGS = folylpolyglutamyl synthase, GGH = glutamyl hydrolase, IMP = inosine monophosphate, IMPDH2 = inosine 5′-monophosphate dehydrogenase, ITP = inosine triphosphate, ITPA = inosine triphosphate pyrophosphatase, MDR1 = multidrug resistance 1, MS = methionine synthase, MTHFD1 = methylenetetrahydrofolate dehydrogenase, MTHFR = methylenetetrahydrofolate reductase, MTR = methionine synthase, MTRR = methionine synthase reductase, MTX = methotrexate, MTX-PGs = methotrexate polyglutamates, RFC-1 = reduced folate carrier 1, SHMT = serine hydroxymethyltransferase, SLC16A7, SLC19A1, SLC46A1, and SLC22A11 = solute carriers, SLCO 1B1 = solute carrier organic anion transporter, THF = tetrahydrofolate, TSER = thymidylate synthase enhancer region, TYMS = thymidylate.

Figure 5

Meta-analysis of MTHFR 677C > T (rs1801133) single-nucleotide polymorphism and associated risk of toxicity of MTX (CC vs CT + TT genotypes). % weight = the percentage weight attributed to each study in the meta-analysis, CI = confidence interval, OR = odds ratio. Squares represent point estimates for effect size expressed as an OR with the size proportional to the inverse variance of the estimate. Lines represent 95% CIs. The diamonds represent the overall pooled estimate.

Figure 6

Meta-analysis of MTHFR 1298A > C (rs1801131) single-nucleotide polymorphism and the associated risk of of MTX (AA vs AC + CC genotypes). % weight = the percentage weight attributed to each study in the meta-analysis, CI = confidence interval, OR = odds ratio. Squares represent point estimates for effect size expressed as a OR with the size proportional to the inverse variance of the estimate. Lines represent 95% CIs. The diamonds represent the overall pooled estimate.

Figure 7

Meta-analysis of ATIC 347C > G (rs2372536) polymorphism and associated risk of toxicity of MTX (CC vs CG + GG genotypes). % weight = the percentage weight attributed to each study in the meta-analysis, CI = confidence interval, OR = odds ratio. Squares represent point estimates for effect size expressed as an OR with the size proportional to the inverse variance of the estimate. Lines represent 95% CIs. Diamond represents the overall pooled estimate.

Figure 8

Meta-analysis of MTR 2756A > G (rs1805087) single-nucleotide polymorphism and associated risk of toxicity of MTX (AA vs AG + GG genotypes). % weight = the percentage weight attributed to each study in the meta-analysis, CI = confidence interval, OR = odds ratio. Squares represent point estimates for effect size expressed as a OR with the size proportional to the inverse variance of the estimate. Lines represent 95% CIs. Diamond represents the overall pooled estimate.

Figure 9

Meta-analysis of MTRR 66A > G (rs1801394) single-nucleotide polymorphism and associated risk of toxicity of MTX (AA vs AG + GG genotypes). % weight = the percentage weight attributed to each study in the meta-analysis, CI = confidence interval, OR = odds ratio. Squares represent point estimates for effect size expressed as a OR with the size proportional to the inverse variance of the estimate. Lines represent 95% CIs. Diamond represents the overall pooled estimate.

Figure 10

Meta-analysis of RFC-1 80G > A (rs1051266) single-nucleotide polymorphism and associated risk of toxicity of MTX (GG vs GA + AA genotypes). % weight = the percentage weight attributed to each study in the meta-analysis, CI = confidence interval, OR = odds ratio. Squares represent point estimates for effect size expressed as a OR with the size proportional to the inverse variance of the estimate. Lines represent 95% CIs. The diamonds represent the overall pooled estimate.

Figure 11

Meta-analysis of ABCB1 3435C > T (rs1045642) single-nucleotide polymorphism and associated risk of toxicity of MTX (TT vs CC + CT genotypes). % weight = the percentage weight attributed to each study in the meta-analysis, CI = confidence interval, OR = odds ratio. Squares represent point estimates for effect size expressed as a OR with the size proportional to the inverse variance of the estimate. Lines represent 95% CIs. Diamond represents the overall pooled estimate.