Genetic polymorphisms of enzyme proteins and transporters related to methotrexate response and pharmacokinetics in a Japanese population

Table 4 Summarized characteristics of MTX-related enzyme gene and transporter polymorphisms

Gene	SNP ID	SNP allele	Effects on gene product/ enzyme	Clinical significance
MTHFR	rs1801131	1298 A > C	Decreases MTHFR activity	Associated with MTX efficacy, not associated with MTX toxicity, or associated with MTX toxicity
TYMS	rs16430	3'-UTR - 6/6	Decreases TYMS mRNA expression	Associated with MTX toxicity
RFC1	rs1051266	80 G > A	Affects transcriptional activity of RFC1 gene and MTX entry into cells	Increases MTX-PG concentrations and good clinical response to MTX treatment
RFC1	rs1131596	−43 T > C	Decreases the expression of RFC1 protein	Unknown
FPGS	rs10106	1994 G > A	Associated with FPGS mRNA expression	Not associated with MTX efficacy/toxicity, or poor response to MTX treatment
GGH	rs11545078	452 C > T	Associated with lower GGH activity, greater accumulation of long-chain MTX-PGs	Not associated with MTX efficacy/toxicity
GGH	rs3758149	−401 C > T	Associated with greater GGH promotor activity, decrease polyglutamation	Affects MTX toxicity
ABCB1	rs1045642	3435 C > T	Decreases stability/expression of mRNA, reduces the activity of efflux transporters	Associated with MTX efficacy
ABCC2	rs4148396	IVS23 + 56 T > C	Affects ABCC2 enzyme activity and MTX efflux from cell	Associated with MTX toxicity (adverse GI effects)
ABCG2	rs2231142	914 C > A	Increases MTX-PG1/MTX-PG2 concentrations	Associated with MTX toxicity

MTX: methotrexate, MTHFR: methylenetetrahydrofolate reductase, TYMS: thymidylate synthase, RFC1: reduced folate carrier 1, FPGS: folypolyglutamayl synthase, GGH: γ-glutamyl hydrolase, ABCB1: ATP-binding cassette sub-family B member 1, ABCC2: ATP-binding cassette subfamily C member 2, ABCG2: ATP-binding cassette sub-family G member 2, GI: gastrointestinal

ISSN: 2055-0294