Table 2.

Pharmacogenetics of Methotrexate (MTX) in Rheumatoid Arthritis (RA)

Gene Symbol	Polymorphism	Effect of Polymorphism	Pharmacogenetics	References
RFC1	G80A	Increased MTX entry into cell	Increased response to MTX	[58]
ABCB1	C3435T	Involved in MTX transport	Increased response to MTX	[59]
MTHFR	C677T	Thermolabile variant of MTHFR enzyme with decreased enzyme activity	Increased gastrointestinal side effects and increased hepatic toxicity	[61, 62]
			Overall adverse events	[63]
			No effects on toxicity or efficacy	[65, 66]
	A1298C	Decreased MTHFR activity	Increased MTX efficacy	[62, 63]
			Increased susceptibility to RA	[65]
			No effects on toxicity or efficacy	[64, 66]
			Increased risk of toxicity	[64, 67, 68]
TYMS	5´UTR 28 bp repeat	Increased mRNA expression and enzyme activity	Decreased MTX efficacy	[66]
	3´UTR 6bp deletion	Decreased mRNA stability and expression	Increased MTX efficacy	[66]
ATIC	C347G	AICAR accumulation and increased adenosine	In combination with double-repeat allele in TYMS or the RFC1 G80A SNP seems to correlate with an increased response to MTX	[73]

RFC1 = reduced folate carrier 1; ABCB1 = adenosine triphospate-binding cassette B1; MTHFR = methylenetetrahydrofolate reductase; TYMS = thymidylate synthase; ATIC = aminoimidazole carboxamide ribonucleotide transformylase; SNP = single nucleotide pohymorphism.