Table 4

Summary of genetic biomarkers of response to MTX and other DMARDs.

Factors

Predictors of response?

Comments


SE

Yes, worse response to MTX

SE-positive patients seem to respond worse to MTX, especially carriers of the HLA-DRB1*04 allele; association with remission controversial; not extendable to other DMARDs

RFC1

Likely, better response to MTX

80G>A: evidence suggests favorable response in variant allele carriers, although some studies did not confirm it; other identified SNPs may have a role and explain discrepancies

ABCB1

Uncertain

3435C>T: several studies suggesting association with better response, not confirmed in others

ABCC1-4/ABCG2

Unknown

Not thoroughly studied

GGH

Uncertain

Conflicting results regarding SNPs 401C>T, 452C>T and 16T>C

FPGS

Uncertain

Few studies; contradicting findings with SNP 14G>A, no association of 14G>A with response in two studies

TYMS

Uncertain

TSER *R/*R: opposite results suggesting better responses for both 2R/2R and 3R/3R and others showing no effect

6 bp-del: favorable role suggested, but not found in other studies

DHFR

Uncertain

Several SNPs described but addressed in single studies; 317A>G was the only one associated with response but only when using rDAS28 and with marginal effect

ATIC

Uncertain

347C>G is the most studied, but conflicting results did not allow a definition of its role; other SNPs have been identified and associated with response in a few studies but lack replication

MTHFR

No

677C>T and 1298A>C have been extensively studied and two large meta-analysis found no association with MTX effectiveness

Polygenic combinations

Uncertain, but promising

Several reports of SNPs combinations associated with response, but lacking replication


Conclusions and comments are based on the findings reported and discussed in the text. ABC, ATP-binding cassette (B1, C1-4 and G2); ATIC, 5-aminoimidazole-4-carbox-amide ribonucleotide transformylase; DMARDs, disease modifying anti-rheumatic drugs; DHFR, dihydrofolate reductase; FPGS, folylpolyglutamate synthetase; GGH, γ-glutamyl hydrolase; HCQ, hydroxychloroquine; HLA, human leukocyte antigen; MTHFR, 5,10-methylene-tetrahydrofolate reductase; MTX, methotrexate; rDAS28, relative disease activity score - 28 joint; RFC1, reduced folate carrier 1; SE, shared epitope; SNPs, single nucleotide polymorphisms; TYMS, thymidylate synthase.

Romão et al. BMC Medicine 2013 11:17   doi:10.1186/1741-7015-11-17

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