Table 4.
Candidate gene polymorphisms associated with either efficacy and/or toxicity of MTX pharmacotherapy in rheumatoid arthritis patients
| Gene | Variant | Function | Effect on MTX therapy | Ref. |
|---|---|---|---|---|
| Variants affecting transport of MTX | ||||
| RFC-1 | 80G>A | Minimal effect on transport of folate and MTX into cells | AA genotype associated with 3.7-fold greater response (95% CI: 1.7–9.1, P < 0.01) | 114 |
| GA/AA genotype associated with increased risk for overall MTX toxicity (OR = 3.574, 95% CI: 1.1–12.0; P = 0.039) | 118 | |||
| MDR1 | 3435C>T | ? | TT genotype associated with a higher remission probability (OR = 4.65, 95% CI: 1.7–13.0; P = 0.003) | 118–120 |
| Variants affecting intracellular metabolism of MTX | ||||
| MTHFR | 677C>T | Decreased reduction of 5,10-CH2-THF to 5-CH3-THF | CT/TT genotype associated with increased ADRs (RR = 2.0, 95% CI: 1.1–3.7) | 126 |
| CT/TT genotype associated with higher rate of MTX toxicity (RR = 1.2, 95% CI: 1.0–1.5; P < 0.05) | 128 | |||
| No effect on efficacy | 126, 127 | |||
| CC genotype associated with greater response in early RA | 117 | |||
| 1298A>C | Decreased reduction of 5,10-CH2-THF to 5-CH3-THF | AC/CC genotype required lower doses of MTX (RR = 2.2, 95% CI: 1.2–4.1, P < 0.05) | 128 | |
| CC genotype associated with fewer ADRs | 127, 129 | |||
| AC/AA genotype associated with higher rate of MTX toxicity (OR = 15.9, 95% CI: 1.5–167.0; P = 0.021) | 127 | |||
| AA genotype associated with greater response in early RA | 117 | |||
| AC genotype associated with more ADRs | 117 | |||
| TYMS | 28bp tandem repeat | Decreased conversion of CH2-THF to DHF | Alleles with three repeats associated with MTX resistance | 114, 132 |
| Alleles with only two repeats associated with improved response | 114, 132 | |||
| ATIC | 347C>G | Decreased de novo purine synthesis | GG genotype associated with improved response | 130, 114 |
| GG genotype associated with ADRs | 131 | |||
Abbreviations: RFC-1, reduced folate carrier – 1; MDRI, multi-drug resistance – 1; MTHFR, 5,10-methylenetetrahydrofolate reductase (NADPH); TYMS, thymidylate synthetase; ATIC, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase.