Genes and 21 single-nucleotide polymorphisms (SNP) within cellular methotrexate (MTX) transport routes and polyglutamylation in relation to response (ACRped70) over the first year of MTX therapy in 287 patients with juvenile idiopathic arthritis. Analyses were performed according to a recessive inheritance model.
| SNP | GC (%) | HWE p | WT/het/var | MAF | Genotype Frequency (WT/het/var) | OR (95% CI) Univariate | p | Study |
|---|---|---|---|---|---|---|---|---|
| ABCB1 rs1128503 | 7.5 | 0.560 | GG/GA/AA | 0.40 | 0.38/0.46/0.16 | 1.85 (0.64–5.35) | 0.254 | 22 |
| ABCB1 rs2032582 | 7.5 | 0.682 | CC/CA/CT/TA/AA | 0.38/0.02 | 0.36/0.47/0.01/0.02/0.13 | 1.86 (0.63–5.52) | 0.263 | 22 |
| ABCB1 rs1045642 | 7.5 | 0.060 | GG/GA/AA | 0.48 | 0.29/0.45/0.26 | 3.72 (1.62–8.55) | 0.002 | 23 |
| ABCC1 rs35592 | 2.8 | 0.175 | TT/TC/CC | 0.23 | 0.61/0.32/0.07 | 4.93 (1.04–23.26) | 0.045 | 24 |
| ABCC1 rs3784862 | 2.8 | 0.260 | AA/AG/GG | 0.28 | 0.53/0.38/0.09 | 1.49 (0.49–4.50) | 0.482 | 24 |
| ABCC2 rs4148396 | 6.3 | 0.329 | CC/CT/TT | 0.36 | 0.39/0.49/0.12 | 1.02 (0.34–3.03) | 0.973 | 24 |
| ABCC2 rs717620 | 6.3 | 0.038* | CC/CT/TT | 0.19 | 0.63/0.35/0.02 | 2.87 (0.14–58.82) | 0.493 | 24 |
| ABCC3 rs4793665 | 3.8 | 0.347 | CC/CT/TT | 0.57 | 0.17/0.52/0.31 | 2.99 (1.39–6.41) | 0.005 | 25 |
| ABCC3 rs3785911 | 3.8 | 0.298 | AA/AC/CC | 0.32 | 0.48/0.41/0.11 | 1.09 (0.35–3.40) | 0.879 | † |
| ABCC4 rs868853 | 0.5 | 0.638 | TT/TC/CC | 0.07 | 0.86/0.14/0.00 | ** | 26 | |
| ABCC4 rs2274407 | 0.5 | 0.243 | CC/CA/AA | 0.06 | 0.87/0.13/0.00 | ** | 26 | |
| ABCC5 rs2139560 | 17.5 | 0.092 | GG/GA/AA | 0.40 | 0.34/0.53/0.13 | 0.51 (0.18–1.46) | 0.208 | ‡ |
| ABCG2 rs13120400 | 9.1 | 0.622 | TT/TC/CC | 0.27 | 0.53/0.39/0.08 | 0.17 (0.03–0.89) | 0.036 | 24 |
| ABCG2 rs2231142 | 9.1 | 0.351 | GG/GT/TT | 0.11 | 0.80/0.18/0.02 | ** | 27 | |
| FPGS rs4451422 | 16.2 | 0.568 | AA/AC/CC | 0.40 | 0.37/0.46/0.17 | 2.14 (0.90–5.13) | 0.087 | ‡ |
| FOLR1 rs11235462 | 5.6 | 0.925 | TT/TA/AA | 0.16 | 0.71/0.27/0.02 | ** | † | |
| FOLR2 rs514933 | 7.1 | 0.514 | TT/TC/CC | 0.35 | 0.44/0.43/0.13 | 0.59 (0.20–1.73) | 0.338 | 28 |
| GGH rs10106587 | 14.9 | 0.992 | AA/AC/CC | 0.29 | 0.50/0.42/0.08 | 2.28 (0.54–9.62) | 0.260 | ‡ |
| GGH rs3758149 | 14.9 | 0.921 | GG/GA/AA | 0.30 | 0.49/0.42/0.09 | 0.69 (0.19–2.47) | 0.563 | 24 |
| SLC46A1 rs2239907 | 48.4 | 0.643 | CC/CT/TT | 0.44 | 0.32/0.48/0.20 | 1.05 (0.42–2.63) | 0.914 | 29 |
| SLC19A1 rs1051266 | 57.3 | 0.839 | CC/CT/TT | 0.37 | 0.39/0.47/0.14 | 0.34 (0.11–1.02) | 0.054 | 30 |
↵* ABCC2 rs717620 had a low number of homozygous variants (5 patients). As this could have contributed to the HWE p value < 0.05, we kept this SNP in the analysis.
↵** Insufficient distribution of data for statistical analysis (not at least 1 responder and 1 nonresponder for each genotype on every visit).
↵† No tagging SNP were available and an SNP with minor allele frequency > 0.10 was chosen.
↵‡ Tagging SNP were selected by Hapmap database and Haploview. ACRped70: American College of Rheumatology 70% pediatric criteria; GC: gene coverage; HWE: Hardy-Weinberg equilibrium; WT: wild type; het: heterozygous; var: variant; ABCB1/ABCC1/ABCC2/ABCC3/ABCC4/ABCC5/ABCG2: adenosine triphosphate-binding cassette transporter subfamily B/C/G member 1/2/3/4/; FPGS: folylpolyglutamate synthetase; FOLR1/FOLR2: folate receptor 1/2; GGH: gamma glutamyl hydrolase; SLC 46A1/SLC19A: solute carrier 46A1/19A1; rs: reference SNP number.