SNP within cellular folate transport and metabolism routes in relation to MTX polyglutamate levels at 3 months of treatment in MTX-R and tREACH cohorts. Analysis was done using ANCOVA with correction for age and sex. Only SNP with a significant correlation with any MTX-PG in the derivation or validation cohort are shown (full table in Supplementary Table 2, available online at jrheum.com).
| Derivation | Validation | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Estimated Marginal Means (SE) | Estimated Marginal Means (SE) | |||||||||||||
| n | MTX-PG1 | MTX-PG2 | MTX-PG3 | MTX-PG4+5 | MTX-PG Total | n | MTX-PG1 | MTX-PG2 | MTX-PG3 | MTX-PG4+5 | MTX-PG Total | |||
| rs1127354 ITPA | C/A | WT | 81 | 44.8 (5.4) | 27.1 (1.6) | 39.1 (2.2) | 13.2 (2.1)* | 79.3 (4.6) | 211 | 43.3 (3.4) | 23.1 (0.7) | 50.5 (1.3) | 30.4 (1.5) | 103.9 (2.8) |
| Het/Var | 12 | 62.0 (13.0) | 27.5 (3.8) | 49.6 (5.6) | 25.1 (4.9)* | 102.2 (11.0) | 36 | 40.7 (7.8) | 20.6 (1.5) | 48.7 (2.8) | 27.6 (3.4) | 96.9 (6.3) | ||
| rs17602729 AMPD1 | G/A | WT | 66 | 46.7 (6.3) | 28.2 (1.8) | 41.6 (2.5) | 15.6 (2.4) | 85.4 (5.3) | 198 | 41.8 (3.6) | 21.9 (0.7)* | 49.4 (1.3) | 29.9 (1.6) | 101.2 (2.9) |
| Het/Var | 17 | 54.2 (11.2) | 27.3 (3.2) | 40.5 (4.5) | 14.2 (4.3) | 82.0 (9.4) | 42 | 48.4 (7.3) | 25.7 (1.4)* | 52.6 (2.6) | 30.3 (3.2) | 108.6 (5.9) | ||
| rs35592 ABCC1 | T/C | WT/Het | 76 | 48.2 (5.8) | 27.8 (1.7) | 42.6 (2.3)* | 16.1 (2.2) | 86.5 (4.8) | 229 | 43.3 (3.3) | 22.7 (0.7) | 50.0 (1.2) | 30.2 (1.5) | 102.9 (2.7) |
| Var | 7 | 49.9 (17.8) | 30.1 (5.1) | 25.9 (6.9)* | 4.5 (6.7) | 60.5 (14.6) | 11 | 36.6 (14.5) | 20.7 (2.9) | 47.9 (5.2) | 23.5 (6.4) | 92.1 (11.6) | ||
| rs3784862 ABCC1 | A/G | WT | 38 | 46.8 (7.9) | 25.9 (2.2) | 42.1 (3.2) | 17.8 (3.0) | 85.8 (6.7) | 133 | 47.0 (4.2)* | 23.6 (0.8) | 49.9 (1.5) | 28.0 (1.9) | 101.5 (3.4) |
| Het | 34 | 52.9 (8.0) | 30.9 (2.3) | 40.9 (3.3) | 12.2 (3.1) | 84.0 (6.8) | 90 | 32.7 (5.1)* | 21.1 (1.0) | 49.9 (1.9) | 33.4 (2.3) | 104.4 (4.2) | ||
| Var | 11 | 35.0 (15.0) | 24.6 (4.3) | 39.6 (6.1) | 17.4 (5.8) | 81.6 (12.7) | 17 | 63.6 (11.3)* | 22.5 (2.3) | 50.6 (4.1) | 28.2 (5.0) | 101.4 (9.2) | ||
| rs868853 ABCC4 | T/C | WT/Het | 65 | 48.4 (6.1) | 27.5 (1.7) | 41.1 (2.3) | 15.3 (2.3) | 83.9 (4.9) | 205 | 45.6 (3.5)* | 22.8 (0.7) | 49.9 (1.3) | 29.4 (1.5) | 102.0 (2.8) |
| Var | 15 | 51.1 (13.0) | 32.2 (3.7) | 46.2 (5.0) | 16.8 (5.0) | 95.3 (10.6) | 34 | 27.5 (8.2)* | 21.7 (1.6) | 50.9 (2.9) | 34.5 (3.6) | 107.0 (6.6) | ||
| rs2139560 ABCC5 | G/A | WT | 34 | 34.2 (7.7)** | 24.3 (2.3)* | 38.5 (3.3) | 16.4 (3.2) | 79.3 (7.0) | 85 | 40.7 (5.2) | 22.5 (1.0) | 50.5 (1.8) | 31.5 (2.3) | 104.5 (4.1) |
| Het | 38 | 48.7 (7.1)** | 28.7 (2.1)* | 41.5 (3.1) | 14.2 (3.0) | 84.4 (6.4) | 111 | 45.9 (4.7) | 22.9 (0.9) | 49.8 (1.7) | 29.4 (2.1) | 102.1 (3.8) | ||
| Var | 11 | 90.6 (13.0)** | 36.6 (3.9)* | 49.2 (5.6) | 15.5 (5.5) | 101.4 (11.7) | 44 | 40.2 (7.5) | 22.0 (1.5) | 48.9 (2.7) | 27.9 (3.3) | 98.8 (6.0) | ||
| rs2372536 ATIC | C/G | WT | 37 | 37.0 (7.7)** | 25.9 (2.4) | 37.3 (3.2) | 15.6 (3.2) | 78.8 (6.8) | 108 | 43.5 (4.7) | 22.8 (0.9) | 50.1 (1.7) | 28.7 (2.1) | 101.7 (3.7) |
| Het | 39 | 50.1 (7.2)** | 29.5 (2.2) | 43.1 (3.0) | 14.3 (2.9) | 86.9 (6.3) | 98 | 42.3 (5.0) | 23.0 (1.0) | 51.0 (1.8) | 32.3 (2.2) | 106.3 (4.0) | ||
| Var | 7 | 94.0 (16.5)** | 29.9 (5.0) | 50.6 (50.6) | 19.1 (6.8) | 99.6 (14.6) | 34 | 43.6 (8.2) | 21.0 (1.6) | 46.5 (2.9) | 27.5 (3.6) | 94.9 (6.5) | ||
| rs4451422 FPGS | A/C | WT | 61 | 55.8 (10.3) | 31.6 (3.0) | 52.3 (52.3)** | 24.8 (3.8)** | 108.7 (8.1)*** | 172 | 46.5 (5.8) | 24.3 (1.2) | 53.3 (2.1)* | 34.3 (2.6)* | 111.8 (4.6)* |
| Het/Var | 22 | 46.0 (6.3) | 26.9 (1.8) | 37.8 (2.4)** | 12.2 (2.3)** | 76.8 (4.9)*** | 68 | 41.6 (3.8) | 21.9 (0.8) | 48.6 (1.4)* | 28.3 (1.7)* | 98.8 (3.0)* | ||
| rs1045642 ABCB1 | G/A | WT | 14 | 37.1 (12.7)* | 20.6 (3.5)** | 31.7 (5.1)* | 10.3 (5.0) | 62.6 (10.3)** | 52 | 38.6 (6.8) | 22.3 (1.4) | 50.5 (2.4) | 29.3 (3.0) | 102.1 (5.4) |
| Het | 41 | 37.9 (7.3)* | 25.0 (2.0)** | 38.4 (2.9)* | 13.3 (2.9) | 76.7 (6.0)** | 122 | 43.9 (4.5) | 22.6 (0.9) | 49.2 (1.6) | 30.5 (2.0) | 102.2 (3.6) | ||
| Var | 28 | 66.0 (8.5)* | 34.5 (2.3)** | 48.5 (3.4)* | 19.5 (3.3) | 102.5 (6.9)** | 66 | 44.6 (6.0) | 22.9 (1.2) | 50.9 (2.1) | 29.6 (2.6) | 103.4 (4.8) | ||
| rs1801131 MTHFR | T/G | WT | 44 | 45.4 (7.2) | 26.4 (2.1) | 38.8 (2.9) | 15.2 (2.8) | 80.5 (6.0) | 111 | 36.1 (4.7)* | 22.1 (0.9) | 50.9 (1.7) | 32.3 (2.1) | 105.3 (3.8) |
| Het | 29 | 54.1 (9.4) | 29.3 (2.7) | 44.8 (3.8) | 15.8 (3.6) | 90.0 (7.9) | 107 | 45.5 (4.6)* | 22.4 (0.9) | 48.6 (1.7) | 28.4 (2.1) | 99.5 (3.7) | ||
| Var | 10 | 47.7 (14.7) | 32.0 (4.2) | 44.2 (5.9) | 13.9 (5.7) | 90.1 (12.3) | 22 | 63.5 (10.0)* | 25.8 (2.0) | 51.8 (3.6) | 26.7 (4.5) | 104.4 (8.1) | ||
| rs3785911 ABCC3 | A/C | WT | 43 | 49.0 (7.4) | 27.1 (2.1) | 40.9 (3.0) | 13.8 (2.9) | 81.8 (6.2) | 126 | 46.4 (44.4) | 22.9 (0.9) | 48.3 (1.6) | 27.5 (1.9)** | 98.7 (3.5)* |
| Het | 30 | 44.7 (8.8) | 28.0 (2.5) | 41.8 (3.6) | 16.8 (3.4) | 86.5 (7.4) | 93 | 40.5 (5.0) | 22.4 (1.0) | 50.6 (1.8) | 30.1 (2.2)** | 103.0 (4.0)* | ||
| Var | 10 | 59.4 (15.2) | 33.6 (4.4) | 41.8 (6.2) | 17.4 (5.9) | 92.8 (12.8) | 21 | 34.6 (10.3) | 21.9 (2.1) | 56.8 (3.7) | 43.5 (4.5)** | 122.2 (8.2)* | ||
| rs4793665 ABCC3 | T/C | WT | 22 | 32.3 (10.1) | 23.8 (2.9) | 41.8 (4.2) | 18.6 (4.0) | 84.4 (8.7) | 79 | 44.2 (5.4)* | 23.4 (1.1) | 49.3 (1.9) | 29.1 (2.4) | 101.8 (4.4) |
| Het | 41 | 58.7 (7.8) | 28.9 (2.3) | 40.4 (3.2) | 14.2 (3.1) | 83.4 (6.7) | 119 | 37.1 (4.4)* | 21.8 (0.9) | 49.3 (1.6) | 30.0 (2.0) | 101.1 (3.6) | ||
| Var | 20 | 46.4 (10.0) | 30.3 (2.9) | 42.3 (4.1) | 14.0 (3.9) | 86.6 (8.6) | 42 | 58.6 (7.4)* | 23.2 (1.5) | 53.5 (2.7) | 31.6 (3.3) | 108.2 (6.0) | ||
| rs2239907 SLC46A1 | C/T | WT | 26 | 46.9 (9.0) | 26.9 (2.5)* | 41.4 (3.6) | 15.9 (3.5) | 84.2 (7.6) | 73 | 37.6 (5.6)* | 23.8 (1.1) | 51.2 (2.0) | 30.7 (2.5) | 105.7 (4.6) |
| Het | 47 | 46.4 (7.7) | 26.1 (2.1)* | 39.7 (3.1) | 15.7 (3.0) | 81.6 (6.5) | 119 | 39.0 (4.4)* | 21.2 (0.9) | 48.9 (1.6) | 30.5 (2.0) | 100.6 (3.6) | ||
| Var | 10 | 59.7 (14.6) | 38.0 (4.0)* | 47.1 (5.9) | 11.8 (5.6) | 96.9 (12.2) | 48 | 60.9 (6.8)* | 24.2 (1.4) | 50.7 (2.5) | 27.6 (3.0) | 102.5 (5.5) | ||
↵* p < 0.05.
↵** p < 0.01.
↵*** p < 0.001. ABCB1/ABCC1/ABCC2/ABCC3/ABCC4/ABCC5/ABCG2: adenosine triphosphate-binding cassette transporter subfamily B/C/G member 1/2/3/4/; FPGS: folylpolyglutamate synthetase; SLC 46A1/SLC19A: solute carrier 46A1/19A1; SNP: single-nucleotide polymorphism; MTX: methotrexate; tREACH: treatment in Rotterdam Early Arthritis Cohort; PG: polyglutamate; WT: wild type; Het: heterozygous; Var: homozygous variant.