Table 4.

Multivariate regression model of the 3 strongest determinants. Variables that after correction for confounders had a significant correlation in both cohorts were included in 1 multivariate regression model. FPGS rs4451422 was dichotomized into wild type versus heterozygous/variant. Correlations with p < 0.05 are considered significant. Confounders are not shown and were serum folate (for erythrocyte folate) and sex (for FPGS rs4451422).

	MTX-PG1		MTX-PG2		MTX-PG3		MTX-PG4+5		MTX-PG2–5
	stβ	p	stβ	p	stβ	p	stβ	p	stβ	p
Derivation cohort
Age	0.21	0.06	0.2	0.09	0.24	0.03	0.2	0.08	0.28	0.01
Erythrocyte folate	–0.19	0.13	0.04	0.75	0.21	0.08	0.18	0.15	0.19	0.1
FPGS rs4451422 WT vs het/var	–0.08	0.47	–0.17	0.13	–0.36	< 0.001	–0.33	0.003	–0.38	< 0.001
R²	0.14		0.04		0.21		0.11		0.21
Validation cohort
Age	0.13	0.08	0.22	0.002	0.23	0.001	0.22	0.002	0.28	< 0.001
Erythrocyte folate	0.05	0.53	0.03	0.66	0.12	0.09	0.1	0.16	0.11	0.099
FPGS rs4451422 WT vs het/var	0.01	0.84	–0.07	0.3	–0.08	0.25	–0.09	0.18	–0.10	0.12
R²	0		0.03		0.07		0.07		0.1
Combined cohort
Dose	–0.07	0.26	–0.22	< 0.001	0.23	< 0.001	0.3	< 0.001	0.2	< 0.001
Age	0.15	0.013	0.2	0.001	0.23	< 0.001	0.21	< 0.001	0.27	< 0.001
Erythrocyte folate	0.03	0.65	0.03	0.66	0.15	0.01	0.11	0.06	0.13	0.024
FPGS rs4451422 WT vs het/var	–0.01	0.8	–0.09	0.106	–0.16	0.003	–0.15	0.005	–0.18	< 0.001
R²	0.01		0.08		0.15		0.15		0.16

FPGS: folylpolyglutamate synthetase; MTX: methotrexate; PG: polyglutamate; WT: wild type; het: heterozygous; var: homozygous variant.