ABCMdb

PMID: 18607581

Bohanec Grabar P, Logar D, Lestan B, Dolzan V
Genetic determinants of methotrexate toxicity in rheumatoid arthritis patients: a study of polymorphisms affecting methotrexate transport and folate metabolism.
Eur J Clin Pharmacol. 2008 Nov;64(11):1057-68. Epub 2008 Jul 8., [PubMed]

Sentences

No. Mutations Sentence Comment

1 ABCB1 p.Ala80Gly Genetic polymorphisms of reduced folate carrier (RFC1 A80G), P-glycoprotein (MDR1 G2677T>A/C and C3435T), 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), thymidylate synthase (TS 2R→3R), methionine synthase (MS A2756G) and methionine synthase reductase (MTRR A66G) modify MTX transport and metabolic effects and may influence the treatment response. Login to comment 4 ABCB1 p.Ala80Gly RFC1 A80G and MDR1 C3435T polymorphisms increased the risk for overall MTX toxicity (P=0.039, OR=3.574, 95% CI=1.065-11.993 and P=0.032, OR=7.801, 95% CI= 1.194-50.960 respectively), while MTHFR A1298C polymorphism had a protective effect on overall MTX toxicity (P=0.027, OR=0.170, 95% CI=0.035-0.820). Login to comment 18 ABCB1 p.Ala80Gly The most common SNP in RFC1 is A80G (rs1051266), which results in an amino acid substitution of Arg with His at position 27 that may alter the affinity for folate [8]. Login to comment 68 ABCB1 p.Ala80Gly ABCB1 p.Ala80Gly To determine RFC1 A80G polymorphism, the region encompassing the A80G polymorphic site was amplified and PCR products were digested with HhaII (New England Biolabs) as previously described [32]. Login to comment 104 ABCB1 p.Ala80Gly The frequencies of RFC1 A80G, MTHFR C677T and A1298C, MS A2756G, MTRR A66G, TS 2R→3R, MDR1 G2677A/T and MDR1 C3435T polymorphisms were determined in all the patients and are presented in Table 3. Login to comment 107 ABCB1 p.Ala80Gly No association between RFC1 A80G, MTHFR C677T and A1298C, MS A2756G, MTRR A66G, TS 2R→3R, MDR1 G2677A/T and MDR1 C3435T polymorphisms and ESR, CRP and DAS28 values was observed in a multiple regression model adjusted for sex, age, disease duration, treatment duration, RF seropositivity and MTX dose (data not shown). Login to comment 110 ABCB1 p.Ala80Gly Regarding MTX treatment response, RFC1 A80G, MTHFR C677T and A1298C, MS A2756G, MTRR A66G, TS 2R→3R, MDR1 G2677A/T and MDR1 C3435T polymorphisms did not influence the efficacy of the MTX treatment (data not shown). Login to comment 111 ABCB1 p.Ala80Gly Nevertheless, the frequencies of RFC1 A80G polymorphism were significantly different in patients suffering from AEs and in patients without the presence of AEs (AA+AG: 66.9 and 83.1%, GG: 33.1 and 16.9% respectively; P=0.038). Login to comment 115 ABCB1 p.Ala80Gly When patients receiving concomitant therapy with MTX and other DMARDs were excluded from the logistic regression model, an even stronger impact of RFC1 A80G polymorphism on the overall MTX toxicity was observed in the remaining 150 patients (P=0.039, OR=3.574, 95% CI= 1.065-11.993). Login to comment 120 ABCB1 p.Ala80Gly When AEs were specified, the data revealed strong association between the occurrence of infections and RFC1 A80G polymorphism, since patients with RFC1 80GG genotype had a 15.067-fold higher risk for developing infections as compared to patients with RFC1 80AA/ AG genotype (P=0.006, 95% CI=2.182-104.060, Table 4). Login to comment 124 ABCB1 p.Ala80Gly When investigating SNPs in MTX transporters we observed a significant association between RFC1 A80G polymorphism and low-dose MTX toxicity. Login to comment 125 ABCB1 p.Ala80Gly Of all the studied polymorphisms, RFC1 A80G had the strongest impact on the overall MTX toxicity and on the risk for developing infections, but did not influence MTX efficacy. Login to comment 126 ABCB1 p.Ala80Gly In vitro studies on human skin fibroblasts showed that RFC1 A80G polymorphism alters the affinity for folate and may thus result in altered cellular MTX concentrations [8]. Login to comment 130 ABCB1 p.Ala80Gly Nevertheless, studies investigating the influence of the RFC1 A80G polymorphism and low-dose MTX treatment response reported contradictory results. Login to comment 132 ABCB1 p.Ala80Gly Patients with the MTHFR 677CT and/or TT genotype had significantly higher plasma total homocysteine concentrations as compared to patients with the MTHFR 677CC genotype Table 4 Occurrence of specific MTX-induced AEs according to risk genotypes Genotype Infections Dermatological complaint Bone-marrow toxicity Yes, n (%) No, n (%) Yes, n (%) No, n (%) Yes, n (%) No, n (%) RFC1 80 AA+AG 2 (22.2) 108 (76.6) 10 (55.6) 100 (75.8) 15 (13.6) 95 (86.4) GG 7 (77.8)a 33 (23.4)a 8 (44.4) 32 (24.2) 6 (15.0) 34 (85.0) MTRR 66 AA 2 (22.2) 25 (17.7) 7 (38.9) 20 (15.2) 2 (7.4) 25 (92.6) AG+GG 7 (77.8) 116 (82.3) 11 (61.1)b 112 (84.8)b 19 (15.4) 104 (84.6) TS 2R/2R+2R/3R 6 (6.3) 90 (93.8) 10 (10.4) 86 (89.6) 9 (9.4) 87 (90.6) 3R/3R+3R/4R 3 (5.6) 51 (94.4) 8 (14.8) 46 (85.2) 12 (22.2)c 42 (77.8)c Patients receiving cotreatment with other DMARDs were excluded from the analysis a P=0.006, OR=15.067, 95% CI=2.182-104.6 b P=0.007, OR=0.191, 95% CI=0.057-0.637 c P=0.028, OR=2.959, 95% CI=1.127-7.768 independent studies based on Japanese and Caucasian RA patients no association between the RFC1 A80G polymorphism and MTX efficacy and/or toxicity was observed [20, 42, 43]. Login to comment 181 ABCB1 p.Ala80Gly Our results suggest that RFC1 A80G and MDR1 C3435T polymorphisms influence the risk for MTX-induced AEs, while MTHFR A1298C polymorphism has a protective effect on MTX toxicity. Login to comment