Genetic determinants of methotrexate toxicity in rheumatoid arthritis patients: a study of polymorphisms affecting methotrexate transport and folate metabolism

• Published in: European journal of clinical pharmacology Vol. 64; no. 11; pp. 1057 - 1068
• Main Authors: Bohanec Grabar, Petra, Logar, Dušan, Lestan, Boris, Dolžan, Vita
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-11-2008; Springer; Springer Nature B.V
• Subjects: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase - genetics; Aged; Arthritis, Rheumatoid - drug therapy; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Biological and medical sciences; Biological Transport; Biomedical and Life Sciences; Biomedicine; Diseases of the osteoarticular system; Drug dosages; Female; Ferredoxin-NADP Reductase - genetics; Folic Acid - metabolism; Humans; Inflammatory joint diseases; Male; Medical sciences; Membrane Transport Proteins - genetics; Metabolism; Methotrexate - metabolism; Methotrexate - toxicity; Methylenetetrahydrofolate Reductase (NADPH2) - genetics; Middle Aged; Pharmacogenetics; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Polymorphism; Polymorphism, Genetic; Prescription drugs; Rheumatoid arthritis; Thymidylate Synthase - genetics; Methotrexate; Folate metabolic pathway; Rheumatoid arthritis; Genetic polymorphism; Antineoplastic agent; Genetic variability; Toxicity; Biological transport; Diseases of the osteoarticular system; Vitamin; Autoimmune disease; Inflammatory joint disease; Metabolic pathway; Genetic determinism; Folic acid; Folate; Antifolate; Human; Immunopathology; Genotype; Metabolism; Chronic; Antimetabolic; Pharmacokinetics; Polymorphism
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-008-0521-7

Objective
Methotrexate (MTX) is a disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis (RA). Genetic polymorphisms of reduced folate carrier (RFC1 A80G), P-glycoprotein (
MDR
1 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.
Methods
A genotyping approach was used to determine the studied polymorphisms in 213 RA patients.
Results
We observed that 56 (26.3%) patients discontinued MTX treatment due to poor response and/or toxicity. RFC1 A80G and
MDR
1 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).
Conclusion
Our results suggest that genetic polymorphisms in the folate metabolic pathway and MTX transporters modify the toxicity but not the efficacy of MTX treatment.