Methotrexate (MTX) pathway gene polymorphisms and their effects on MTX toxicity in Caucasian and African American patients with rheumatoid arthritis

• Published in: Journal of rheumatology Vol. 35; no. 4; pp. 572 - 579
• Main Authors: RANGANATHAN, Prabha, CULVERHOUSE, Robert, MARSH, Sharon, MODY, Ami, SCOTT-HORTON, Tiffany J, BRASINGTON, Richard, JOSEPH, Amy, REDDY, Virginia, EISEN, Seth, MCLEOD, Howard L
• Format: Journal Article
• Language: English
• Published: Toronto, ON The Journal of Rheumatology 01-04-2008; Journal of Rheumatology Publishing
• Subjects: African Americans - genetics; Antirheumatic Agents - adverse effects; Antirheumatic Agents - therapeutic use; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - ethnology; Arthritis, Rheumatoid - genetics; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Diseases of the osteoarticular system; European Continental Ancestry Group - genetics; Female; Genetic Predisposition to Disease; Humans; Inflammatory joint diseases; Medical sciences; Membrane Transport Proteins - genetics; Methotrexate - adverse effects; Methotrexate - therapeutic use; Methylenetetrahydrofolate Reductase (NADPH2) - genetics; Multidrug Resistance-Associated Proteins - genetics; Peptide Synthases - genetics; Peptide Synthases - metabolism; Pharmacogenetics; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide; Retrospective Studies; Risk Factors; Thymidylate Synthase - genetics; Thymidylate Synthase - metabolism; Antineoplastic agent; Human; Immunopathology; Toxicity; Diseases of the osteoarticular system; Rheumatology; Autoimmune disease; Inflammatory joint disease; Antifolate; Chronic; POLYMORPHISMS; Antimetabolic; Rheumatoid arthritis; Antirheumatic agent; Methotrexate; African American; Polymorphism
• ISSN: 0315-162X; 1499-2752

OBJECTIVE: Research has examined the association of folate-dependent gene polymorphisms with methotrexate (MTX) toxicity in
racially homogenous patients with rheumatoid arthritis (RA). We examined the influence of MTX transporter gene polymorphisms
on MTX toxicity in 2 racial groups of patients with RA. METHODS: Using a retrospective cross-validation approach, the association
of polymorphisms in 6 genes in the MTX cellular pathway with MTX toxicity was examined in training and validation cohorts.
The genes analyzed were ATP-binding cassette transporter B1 (ABCB1), C1 (ABCC1), C2 (ABCC2), folylpolyglutamyl synthase (FPGS),
methylenetetrahydrofolate reductase (MTHFR), and thymidylate synthase (TYMS). Both cohorts included Caucasian Americans and
African Americans. Statistical analyses consisted of Fisher exact tests, multivariable logistic regression models, and survival
analyses. RESULTS: Four of 25 variants displayed significant associations with MTX toxicity in the training cohort. The intronic
single-nucleotide polymorphism (SNP) ABCC2 IVS 23+56 T --> C was associated with alopecia in Caucasians (p = 0.035). ABCB1
1236 C --> T was associated with overall toxicity (p = 0.013); ABCC2 1249 G --> A with gastrointestinal toxicity (p = 0.009);
and ABCC2 1058 G --> A with hepatotoxicity (p = 0.04) in African Americans. These 4 SNP and the MTHFR 677 C --> T variant
were assessed in the validation cohort. Of these, only the MTHFR 677 C --> T SNP was associated with alopecia, and only in
African Americans (p = 0.032). The ABCC2 IVS 23+56 T --> C genotype influenced toxicity-related time to discontinuation or
dose decrease in the Caucasian validation cohort (p < 0.0001). CONCUSION: In addition to SNP in folate-dependent genes, MTX
transporter gene SNP may be important markers of MTX toxicity in RA. Such pharmacogenetic associations are race-specific.