Methotrexate (MTX) Pathway Gene Polymorphisms and Their Effects on MTX Toxicity in Caucasian and African American Patients with Rheumatoid Arthritis

PRABHA RANGANATHAN, ROBERT CULVERHOUSE, SHARON MARSH, AMI MODY, TIFFANY J. SCOTT-HORTON, RICHARD BRASINGTON, AMY JOSEPH, VIRGINIA REDDY, SETH EISEN, and HOWARD L. McLEOD

ABSTRACT.

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).

Conclusion. 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. (J Rheumatol First Release Mar 15 2008)

Key Indexing Terms:

METHOTREXATE
TOXICITY
POLYMORPHISMS
RHEUMATOID ARTHRITIS

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From the Department of Medicine, Washington University School of Medicine, St. Louis, Missouri; St. Louis VA Medical Center, St. Louis, Missouri; and the University of North Carolina Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, North Carolina, USA.

Supported by the BIRCWH Career Development Program, NIH K12 HD001459, and NIH U01 GM63340.

P. Ranganathan; A. Joseph; S. Eisen, Department of Medicine, Washington University School of Medicine, St. Louis VA Medical Center; R. Culverhouse; S. Marsh; A. Mody; T.J. Scott-Horton; R. Brasington; V. Reddy, Department of Medicine, Washington University School of Medicine; H.L. McLeod, Department of Medicine, Washington University School of Medicine, UNC Institute for Pharmacogenomics and Individualized Therapy.

Address reprint requests to Dr. P. Ranganathan, Division of Rheumatology, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8045, St. Louis, MO 63110. E-mail: prangana@im.wustl.edu

Accepted for publication November 15, 2007.