Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement

The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.

Gene-Gene Interactions Among Folate, Purine and Pyrimidine Gene Pathways Impact Methotrexate Tolerability in Rheumatoid Arthritis

Dervieux1,  Thierry, Wessels2,  Judith, van der Straaten2,  Tahar, Moore3,  Jason, Penrod3,  Nadia, Guchelaar2,  Henk-Jan, Kremer4,  Joel M.

Cypress Bioscience, San Diego, CA,
Leiden Medical Center, Leiden, Netherlands,
Dartmouth-Hitchcock Medical Center, Lebanon,
Albany Medical College, Albany, NY


Dose-limiting gastrointestinal and neurological toxicities are common in patients with rheumatoid arthritis (RA) treated with the antimetabolite Methotrexate (MTX). We sought to evaluate whether gene-gene interactions (epistasis) in folate, purine and pyrimidine gene pathways contributed to these idiosyncrasies in RA.


A total of 158 patients under MTX for more than three months were evaluated. MTX side effects were defined as those affecting the gastrointestinal tract (nausea, diarrhea, stomatitis, dyspepsia, elevation of aspartate aminostransferase (AST)>twice the upper limit normal) or the central nervous system (headache, lethargy). Fourteen single nucleotide polymorphisms were measured. Detection and interpretation of non-linear gene-gene interactions was performed using multifactor dimensionality reduction (MDR) which reduces genetic information to one-dimension by combining higher and lower-risk genotype combinations into two separate groups.


Gastrointestinal and neurological side effects were observed in 23% and 21% of patients, respectively. MDR analysis identified epistatic interactions among variants in Methylene Tetrahydrofolate Reductase (MTHFR A1298C), Inosine-Triphosphate Pyrophosphatase (ITPA C94A) and g-Glutamyl Hydrolase (GGH -354 G/T). These contributed to MTX-induced gastrointestinal idiosyncrasies, with a 7.3-fold higher likelihood of these adverse events in patients having the higher-risk genotype combination (vs. without; CI95%: 3.2–16.8;p<0.001). Interactions among MTHFR A1298C, Thymidylate Synthase (TSER*2/*3), and Serine HydroxyMethyltransferase (SHMT C1420T) variants contributed to neurological toxicities which were 10.1-fold more likely to occur in patients carrier of a predisposing risk-genotype combination (CI 95%: 4.3–23.8; p<0.001). Altogether, the presence of risk genotype combinations for gastrointestinal or neurological toxicities (52%) was associated with an 8.9-fold higher likelihood to present gastrointestinal or neurological toxicities (CI 95%: 3.6–21.9; p<0.001). There was a 2-fold overrepresentation of patients without predisposing risk genotypes in those who received MTX for more than 12-months (72%) versus those who received MTX for less than 12-months (37%) (p<0.001). Seventy-two percent of patients receiving MTX after 12 months did not carry either predisposing risk genotype combinations, while only 12% who carried both predisposing risk genotypes continued treatment beyond this time period (p<0.001).


These hypothesis generating data indicate that gene-gene interactions contribute to MTX-induced adverse events in RA and suggest that the presence of risk genotypes may impact the rate of MTX discontinuation.

To cite this abstract, please use the following information:
Dervieux, Thierry, Wessels, Judith, van der Straaten, Tahar, Moore, Jason, Penrod, Nadia, Guchelaar, Henk-Jan, et al; Gene-Gene Interactions Among Folate, Purine and Pyrimidine Gene Pathways Impact Methotrexate Tolerability in Rheumatoid Arthritis [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1953
DOI: 10.1002/art.27026

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