Gene-gene interactions in folate and adenosine biosynthesis pathways affect methotrexate efficacy and tolerability in rheumatoid arthritis.
OBJECTIVE
As no single nucleotide polymorphism has emerged as pivotal to predict the lack of efficacy and dose-limiting toxicities to methotrexate (MTX), we evaluated the contribution of gene-gene interactions to the effects of this prodrug in rheumatoid arthritis.


METHODS
A total of 255 patients treated with MTX for at least 3 months were evaluated with efficacy assessed using the European League Against Rheumatism response criteria or a physician's assessment of patient's response to MTX visual analog scale. Gastrointestinal and neurological idiosyncrasies were recorded in 158 patients. Fourteen single nucleotide polymorphisms in folate and adenosine biosynthesis pathways were measured and detection of gene-gene interactions was performed using multifactor-dimensionality reduction, a method that reduces high-dimensional genetic data into a single dimension of predisposing or risk-genotype combinations.


RESULTS
Efficacy to MTX (53% responders) was associated with high-order epistasis among variants in inosine-triphosphate pyrophosphatase, aminoimidazole-carboxamide ribonucleotide transformylase, and reduced folate carrier genes. In the absence of predisposing genotype combinations, a 3.8-fold lower likelihood of efficacy was observed (vs. in their presence, 95% confidence interval: 2.2-6.4; P<0.001). Increasing MTX polyglutamate concentrations tended to partially overcome this selective disadvantage. Idiosyncrasies occurred in 29% of patients. In the presence of risk-genotype combinations among variants in methylene tetrahydrofolate reductase, γ-glutamyl-hydrolase, thymidylate synthase, serine hydroxymethyltransferase, and inosine-triphosphate pyrophosphatase genes, an 8.9-fold higher likelihood to exhibit toxicities was observed (vs. in their absence, 95% confidence interval: 3.6-21.9; P<0.001). False-positive report probabilities were below 0.2, thereby indicating that true signals were likely detected in this cohort.


CONCLUSIONS
These data indicate that gene-gene interactions impact MTX efficacy and tolerability in rheumatoid arthritis.
Cypress Bioscience, San Diego, California 92121, USA. tdervieux@cypressbio.com
Thierry
T
Dervieux
Judith A M
JA
Wessels
Tahar
T
van der Straaten
Nadia
N
Penrod
Jason H
JH
Moore
Henk-Jan
HJ
Guchelaar
Joel M
JM
Kremer
D000241:Adenosine / Q000096:biosynthesis*; D000328:Adult; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D053898:Biosynthetic Pathways; D004843:Epistasis, Genetic; D005260:Female; D005492:Folic Acid / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
D018501:Antirheumatic Agents; D005492:Folic Acid; D000241:Adenosine; D008727:Methotrexate