Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis.
OBJECTIVE
Methotrexate (MTX) is an antifolate agent that is often associated with toxicity. This study investigated whether risk genotypes for folate-dependent enzymes are associated with the toxicity of MTX in patients with rheumatoid arthritis (RA).


METHODS
Blood was collected for analysis in a muticenter, cross-sectional study of RA patients who had been receiving MTX for at least 1 month prior to enrollment, and side effects occurring at the time of a single study visit were recorded. Low-penetrance risk genotypes in methylenetetrahydrofolate reductase (MTHFR) 677TT, thymidylate synthase (TSER) *2/*2 (variable number of tandem repeats), amino imidazole ribonucleotide transformylase (ATIC) 347GG, and serine hydroxymethyltransferase (SHMT1) 1420CC were measured and summed to constitute the toxicogenetic index specific to each patient. Statistical analyses consisted of logistic regression models with clustered-center effects, and associations with risk genotypes were expressed as adjusted odds ratios (ORs).


RESULTS
Among 214 patients enrolled at 4 study sites, a total of 67 patients (31%) presented with a side effect (gastrointestinal event, headache, lethargy, alopecia, cough, or dyspnea). Risk genotypes associated with side effects in the central nervous system were MTHFR 677TT (OR 3.3, P < 0.01) and SHMT1 1420CC (OR 2.4, P < 0.05). ATIC 347GG was associated with gastrointestinal side effects (OR 3.0, P < 0.01), while TSER*2/*2 (OR 5.4, P < 0.01) and SHMT1 1420CC (OR 3.2, P < 0.01) were associated with alopecia. The toxicogenetic index ranged from 0 to 3 (median 1). An index of 3 was associated with an approximately 7-fold higher likelihood of having a side effect compared with an index of 0 (P < 0.01).


CONCLUSIONS
These data suggest that a composite index of the cumulative risk genotypes in folate-dependent enzymes may be an effective means of profiling RA patients who develop side effects to MTX.
Weisman
Michael H
MH
Cedars-Sinai Medical Center, Los Angeles, California, USA.
Furst
Daniel E
DE
Park
Grace S
GS
Kremer
Joel M
JM
Smith
Katie M
KM
Wallace
Daniel J
DJ
Caldwell
Jacques R
JR
Dervieux
Thierry
T
D000368:Aged; D018501:Antirheumatic Agents / Q000009:adverse effects*; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000235:genetics*; D003430:Cross-Sectional Studies; D004798:Enzymes / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D005819:Genetic Markers; D005838:Genotype; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000009:adverse effects*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D009709:Nucleotide Deaminases / Q000235:genetics / Q000378:metabolism; D016017:Odds Ratio; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism
D018501:Antirheumatic Agents; D004798:Enzymes; D005819:Genetic Markers; D009097:Multienzyme Complexes; C113120:inosine monophosphate synthase; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D019877:Hydroxymethyl and Formyl Transferases; D012696:Glycine Hydroxymethyltransferase; D009709:Nucleotide Deaminases; D008727:Methotrexate