RESEARCH - Risk genotypes in folate-dependent enzymes and their association with MTX-related side effects in RA

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Arthritis Rheum. 2006 Feb;54(2):607-12.

Risk genotypes in folate-dependent enzymes and their association with

methotrexate-related side effects in rheumatoid arthritis.

Weisman MH, Furst DE, Park GS, Kremer JM, KM, Wallace DJ, Caldwell JR,

Dervieux T.

Cedars-Sinai Medical Center, Los Angeles, California, USA.

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).

CONCLUSION: 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.

PMID: 16447238

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\

ct & list_uids=16447238 & itool=iconabstr & query_hl=5 & itool=pubmed_DocSum

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