The pharmacogenetics of methotrexate in inflammatory bowel disease.
OBJECTIVE
Methotrexate (MTX) is an effective immunosuppressive treatment in inflammatory bowel disease (IBD) but its use is limited by unpredictable toxicity and efficacy. MTX metabolism is complex involving a number of enzymes. An individual's response to MTX may in part be genetically determined by functional genetic variation in genes encoding these enzymes. We report a pharmacogenetic evaluation of MTX therapy in IBD.


METHODS
We studied 102 IBD patients treated with MTX, and 202 patients with Crohn's disease (CD), 205 patients with ulcerative colitis (UC) and 189 healthy volunteers served as controls to assess allele frequencies in the disease and healthy populations. All subjects were genotyped for four polymorphisms: G80A in the reduced folate carrier (RFC1) gene, G452T in the gamma-glutamyl hydrolase (GGH) gene and C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene. Three non-conservative SNPs in the RFC1 and the MTHFR gene could not be detected in our patient cohort. Genotype-phenotype associations were evaluated with respect to efficacy and toxicity of MTX therapy.


RESULTS
No significant differences in the allele frequencies between CD, UC and healthy controls were detected. Overall 21% of patients experienced MTX side effects. Patients homozygous for the MTHFR 1298C allele were more likely to experience one or more side effects compared to patients with the wild-type 1298AA genotype (21.0 vs. 6.3%, P < 0.05). None of the genotyped SNPs or haplotypes, either alone or in combination, was associated with short-term efficacy or sustained response.


CONCLUSIONS
Side effects of MTX in IBD are associated with a SNP in the MTHFR gene but response cannot be predicted by any of the investigated SNPs.
Herrlinger
Klaus R
KR
Gastroenterology Unit, University of Oxford, Gibson Laboratories, Radcliffe Infirmary, Oxford, UK. klaus.herrlinger@rbk.de
Cummings
J R Fraser
JR
Barnardo
Martin C N M
MC
Schwab
Matthias
M
Ahmad
Tariq
T
Jewell
Derek P
DP
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000235:genetics*; D003424:Crohn Disease / Q000188:drug therapy / Q000235:genetics*; D004247:DNA / Q000097:blood; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D058978:Reduced Folate Carrier Protein / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D016896:Treatment Outcome; D011623:gamma-Glutamyl Hydrolase / Q000235:genetics
D018501:Antirheumatic Agents; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D014157:Transcription Factors; D004247:DNA; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D011623:gamma-Glutamyl Hydrolase; D008727:Methotrexate