title: Should thiopurine methyltransferase genotypes and phenotypes be measured before thiopurine therapy in patients with inflammatory bowel disease?
abstract: OBJECTIVE
  Not all of the adverse effects to thiopurine therapy can be explained by thiopurine methyltransferase (TPMT) polymorphisms. This study was intended to evaluate the value of TPMT genotype and phenotype measurement during the first year of thiopurine therapy.
  
  
  METHODS
  Consecutive patients with inflammatory bowel disease (IBD) who were receiving azathioprine or 6-mercaptopurine were followed up for 12 months. TPMT genotypes and phenotypes were examined in patients with IBD before thiopurine therapy and in unrelated healthy volunteers by polymerase chain reaction and high-performance liquid chromatography.
  
  
  RESULTS
  A total of 199 patients and 300 healthy volunteers were included at 2 centers. Forty-seven of the 199 patients (23.62%) exhibited adverse effects during the entire course of thiopurine therapy. Two (1%) patients carrying TPMT*3C developed leucopenia at week 4 of azathioprine treatment. The TPMT*3C had a specificity of 100% (163/163) but a sensitivity of 5.56% (2/36) for predicting leucopenia. The calculated optimal cutoff activity for high TPMT activity and decreased TPMT activity was 4.75 U/mL red blood cells. The risk of leucopenia increased in the decreased TPMT group (odds ratio: 20.25; 95% confidence interval: 2.19-187.17; P = 0.004) and increased more during the initial 3 months of thiopurine therapy (odds ratio: 34.80; 95% confidence interval: 3.71-326.77; P = 0.001). Leucopenia occurred more frequently in the patients cotreated with 5-aminosalicylates than in those not cotreated (32.81% versus 11.11%, respectively, P < 0.001).
  
  
  CONCLUSIONS
  The results of this study suggest that the value of TPMT genotyping before thiopurine therapy is limited in Chinese patients with IBD, considering the low sensitivity of predicting leucopenia, and that phenotyping is a more cost-effective tool that can be successfully used in patients. The coadministration of 5-aminosalicylates results in a high frequency of leucopenia in patients receiving azathioprine or 6-mercaptopurine.
authors.affiliation: Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Fangbin
authors.forename: Gao
authors.initials: G
authors.lastname: Xiang
authors.forename: Chen
authors.initials: C
authors.lastname: Minhu
authors.forename: Ding
authors.initials: D
authors.lastname: Liang
authors.forename: Xu
authors.initials: X
authors.lastname: Feng
authors.forename: Huang
authors.initials: H
authors.lastname: Min
authors.forename: Hu
authors.initials: H
authors.lastname: Pinjin
mesh_terms: D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000627:therapeutic use; D001379:Azathioprine / Q000009:adverse effects / Q000627:therapeutic use; D002681:China / Q000453:epidemiology; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D007970:Leukopenia / Q000139:chemically induced / Q000453:epidemiology; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects* / Q000627:therapeutic use; D019804:Mesalamine / Q000009:adverse effects / Q000627:therapeutic use; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007166:Immunosuppressive Agents; D019804:Mesalamine; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine