title: Prevalence of TPMT polymorphism in Indian patients requiring immunomodulator therapy and its clinical significance.
abstract: BACKGROUND
  Thiopurine methyltransferase (TPMT) enzyme plays a key role in the metabolism of azathioprine/6-mercaptopurine (6-MP). Mutations in the enzyme lead to generation of excess thioguanine, which causes suppression of various cell lineages, especially neutrophils. Data on the prevalence of TPMT polymorphism are available from Western and some Asian countries; such data from India are sparse.
  
  
  OBJECTIVE
  The aim of this research is to study the prevalence of TPMT mutation in Indian patients requiring immunomodulator therapy and its relation to the development of neutropenia on azathioprine therapy.
  
  
  METHODS
  In this retrospective study, data of all patients who underwent TPMT genotyping by PCR-RFLP and allele-specific PCR prior to immunomodulator therapy were analyzed. The frequency of on-treatment development of neutropenia (total neutrophil count <1,500 per cubic millimeters) was noted.
  
  
  RESULTS
  Data were available on 126 patients (mean age, 42 [SD 13.6] years; 73 men and 53 women). The disease indications included ulcerative colitis (61), Crohn's disease (43), indeterminate colitis (1), autoimmune hepatitis (16), and others (5). TPMT genotype was wild in 120 patients (95.23 %) and heterozygous in 6 patients (4.77 %); no patient had homozygous mutation. Seven of 87 patients (6.8 %) who received azathioprine developed neutropenia; blood counts normalized on cessation of the drug in all. The incidence of neutropenia in patients with wild type was 6/84 (7.14 %) and with heterozygous type 1/3 (33 %) (p = 0.5764).
  
  
  CONCLUSIONS
  Nearly 5 % of this population of patients requiring immunomodulator therapy was heterozygous carriers of the TPMT gene. Neutropenia was equally common in patients without and with the mutation.
authors.affiliation: Department of Gastroenterology, P D Hinduja National Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim, Mumbai, 400 016, India, drsdavavala@gmail.com.
authors.forename: Sandeep Kirit
authors.initials: SK
authors.lastname: Davavala
authors.forename: Devendra C
authors.initials: DC
authors.lastname: Desai
authors.forename: Philip
authors.initials: P
authors.lastname: Abraham
authors.forename: Tester
authors.initials: T
authors.lastname: Ashavaid
authors.forename: Anand
authors.initials: A
authors.lastname: Joshi
authors.forename: Tarun
authors.initials: T
authors.lastname: Gupta
mesh_terms: D000328:Adult; D001379:Azathioprine / Q000009:adverse effects* / Q000378:metabolism* / Q000627:therapeutic use; D005260:Female; D005767:Gastrointestinal Diseases / Q000188:drug therapy* / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000378:metabolism* / Q000627:therapeutic use; D007194:India / Q000453:epidemiology; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects* / Q000378:metabolism* / Q000627:therapeutic use; D008780:Methyltransferases / Q000235:genetics* / Q000502:physiology*; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics*; D011110:Polymorphism, Genetic; D015995:Prevalence; D012189:Retrospective Studies
chemical_list: D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine