ORIGINAL ARTICLE Prevalence of TPMT polymorphism in Indian patients requiring immunomodulator therapy and its clinical significance Sandeep Kirit Davavala & Devendra C. Desai & Philip Abraham & Tester Ashavaid & Anand Joshi & Tarun Gupta Received: 15 March 2013 /Accepted: 29 July 2013 /Published online: 31 August 2013 # Indian Society of Gastroenterology 2013 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. Aims The aim of this research is to study the prevalence of TPMT mutation in Indian patients requiring immunomodula- tor 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), indetermi- nate 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 devel- oped 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). Conclusion Nearly 5 % of this population of patients requir- ing immunomodulator therapy was heterozygous carriers of the TPMT gene. Neutropenia was equally common in patients without and with the mutation. Keywords Azathioprine . 6-Mercaptopurine . Thiopurine methyltransferase Introduction Thiopurine methyltransferase (TPMT) enzyme plays a key role in the metabolism of azathioprine (AZA) and 6-mercaptopurine (6-MP). Mutations in the enzyme cause abnormal metabolism and lead to generation of excess thioguanines (TGN), which causes suppression of various cell lineages, especially neutro- phils, resulting in neutropenia [1, 2]. With a view to predict or monitor toxicity of these agents, studies have recommended that TPMT gene testing be done prior to initiating therapy with these agents and patients on these drugs should be monitored regularly with 6-TGN levels (phenotype analysis), and the dose of these drugs should be modified accordingly [3–5]. Patients on these drugs usually need long-term maintenance treatment, and there are no def- inite guidelines in literature on the frequency of monitoring. Only a few laboratories across India are equipped to con- duct this test; also, the cost of the test is high. Considering these problems, phenotypic analysis, although ideal, is practi- cally difficult. A study of occurrence of genotypic polymor- phism of the TPMT enzyme in our population may help us to decide the need for its testing. Data on prevalence of TPMT polymorphism are available from Western and some Asian countries [4, 5]; such data from India are sparse. S. K. Davavala (*) : D. C. Desai : P. Abraham : A. Joshi : T. Gupta Department of Gastroenterology, P D Hinduja National Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim, Mumbai 400 016, India e-mail: drsdavavala@gmail.com T. Ashavaid Department of Biochemistry, P D Hinduja National Hospital and Medical Research Centre, Veer Savarkar Marg, Mahim, Mumbai 400 016, India Indian J Gastroenterol (January–February 2014) 33(1):41–45 DOI 10.1007/s12664-013-0374-6