Brief Article
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World J Gastroenterol. Mar 28, 2014; 20(12): 3327-3334
Published online Mar 28, 2014. doi: 10.3748/wjg.v20.i12.3327
Thiopurine-methyltransferase variants in inflammatory bowel disease: Prevalence and toxicity in Brazilian patients
Ana Teresa P Carvalho, Barbara C Esberard, Renata S B Fróes, Davy C M Rapozo, Ana B Grinman, Tatiana A Simão, Juliana C V C Santos, Antonio José V Carneiro, Luis Felipe Ribeiro-Pinto, Heitor S P de Souza
Ana Teresa P Carvalho, Barbara C Esberard, Renata S B Fróes, Ana B Grinman, Disciplina de Gastroenterologia e Endoscopia Digestiva, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ 20551-900, Brazil
Tatiana A Simão, Luis Felipe Ribeiro-Pinto, Laboratório de Toxicologia e Biologia Molecular, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ 20551-900, Brazil
Davy C M Rapozo, Tatiana A Simão, Juliana C V C Santos, Luis Felipe Ribeiro-Pinto, Programa de Carcinogênese Molecular, Instituto Nacional de Câncer, Rio de Janeiro, RJ 20230-130, Brazil
Antonio José V Carneiro, Heitor S P de Souza, Serviço de Gastroenterologia, Departamento de Clínica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-913, Brazil
Author contributions: Carvalho ATP and Esberard BC participated in the conception and design of the study, the acquisition, analysis, and interpretation of data, and the drafting of the manuscript; Fróes RSB, Rapozo DCM, Grinman AB, Simão TA, Santos JCVC and Carneiro AJV participated in the acquisition, analysis, and interpretation of the data and the drafting of parts of the manuscript; Ribeiro-Pinto LF and de Souza HSP participated in the conception and design of the study, obtained funding, analyzed and interpreted data, and critically revised the manuscript for important intellectual content; all authors gave final approval of the submitted version of the manuscript.
Supported by Brazilian research agencies CNPq and FAPERJ for financial support
Correspondence to: Heitor S P de Souza, MD, Serviço de Gastroenterologia, Departamento de Clínica Médica, Universidade Federal do Rio de Janeiro. Rua Prof. Rodolpho Paulo Rocco, 255, Ilha do Fundão, Rio de Janeiro, RJ 21941-913, Brazil. heitor.souza@gmail.com
Telephone: +55-21-25622669 Fax: +55-21-25622669
Received: September 7, 2013
Revised: November 8, 2013
Accepted: November 28, 2013
Published online: March 28, 2014
Abstract

AIM: To analyze the prevalence of thiopurine-methyltransferase (TPMT) genotypes and their association with drug toxicity in inflammatory bowel disease (IBD) patients from southeastern Brazil.

METHODS: A total of 219 consecutive patients with IBD, of which 146 had Crohn’s disease and 73 had ulcerative colitis, regularly seen at the outpatient unit of the Division of Gastroenterology at the University Hospital Pedro Ernesto of the State University of Rio de Janeiro, a tertiary referral center, were enrolled in this study from February 2009 to January 2011. We analyzed the presence of major TPMT genetic variants (TPMT*2, *3A, *3C) in IBD patients by means of a specific allele and RFLP-PCR. Genomic DNA was isolated from peripheral blood leukocytes by proteinase-K/Sodium Dodecyl Sulfate digestion and phenol-chloroform extraction. TPMT*2 (C238G), TPMT*3A (G460A/A719G), and TPMT*3C (A719G) genotypes were detected by real-time polymerase chain reaction followed by direct sequencing with specific primers. Clinical data were systematically recorded, and correlated with the genotype results.

RESULTS: The distribution of the selected TPMT gene polymorphism TPMT*2 (C238G), TPMT*3A (G460A/A719G), and TPMT*3C (A719G) genotypes was 3.6%, 5.4%, and 7.7% of the patients, respectively. Among the side effects recorded from patients taking azathioprine, 14 patients presented with pancreatitis and/or an elevation of pancreatic enzymes, while 6 patients had liver toxicity, and 2 patients exhibited myelosuppression/neutropenia. TPMT polymorphisms were detected in 37/219 patients (8 heterozygous for *2, 11 heterozygous for *3A, and 18 heterozygous for *3C). No homozygotic polymorphisms were found. Despite the prevalence of the TPMT*3C genotype, no differences among the genotype frequencies were significant. Although no association was detected regarding myelotoxicity or hepatotoxicity, a trend towards the elevation of pancreatic enzymes was observed for TPMT*2 and TPMT*3C genotypes.

CONCLUSION: The prevalence of TPMT genotypes was high among Brazilian patients. Variants genes *2 and *3C may be associated with azathioprine pancreatic toxicity in a IBD southeastern Brazilian population.

Keywords: Inflammatory bowel disease, Thiopurine-methyl-transferase, Azathioprine, Drug toxicity, Pancreatitis

Core tip: Although commonly used to treat patients with inflammatory bowel disease, the potentially severe side effects of azathioprine remain a concern. To determine a patient’s predisposition to azathioprine toxicity, the thiopurine-methyl-transferase genotype must be determined prior to azathioprine administration.