P686. Thiopurine methyltransferase polymorphism in Lithuanian inflammatory bowel disease patients
J. Kupcinskas1, R. Steponaitiene1, G. Kiudelis1, G. Denapiene2, J. Valantinas2, L. Jonaitis1, L. Kupcinskas1, J. Skieceviciene1, 1Lithuanian University of Health Sciences, Institute for Digestive Research, Kaunas, Lithuania, 2Vilnius University, Center of Hepatology, Gastroenterology and Dietetics, Vilnius, Lithuania
Inter-individual drug metabolism variability can influence treatment outcome. Genetic polymorphisms in thiopurine methyltransferase gene (TPMT) are known to correlate with the toxicity of azathioprine (AZA). Patients with low TPMT activity (poor metabolizers) are at high risk of developing severe haematopoietic toxicity. TPMT genetic polymorphisms were not investigated in Lithuanian IBD patients previously. The aim of this study was to investigate frequencies of TPMT polymorphisms and their association with adverse events during AZA therapy in the Lithuanian IBD patients.
The genotyping of TPMT*2 (rs1800462), TPMT*3B (rs1800460) and TPMT*3C (rs1142345) was performed using allele-specific PCR or restriction fragment length polymorphism analysis methods. In total 460 consecutive IBD patients, referred to two university hospitals in Lithuania, were genotyped for TPMT*2 (G238C), TPMT*3A (G460A and A719G), TPMT*3B (G460A) and TPMT*3C (A719G) mutations. The use of AZA and its' side effect was assessed retrospectively according to the data of hospital medical records during six year period before genetic testing.
Among 460 IBD patients the frequency for the TPMT*1 (wild-type), TPMT*3A and TPMT*3B alleles were 96.63%, 3.04% and 0.33%, respectively. The frequency of the TPMT genotypes were 93.48% for TPMT*1/*1, 5.87% for TPMT*1/3A, 0.43% for TPMT*1/3B, and 0.22% for TPMT*3A/*3B. No significant differences between experimental and expected genotypic frequencies were observed by Hardy-Weinberg equilibrium. Prescription of AZA provoked neutropenia, which required adjustment of the dose or discontinuation of the drug, in 15.4% of cases bearing heterozygous (TPMT*1/3A or TPMT*1/3B) genotype, whereas patients with wild-type (TPMT*1/*1) genotype experienced this side effect only in 2% of cases (p < 0.05). Only one patient had high-risk compound heterozygous genotype (TPMT*3A/*3B) and an alarming experience of severe neutropenia after prescription of AZA.
TPMT*3A is the most prevalent variant allele in the Lithuanian IBD patients. The estimated frequency of variant alleles in the study group was similar to that observed in the Caucasian populations of Northern and Eastern Europe. Our work supports the strong evidence that patients with TPMT genotype TPMT*3A/*3B are at high risk of severe myelosuppression at standard doses of AZA. TPMT heterozygotes also experienced risk of neutropenia in comparison to controls.