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P826 Unexplained higher frequency of mutant thiopurine S-methyltransferase genotypes in inflammatory bowel disease patients of Latvia population

P. Zalizko*1,2, J. Stefanovics2, R. Erts2, V. Rovite3, J. Klovins3, A. Pukitis1,2

1Pauls Stradins Clinical University Hospital, Gastroenterology, hepatology and nutrition center, Riga, Latvia, 2University of Latvia, Riga, Latvia, 3Latvian Biomedical Research and Study centre, Riga, Latvia

Background

The most common variant alleles, TPMT∗2, TPMT∗3A, and TPMT∗3C, account for 95% of TPMT deficiency. This leads to an accumulation of higher levels of cytotoxic thiopurine nucleotides in patients carrying defective TPMT alleles and subsequent severe haematological toxicity with standard doses of the parent drugs (Robert D. Nerenz, 2018). TPMT single-nucleotide polymorphisms can prospectively identify patients at higher risk for thiopurines toxicity [Paugh et al., 2011]. The frequencies of TPMT polymorphisms in the Europe population are in average 4% (*3A), 0.4% (*3C) and 0.2% (*2). TPMT*1/*3B allele is not common to be found in Europe population and reaches not more than 0.3% [Milek et al., 2006; Schaeffeler et al., 2004].

Methods

Blood samples were collected from IBD patients in Genome Database of the Latvia Population. TPMT genotyping with real-time qPCR (TaqMan Drug Metabolism Genotyping Assays) for the detection of rs1800462, rs1800460, rs1142345, respectively, TPMT*2, *3B, *3C polymorphisms, was used. Three TPMT alleles were obtained in 244 adults, 51% (n = 124) women and 59% (n = 120) men. TPMT*2, *3A, *3B, *3C polymorphisms found we have checked and approved with RFLP (restriction fragment length polymorphism) method. Categorical data were analysed by the Pearson’s χ2 test; Fisher exact test was used if the number in any expected cell < 5 (SPSS®23).

Results

Prospective study includes 244 adults, 78% (n = 190) of patients with ulcerative colitis, median age 41 years (Q1-Q3=29.8–54.3) and 22% (n = 54) of patients with Crohn’s disease, median age 43 years (Q1-Q3=30.8–55.0), p = 0.5. 93.9% were wild-type homozygous TPMT*1/*1 genotype, 6.1% heterozygous and had polymorphisms and 4.9% of them were ulcerative colitis patients. The most frequent polymorphisms were: 5.3% TPMT*1/*3A genotype, this allele contains two variants TPMT*3B and TPMT*3C. 0.4% patients had TPMT*1/*3C genotype and 0.4% had TPMT*1/*2 genotype. In our study, no carriers of the TPMT*3B polymorphism were identified. No patients were homozygous for any mutation.

Conclusion

The homozygous wild-type TPMT*1/*1 genotype was the most frequent genotype in both groups of IBD patients. Distributions of TPMT genotype and allele frequency in Latvian population are different from Europe population. We have identified TPMT*3A as the most prevalent polymorphisms in Latvian population, but also the exceptional presence of TPMT*2 polymorphism and the absence of TPMT*3B polymorphism. TPMT*2, *3A, *3B, *3C polymorphisms were approved with both real-time qPCR and RFLP methods.