Ethnic variability of pharmacogenetic TPMT and NUDT15 variants in Russian populations: Implications for personalized thiopurine therapy

Vollständiger Abstract

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Background: Thiopurines, including azathioprine and 6-mercaptopurine, are widely used in the treatment of inflammatory and autoimmune diseases, as well as hematological malignancies; however, their use is limited by the risk of severe myelosuppression. Pharmacogenetic variants in the TPMT and NUDT15 genes significantly affect drug tolerability, and their frequencies vary markedly across ethnic groups, making population-based studies of these markers in different regions of Russia particularly important. Aim: To assess interethnic variability in the frequencies of clinically relevant TPMT rs1142345 and NUDT15 rs116855232 polymorphisms in populations of the Volga-Ural region, North Caucasus, and the Lower Volga region. Methods: Data from 1687 healthy males from 27 populations and 15 ethnogeographic groups (Bashkirs, Tatars, Mordvins, Chuvash, Mari, Udmurts, Komi, Besermyans, Kalmyks, Balkars, Karachays, Circassians, Ingush, Chechens, and Moldovans), collected during field expeditions in 2000–2025, were retrospectively analyzed. Information on date and place of birth, family history of disease, ethnicity of parents and grandparents (maternal and paternal lines), and causes of death of closed relatives was collected by questionnaire. Individuals with mixed ancestry were excluded. Genomic DNA was extracted from venous blood; genotyping of TPMT rs1142345 and NUDT15 rs116855232 was performed by real-time polymerase chain reaction with TaqMan probes. Results: The minor allele rs1142345*C of TPMT (TPMT*3C) was rare or absent in most of the studied groups, with the highest frequencies observed in Chuvash (3.65%), Circassians (3.23%), and Mordvins (3.16%). The minor allele rs116855232*T of NUDT15 (NUDT15*3) was more frequent in Kalmyks (15.6%), Bashkirs from Perm Krai (14.77%), and Bashkirs of the Samara and Saratov Regions (14.63%), whereas it was absent in Moldovans and occurred at minimal frequencies in Mordvins (0.52%), Chechens (1.03%) and Ingush (1.61%). The most significant differences in NUDT15*3 allele frequency were observed between Kalmyks and Mordvins (15.60% vs 0.52%; p = 2.7 × 10-9, p_FDR = 9.3 × 10-7), Kalmyks and Chechens (15.60% vs 1.03%; p = 2.4 × 10-8, p_FDR = 3.8 × 10-6), and Kalmyks and Moldovans (15.60% vs 0.0%; p = 3.2 × 10-8, p_FDR = 3.8 × 10-6). Among the Bashkir subgroups, the greatest differences were found between Bashkirs from Perm Krai and Mordvins (14.77% vs 0.52%; p = 1.4 × 10-6, p_FDR = 1.3 × 10-4), between Bashkirs from Samara and Saratov Regions and Mordvins (14.63% vs 0.52%; p = 2.5 × 10-6, p_FDR = 1.8 × 10-4), and between Bashkirs from Perm Krai and Moldovans (14.77% vs 0.0%; p = 3.4 × 10-6, p_FDR = 2.0 × 10-4) and Chechens (14.77% vs 1.03%; p = 8.0 × 10-6, p_FDR = 3.5 × 10-4). Conclusion: The results confirm substantial ethnic heterogeneity in the distribution of pharmacogenetic markers of thiopurine toxicity. The minor allele rs116855232*T of NUDT15 was significantly more prevalent in the studied populations than the minor allele rs1142345*C of TPMT, and its frequencies in several groups were comparable to those in East Asian populations. This supports the utility of genotyping for personalizing azathioprine therapy in Russian regions.