Genetic profiling of NUDT15 in the Slovenian population

Šmid, Alenka (author), Urbančič, Dunja (author), Vrevc Žlajpah, Jaka (author), Stollarova, Natalia (author), Prelog, Tomaž (author), Kavčič, Marko (author), Jazbec, Janez (author), Mlinarič-Raščan, Irena (author), Karas Kuželički, Nataša (author)

Determining variant TPMT alleles to predict patient response to thiopurine therapy represents one of the first successful implementations of pharmacogenomics in clinical practice. However, despite the TPMT-adjusted thiopurine dosing, some TPMT wild-type patients still exhibit toxicity at standard doses. Over the past decade, the pharmacogene NUDT15 has emerged as a significant co-modulator of thiopurine therapy. Initially, NUDT15 was considered important predominantly in Asian populations, but recent studies have highlighted its relevance in European populations as well. To evaluate the pharmacogenetic significance of NUDT15 in the Slovenian population, we sequenced extended regions of exon 1 and exon 3 in 109 healthy individuals and 37 patients with acute lymphoblastic leukemia. We identified eight variants, including one with established clinical significance (allele *3) and one extremely rare variant (Chr13 at 48045861; GRCh38, NC_000013.11). The frequencies of most previously described variants in both the general population and in the ALL cohort were consistent with those reported in other European populations, except for rs45465203, which was less frequent in the Slovenian population. None of the variants, except for NUDT15*3, were associated with cumulative thiopurine doses in ALL patients. However, these variants warrant further investigation in larger ALL cohorts.

• Language: English
• Keywords: 6-mercaptopurine, acutelymphoblastic leukemia, dose reduction, minorallele frequency, NUDT15, population genetics, thiopurines
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; MF - Faculty of Medicine
• Publication version: Version of Record
• Year: 2024
• Number of pages: Str. 515-525
• Numbering: Vol. 25, no. 12-13
• PID: 20.500.12556/RUL-165844
• UDC: 616.155.392+575.17
• ISSN on article: 1744-8042
• DOI: 10.1080/14622416.2024.2409060
• COBISS.SI-ID: 213081347
• Publication date in RUL: 12.12.2024

Record is a part of a journal

• Title: Pharmacogenomics
• Shortened title: Pharmacogenomics
• Publisher: Future Medicine
• ISSN: 1744-8042
• COBISS.SI-ID: 521752601

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: 6-merkaptopurin, NUDT15, zmanjšanje odmerka, pogostnost manjšega alela, tiopurini, akutna limfoblastna levkemija, populacijska genetika