English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Background A novel thiopurine metabolizing enzyme, nucleotide diphosphate-linked moiety X-type motif 15 (NUDT15) was associated with drug-induced leukopenia in patients with non-synonymous genetic polymorphisms. Thiopurine-induced leukopenia in Japanese patients with genetic variance in NUDT15 (c.415C&amp;gt;T) appears to be independent of the 6-thioguanine nucleotide concentration in red blood cells. However, detailed molecular mechanism how NUDT15 variance causes thiopurine-induced leukopenia remains unclear and NUDT15-associated subcellular thiopurine metabolism has not been investigated in patients with inflammatory bowel diseases (IBD). Methods DNA-incorporated deoxythioguanosine (dTG) was measured in the peripheral blood mononuclear cells (PBMCs) of Japanese patients with IBD under thiopurine treatment. Association of a single-nucleotide polymorphism for NUDT15 (c.415C&amp;gt;T) with dTG in PBMCs (dTGPBMC) was examined. Peripheral blood T lymphocytes were cultured in vitro with 6-thioguanine (6-TG) to examine the Impact of NUDT15 genotypes on incorporation into DNA, cell proliferation and apoptosis. Results NUDT15 variants had significantly higher dTGPBMC per thiopurine dosage than non-variants (homozygous variants (TT) vs. heterozygous variants (CT) vs. non-variants (CC), 4418.0 vs. 663.0 vs. 295.3 dTG mol/106 moles dA per mg/kg/day of 6-MP (Figure A)). dTGPBMC and peripheral lymphocyte counts showed a negative correlation (r = −0.30, p = 0.015) (Figure B). Peripheral blood lymphocytes from patients with NUDT15 variance showed a higher DNA-incorporated dTG associated with increased apoptosis (increase of Annexin V+ PI+ CD4+ lymphocytes; TT vs. CT vs. CC, 158.5 % vs. 80.1 % vs. 57.9 % (p = 0.0427)) (Figure C) and decreased proliferation (decrease of proliferative CD4+ lymphocytes, TT vs. CT vs. CC, 49.0 % vs. 25.0 % vs. 19.1 % (p = 0.0098)) (Figure D) when cultured with 6-thioguanine in vitro. Conclusion DNA-incorporated dTG affected by NUDT15 genotypes induces T lymphocyte apoptosis in patients with IBD.

P035 NUDT15 variance increases DNA-incorporated thiopurine metabolites and lymphocyte apoptosis in patients with inflammatory bowel disease