Recent large-scale clinical studies revealed a strong association between the NUDT15p.Arg139Cys (NUDT15<sup>R139C</sup>) polymorphism and severe thiopurine-induced leukocytopenia.
The aim of this study was to investigate the influence of <i>NUDT15 R139C</i> and thiopurine S-methyltransferase (<i>TPMT</i>) on azathioprine (AZA) induced leukopenia in patients with autoimmune hepatitis (AIH) and related cirrhosis.
Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15R139C.
Apart from genetic variants in thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) genes, polymorphisms in FTO alpha-ketoglutarate dependent dioxygenase (FTO) were found predictive of thiopurine-induced leukopenia, albeit with conflicting results.
Random-effects model meta-analysis provided evidence that T carriers of NUDT15 c.415C>T were significantly correlated with high incidences of thiopurine-induced leukocytopenia [CT + TT vs. CC: RR = 3.79, 95%CI (2.64 ~ 5.44), P < 0.00001].
NUDT15 intermediate activity variant, that is, heterozygous rs116855232 or rs186364861 variant, and the ABCC4 rs3765534 variant showed leukopenia more frequently than either variant alone.
NUDT15 hydrolyzes the thiopurine active metabolites 6-thio-GTP and 6-thio-dGTP; variants of NUDT15 had lower enzyme activities, causing higher levels of thiopurine active metabolites, resulting in thiopurine-induced leukopenia.
Patients with low and intermediate NUDT15 activity, as inferred from haplotype pairs, had significantly higher risks of leukopenia (p = 0.000253) and neutropenia (p = 0.002) compared with patients with normal NUDT15 activity.
Therefore, the variant of <i>NUDT15 R139C</i> is strongly associated with AZA-induced leukopenia in Chinese patients with various autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome, etc.
The NUDT15 variant was a predictor for leukopenia (OR: 3.62, 95% CI 1.377-9.501, P = 0.009) and early-onset leukopenia (OR: 9.63, 95% CI 2.764-33.514, P = 3.75 × 10<sup>- 4</sup>).
NUDT15rs116855232 variants were strongly associated with a higher cumulative incidence of neutropenia (p < 0.01), and a lower median dose of tolerated MP throughout maintenance treatment (p < 0.01).
NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study.
NUDT15p.R139C was strongly associated with early leukopenia and severe alopecia (OR for early leukopenia: 107.624, 95% CI 18.857-614.250, p=1.403 × 10<sup>-7</sup>, OR for severe alopecia: 77.152, 95% CI 17.378-342.526, p=1.101 × 10<sup>-8</sup>).
NUDT15 variant (rs116855232) has been recently identified as a novel polymorphism related with thiopurine-induced leucopenia in inflammatory bowel disease and ALL.
There were strong associations of NUDT15 c.415C>T, c.36_37insGGAGTC, and c.52G>A with thiopurine-induced leukopenia (P = 1.81 × 10, P = 4.74 × 10 and P = 0.04, respectively), whereas there was no relevance for thiopurine S-methyltransferase genotypes (P = 0.25).
Recently, few studies reported on an inherited nucleoside diphosphate-linked moiety X motif 15 (NUDT15) c.415C>T low-function variant that is associated with decreased thiopurine metabolism and leukopenia in childhood acute lymphoblastic leukemia (ALL) and other diseases.
This study aimed to determine the relationship between thiopurine metabolite levels and therapeutic response, and to investigate the association of NUDT15, TPMT, and thiopurine metabolites with leukopenia in patients with CD.