Nucleoside diphosphate-linked moiety X-type motif 15 R139C genotypes impact 6-thioguanine nucleotide cut-off levels to predict thiopurine-induced leukopenia in Crohn’s disease patients

Abstract

BACKGROUNDThiopurine-induced leukopenia (TIL) is a life-threatening toxicity and occurs with a high frequency in the Asian population. Although nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) variants significantly improve the predictive sensitivity of TIL, more than 50% of cases of this toxicity cannot be predicted by this mutation. The potential use of the 6-thioguanine nucleotide (6TGN) level to predict TIL has been explored, but no decisive conclusion has been reached. Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes?AIMTo determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes.METHODSPatients’ clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017. NUDT15 R139C, thiopurine S-methyltransferase, and 6TGN concentrations were measured.RESULTSA total of 411 Crohn’s disease patients were included. TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8 × 108 red blood cells (RBC), which was not different from that of patients without TIL (P = 0.071). Then, we compared the 6TGN levels based on NUDT15 R139C. For CC (n = 342) and CT (n = 65) genotypes, the median 6TGN level in patients with TIL was significantly higher than that in patients without (474.8 vs 306.0 pmol/8 × 108 RBC, P = 9.4 × 10-5; 291.7 vs 217.6 pmol/8 × 108 RBC, P = 0.039, respectively). The four TT carriers developed TIL, with a median 6TGN concentration of 135.8 pmol/8 × 108 RBC. The 6TGN cut-off levels were 411.5 and 319.2 pmol/8 × 108 RBC for the CC and CT groups, respectively.CONCLUSIONThe predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes. Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.

A novel single-tube multiplex real-time PCR assay for genotyping of thiopurine intolerance-causing variant NUDT15 c.415C>T

“…Miao, a representative of the southern minorities of China, is genetically related to Southeast Asian populations, such as Dai from Yunnan Province. 35,[37][38][39] The allelic frequency of NUDT15 c.415C>T in Miao individuals is similar to that reported in Dai (0.048) in the 1000 Genome project. All these data demonstrated genetic diversity in the distribution of NUDT15 c.415C>T in different Chinese ethnicities, suggesting a different molecular mechanism underlying the variability of TIM in different Chinese races.…”

“…The allelic frequency in our studied Han Chinese subjects is consistent with the allelic frequencies reported in other Chinese populations. 37 Kazak and Kirgiz subjects are recruited from Xinjiang Province along the Silk Road, where extensive genetic mixture was observed among East Asians and Western Eurasians. 38 Studies using short tandem repeat analysis demonstrated that the genetic structures of Kazak and Kirgiz are similar to the genetic structure of Uygur.…”

Randomised clinical trial: dose optimising strategy by NUDT15 genotyping reduces leucopenia during thiopurine treatment of Crohn's disease

“…Two recent articles including our study reported a lower threshold of 6TGN level in NUDT15 variant carriers and suggested that a lower thiopurine dosage could be used in these patients. 7,26 However, whether a lower 6TGN level influences the efficacy remains unclear.…”

“…4 The most common and serious adverse event is leucopenia (thiopurine-induced leucopenia), especially in Asian populations. [5][6][7] According to our previous multi-centre study in China, 24.2% of patients with inflammatory bowel disease (IBD) developed thiopurine-induced leucopenia. 8 As a result, the factors that can predict the risk of thiopurine-induced leucopenia and reduce the drug toxicity before treatment initiation are of great significance.…”

“…However, 40%‐50% of patients with Crohn's disease discontinue therapy mainly because of the high incidence of adverse events 4 . The most common and serious adverse event is leucopenia (thiopurine‐induced leucopenia), especially in Asian populations 5‐7 . According to our previous multi‐centre study in China, 24.2% of patients with inflammatory bowel disease (IBD) developed thiopurine‐induced leucopenia 8 .…”