摘要
BACKGROUND Thiopurine-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?AIM To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes.METHODS Patients’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.RESULTS A total of 411 Crohn’s disease patients were included.TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8×10^8 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/8×10^8 RBC,P=9.4×10-^5;291.7 vs 217.6 pmol/8×10^8 RBC,P=0.039,respectively).The four TT carriers developed TIL,with a median 6TGN concentration of 135.8 pmol/8×10^8 RBC.The 6TGN cut-off levels were 411.5 and 319.2 pmol/8×108 RBC for the CC and CT groups,respectively.CONCLUSION The 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.
BACKGROUND Thiopurine-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（6 TGN） level to predict TIL has been explored,but no decisive conclusion has been reached.Can we increase the predictive sensitivity based on6 TGN by subgrouping patients according to their NUDT15 R139 C genotypes?AIM To determine the 6 TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139 C genotypes.METHODS Patients’ clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017.NUDT15 R139 C,thiopurine Smethyltransferase,and 6 TGN concentrations were measured RESULTS A total of 411 Crohn’s disease patients were included.TIL was observed in 72 individuals with a median 6 TGN 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 6 TGN levels based on NUDT15 R139 C.For CC（n=342）and CT（n=65） genotypes,the median 6 TGN 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 6 TGN concentration of 135.8 pmol/8×108 RBC.The 6 TGN cut-off levels were 411.5 and 319.2 pmol/8×108 RBC for the CC and CT groups,respectively.CONCLUSION The predictive sensitivity of TIL based on 6 TGN is dramatically increased after subgrouping according to NUDT15 R139 C genotypes.Applying 6 TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.
基金
Supported by the National Natural Science Foundation of China,No.81573507,No.81473283,No.81173131,and No.81320108027
Guangdong Provincial Key Laboratory Construction Foundation,No.2017B030314030
The National Key Research and Development Program,No.2016YFC0905003
the 111 Project,No.B16047
