PMID- 33846471
OWN - NLM
STAT- MEDLINE
DCOM- 20211102
LR  - 20211102
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 11
IP  - 1
DP  - 2021 Apr 12
TI  - Association of genetic variants in TPMT, ITPA, and NUDT15 with 
      azathioprine-induced myelosuppression in southwest china patients with autoimmune 
      hepatitis.
PG  - 7984
LID - 10.1038/s41598-021-87095-0 [doi]
LID - 7984
AB  - This study aimed to investigate the influence of TPMT*3C, ITPA, NUDT15, and 
      6-thioguanine nucleotides (6-TGN) on azathioprine (AZA)-induced myelosuppression 
      in Southwest China patients with autoimmune hepatitis (AIH). A total of 113 
      Chinese patients with AIH receiving AZA maintenance treatment were evaluated. The 
      relevant clinical data of the patients were collected from the hospital 
      information system. Genotyping of TPMT*3C(rs1142345), ITPA (rs1127354) and 
      NUDT15(rs116855232) was conducted using a TaqMan double fluorescent probe. The 
      concentration of 6-TGN was determined using UPLC-MS/MS. Among AIH patients 
      treated with AZA, 40 (35.4%) exhibited different degrees of myelosuppression. The 
      NUDT15 variant was associated with leukopenia (P = 8.26 x 10(-7); OR = 7.5; 95% 
      CI 3.08-18.3) and neutropenia (P = 3.54 x 10(-6); OR = 8.05; 95% CI 2.96-21.9); 
      however, no significant association with myelosuppression was observed for 
      TPMT*3C and ITPA variants (P > 0.05). There was no significant difference in 
      6-TGN concentration between AIH patients with or without myelosuppression 
      (P = 0.556), nor was there a significant difference between patients with variant 
      alleles of TPMT*3C, ITPA, or NUDT15 and wild-type patients (P > 0.05). 
      Interestingly, it was found that patients with a lower BMI had higher adjusted 
      6-TGN levels and a higher incidence of myelosuppression (P = 0.026 and 0.003). 
      This study confirmed that NUDT15 variants are a potential independent risk 
      predictor for AZA-induced leukopenia and neutropenia. BMI may be a crucial 
      non-genetic factor that affects the concentration of AZA metabolites and 
      myelosuppression. In addition, the 6-TGN concentration in red blood cells does 
      not reflect the toxicity of AZA treatment, and new biomarkers for AZA therapeutic 
      drug monitoring need further research.
FAU - Miao, Qiang
AU  - Miao Q
AD  - Department of Laboratory Medicine/Research Center of Clinical Laboratory 
      Medicine, West China Hospital of Sichuan University, No.37, Guoxue Xiang, Wuhou 
      District, Chengdu, 610041, China.
FAU - Yan, Lin
AU  - Yan L
AD  - Department of Laboratory Medicine/Research Center of Clinical Laboratory 
      Medicine, West China Hospital of Sichuan University, No.37, Guoxue Xiang, Wuhou 
      District, Chengdu, 610041, China.
FAU - Zhou, Yanhong
AU  - Zhou Y
AD  - Department of Laboratory Medicine/Research Center of Clinical Laboratory 
      Medicine, West China Hospital of Sichuan University, No.37, Guoxue Xiang, Wuhou 
      District, Chengdu, 610041, China.
FAU - Li, Yi
AU  - Li Y
AD  - Department of Laboratory Medicine/Research Center of Clinical Laboratory 
      Medicine, West China Hospital of Sichuan University, No.37, Guoxue Xiang, Wuhou 
      District, Chengdu, 610041, China.
FAU - Zou, Yuangao
AU  - Zou Y
AD  - Department of Laboratory Medicine/Research Center of Clinical Laboratory 
      Medicine, West China Hospital of Sichuan University, No.37, Guoxue Xiang, Wuhou 
      District, Chengdu, 610041, China.
FAU - Wang, Lanlan
AU  - Wang L
AD  - Department of Laboratory Medicine/Research Center of Clinical Laboratory 
      Medicine, West China Hospital of Sichuan University, No.37, Guoxue Xiang, Wuhou 
      District, Chengdu, 610041, China.
FAU - Bai, Yangjuan
AU  - Bai Y
AD  - Department of Laboratory Medicine/Research Center of Clinical Laboratory 
      Medicine, West China Hospital of Sichuan University, No.37, Guoxue Xiang, Wuhou 
      District, Chengdu, 610041, China. whitewcums@126.com.
FAU - Zhang, Junlong
AU  - Zhang J
AD  - Department of Laboratory Medicine/Research Center of Clinical Laboratory 
      Medicine, West China Hospital of Sichuan University, No.37, Guoxue Xiang, Wuhou 
      District, Chengdu, 610041, China. immune_hx@126.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210412
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Guanine Nucleotides)
RN  - 0 (Thionucleotides)
RN  - 15867-02-4 (6-thioguanylic acid)
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 2.1.1.67 (TPMT protein, human)
RN  - EC 2.6.1.- (NUDT15 protein, human)
RN  - EC 3.6.1.- (Pyrophosphatases)
RN  - EC 3.6.1.9 (ITPA protein, human)
RN  - MRK240IY2L (Azathioprine)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Alleles
MH  - Azathioprine/*adverse effects
MH  - China
MH  - Female
MH  - *Genetic Association Studies
MH  - Guanine Nucleotides
MH  - Hepatitis, Autoimmune/drug therapy/*genetics
MH  - Humans
MH  - Leukopenia/*chemically induced/genetics
MH  - Male
MH  - Methyltransferases/*genetics
MH  - Middle Aged
MH  - Mutation/*genetics
MH  - Phenotype
MH  - Pyrophosphatases/*genetics
MH  - Thionucleotides
PMC - PMC8042108
COIS- The authors declare no competing interests.
EDAT- 2021/04/14 06:00
MHDA- 2021/11/03 06:00
PMCR- 2021/04/12
CRDT- 2021/04/13 06:14
PHST- 2020/12/07 00:00 [received]
PHST- 2021/03/23 00:00 [accepted]
PHST- 2021/04/13 06:14 [entrez]
PHST- 2021/04/14 06:00 [pubmed]
PHST- 2021/11/03 06:00 [medline]
PHST- 2021/04/12 00:00 [pmc-release]
AID - 10.1038/s41598-021-87095-0 [pii]
AID - 87095 [pii]
AID - 10.1038/s41598-021-87095-0 [doi]
PST - epublish
SO  - Sci Rep. 2021 Apr 12;11(1):7984. doi: 10.1038/s41598-021-87095-0.