PMID- 36322453
OWN - NLM
STAT- MEDLINE
DCOM- 20230712
LR  - 20230718
IS  - 1539-2031 (Electronic)
IS  - 0192-0790 (Linking)
VI  - 57
IP  - 7
DP  - 2023 Aug 1
TI  - Role of Pharmacogenomics in the Efficacy and Safety of Thiopurines in 
      Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.
PG  - 671-685
LID - 10.1097/MCG.0000000000001791 [doi]
AB  - BACKGROUND: Thiopurines' toxicity often leads to dose reduction or 
      discontinuation. This systematic review aims to synthesize the evidence on the 
      effect of genotype-based dosing of thiopurines on treatment efficacy and safety 
      in inflammatory bowel disease (objective #1), and the association between 
      genotype status and the efficacy and safety profile (objective #2). METHODS: The 
      Cochrane Library, MEDLINE, and EMBASE were searched in August 2021. A total of 80 
      studies (19,859 individuals) were included. Meta-analyses for mortality, 
      different types of adverse events (AEs), withdrawal due to AE, change in disease 
      activity and clinical remission were performed following mainly a fixed-effects 
      model. PROSPERO registration: CRD42020148130. RESULTS: Genotype-based dosing was 
      associated to a significantly lower incidence of hematologic AEs (risk 
      ratio=0.71; 95% CI: 0.56-0.90; I2 : 47%; 4 randomized controlled trials; moderate 
      quality), which may be attributable to nudix hydrolase 15 (NUDT15) testing more 
      than to thiopurine methyltransferase (TPMT) genotyping. No differences were found 
      in other outcomes. Mutations in TPMT and NUDT15 genes were associated to a higher 
      probability of serious AEs [odds ratio (OR) TPMT=4.98; OR NUDT15=11.44], 
      hematologic AEs (OR TPMT=3.18), and serious hematologic AEs (OR TPMT=7.88; OR 
      NUDT15=12.83). TPMT was also associated with a higher risk of withdrawals due to 
      AEs (OR=3.38), and NUDT15 with gastrointestinal AEs (OR=2.04). Mutations in the 
      ITPA gene did not lead to significant differences. Evidence of an association 
      between other genes and clinical outcomes is still scarce. CONCLUSIONS: Mutations 
      in TPMT and NUDT15 genes predispose patients to suffer thiopurine-induced 
      toxicity, and genotype-guided treatment has been shown to contribute to the 
      prevention of thiopurine-induced toxicity, especially in the case of NUDT15 in 
      Asians.
CI  - Copyright (c) 2022 Wolters Kluwer Health, Inc. All rights reserved.
FAU - Gutierrez-Valencia, Marta
AU  - Gutierrez-Valencia M
AUID- ORCID: 0000-0002-3229-6614
AD  - Unit of Innovation and Organization, Navarre Health Service.
AD  - Navarre Institute for Health Research (IdiSNA).
FAU - Leache, Leire
AU  - Leache L
AD  - Unit of Innovation and Organization, Navarre Health Service.
AD  - Navarre Institute for Health Research (IdiSNA).
FAU - Saiz, Luis Carlos
AU  - Saiz LC
AD  - Unit of Innovation and Organization, Navarre Health Service.
AD  - Navarre Institute for Health Research (IdiSNA).
FAU - Beloqui, Juan J
AU  - Beloqui JJ
AD  - Navarre Institute for Health Research (IdiSNA).
AD  - Pharmacy Service, Navarra University Hospital, Navarre Health Service.
AD  - Genomic Medicine Unit, Navarrabiomed.
FAU - Barajas, Miguel
AU  - Barajas M
AD  - Biochemistry Area, Department of Health Science, Public University of Navarre.
FAU - Vicuna, Miren
AU  - Vicuna M
AD  - Inflammatory Bowel Disease Unit, Gastroenterology Department, Navarra University 
      Hospital, Navarre Health Service, Pamplona, Navarre, Spain.
FAU - Erviti, Juan
AU  - Erviti J
AD  - Unit of Innovation and Organization, Navarre Health Service.
AD  - Navarre Institute for Health Research (IdiSNA).
LA  - eng
PT  - Journal Article
PT  - Meta-Analysis
PT  - Systematic Review
DEP - 20230801
PL  - United States
TA  - J Clin Gastroenterol
JT  - Journal of clinical gastroenterology
JID - 7910017
RN  - EC 2.1.1.- (Methyltransferases)
RN  - EC 3.6.1.- (Pyrophosphatases)
RN  - MRK240IY2L (Azathioprine)
SB  - IM
MH  - Humans
MH  - *Pharmacogenetics
MH  - *Inflammatory Bowel Diseases/drug therapy/genetics
MH  - Genotype
MH  - Methyltransferases/genetics/therapeutic use
MH  - Pyrophosphatases/genetics/therapeutic use
MH  - Azathioprine/adverse effects
EDAT- 2022/11/03 06:00
MHDA- 2023/07/12 06:42
CRDT- 2022/11/02 12:53
PHST- 2023/07/12 06:42 [medline]
PHST- 2022/11/03 06:00 [pubmed]
PHST- 2022/11/02 12:53 [entrez]
AID - 00004836-990000000-00089 [pii]
AID - 10.1097/MCG.0000000000001791 [doi]
PST - epublish
SO  - J Clin Gastroenterol. 2023 Aug 1;57(7):671-685. doi: 
      10.1097/MCG.0000000000001791.