| Abstract |
Thiopurines are cytotoxic and immunosuppressive drugs widely prescribed,
mainly in inflammatory bowel disease (IBD). They constitute one of the
best success story of pharmacogenetic implementation into clinical
practice based on the screening of thiopurine S-methyltransferase (TPMT)
deficiency, a key enzyme in thiopurine metabolism. Optimization of
thiopurine response is challenging because of its large interindividual
variability such as inefficacy and toxicities. This thesis has explored,
on one hand, the relationships between TPMT activity and metabolite
concentrations, and on the other hand, factors associated with thiopurine
inefficacy. Using a primary care pharmacogenetic database, we first
analyzed TPMT distribution and genotype-phenotype correlation, in relation
with thiopurine metabolites in a large population. Using a PheWAS study
based on a clinical data warehouse we then reported that a very high TPMT
activity ('ultra-rapid' phenotype) was associated with parameters of
active IBD and poor response to thiopurines. Furthermore, a retrospective
study in pediatric IBD identified factors predicting the occurrence of
lymphopenia during thiopurine therapy. Finally, using a lymphoblastoid
cell line (LCL) in vitro model, we established a transcriptomic signature,
including 32 genes predicting thiopurine cellular resistance. A
bioinformatic functional analysis identified metabolic pathways in
relation with p53 and cell cycle, as well as molecular mechanisms
associated with thiopurine resistance. To conclude, this research work,
focusing on the variability of thiopurine response and mainly therapeutic
resistance, provides new hypotheses to individualize and optimize
therapeutic response to thiopurines.
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