Effects of single nucleotide polymorphisms of genes involved in transportation and metabolism of azathio-prine on steady-state of 6-thioguanine nucleotide concentration and leukocyte levels
OBJECTIVE To explore the relationship between polymorphisms of azathioprine metabolizing enzymes and transporters and the levels of 6-thioguanine nucleotides(6-TGNs)and leukocytes in patients of Crohn's disease(CD).METHODS A total of 74 Han patients on a treatment of azathioprine for over 3 months at First Affiliated Hospital of Anhui Medical University were recruited.The steady-state trough concentration of 6-TGNs in red blood cells was measured by high per-formance liquid chromatography(HPLC).Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was uti-lized for detecting 22 loci of single nucleotide polymorphisms,including TPMT rs1 142345.The correlations between genotypes,concentration of 6-TGNs and levels of whiteblood cells were examined by univariate and multiple linear regression analyses.RESULTS The results of univariate and multivariate regression analyses revealed that the elevations in absolute or relative con-centrations of 6-TGNs were associated with mutants of TPMT rs1142345 and ITPA rs1127354.No correlation existed between NUDT15 rs116855232 mutation and the levels of 6-TGNs and white blood cells.However,patients of CT genotype had signifi-cantly lower median standard doses as compared with those with wild-type(CC)genotype(P＜0.05).ATIC rs3821353 mutation served as an independent risk factor for predicting lymphocyte reduction in patients on a treatment of azathioprine.CONCLUSION Detecting TPMT rs1142345,ITPA rs1127354,ATIC rs3821353,NUDT15 rs116855232 genotypes,as well as 6-TGNs and leukocyte levels in CD patients before and after azathioprine dosing are vital in lowering the risk of azathioprine-induced leukopenia and improving therapeutic efficacy.
therapeutic drug monitoringCrohn's disease6-thioguanine nucleotideazathioprinesingle nucleotide polymorphisms
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